Novel Approaches of Dysregulating Lysosome Functions in Cancer Cells by Specific Drugs and Its Nanoformulations: A Smart Approach of Modern Therapeutics

References

• Hesketh GG, Wartosch L, Davis LJ, Bright NA, Luzio JP. The lysosome and intracellular signalling. Prog Mol Subcell Biol. 2018;57:151–180.
   PubMedGoogle Scholar
• Ballabio A, Bonifacino JS. Lysosomes as dynamic regulators of cell and organismal homeostasis. Nat Rev Mol Cell Biol. 2020;21(2):101–118. doi:10.1038/s41580-019-0185-4
   PubMed Web of Science ®Google Scholar
• Weber K, Schilling JD. Lysosomes integrate metabolic-inflammatory cross-talk in primary macrophage inflammasome activation. J Biol Chem. 2014;289(13):9158–9171. doi:10.1074/jbc.M113.531202
   PubMed Web of Science ®Google Scholar
• Englinger B, Pirker C, Heffeter P, et al. Metal drugs and the anticancer immune response. Chem Rev. 2018;119(2):1519–1624.
   PubMedGoogle Scholar
• Egen JG, Ouyang W, Wu LC. Human anti-tumor immunity: insights from immunotherapy clinical trials. Immunity. 2020;52(1):36–54. doi:10.1016/j.immuni.2019.12.010
   PubMedGoogle Scholar
• Sun A. Lysosomal storage disease overview. Ann Transl Med. 2018;6(24):476. doi:10.21037/atm.2018.11.39
   PubMed Web of Science ®Google Scholar
• Maxfield FR, Willard JM, Lu S, editors. Lysosomes: Biology, Diseases, and Therapeutics. John Wiley & Sons; 2016.
   Google Scholar
• Domagala A, Fidyt K, Bobrowicz M, Stachura J, Szczygiel K, Firczuk M. Typical and atypical inducers of lysosomal cell death: a promising anticancer strategy. Int J Mol Sci. 2018;19(8):2256. doi:10.3390/ijms19082256
   PubMedGoogle Scholar
• Pagliero RJ, D’Astolfo DS, Lelieveld D, et al. Discovery of small molecules that induce lysosomal cell death in cancer cell lines using an image-based screening platform. Assay Drug Dev Technol. 2016;14(8):489–510. doi:10.1089/adt.2016.727
   PubMedGoogle Scholar
• Zoroddu MA, Medici S, Ledda A, Nurchi VM, Lachowicz JI, Peana M. Toxicity of nanoparticles. Curr Med Chem. 2014;21(33):3837–3853. doi:10.2174/0929867321666140601162314
   PubMed Web of Science ®Google Scholar
• Trivedi PC, Bartlett JJ, Pulinilkunnil T. Lysosomal biology and function: modern view of cellular debris bin. Cells. 2020;9(5):1131. doi:10.3390/cells9051131
   PubMed Web of Science ®Google Scholar
• Bouche V, Espinosa AP, Leone L, Sardiello M, Ballabio A, Botas J. Drosophila Mitf regulates the V-ATPase and the lysosomal-autophagic pathway. Autophagy. 2016;12(3):484–498. doi:10.1080/15548627.2015.1134081
   PubMed Web of Science ®Google Scholar
• Stoka V, Turk V, Turk B. Lysosomal cathepsins and their regulation in aging and neurodegeneration. Ageing Res Rev. 2016;1(32):22–37. doi:10.1016/j.arr.2016.04.010
   Google Scholar
• Liaudet-Coopman E, Beaujouin M, Derocq D, et al. Cathepsin D: newly discovered functions of a long-standing aspartic protease in cancer and apoptosis. Cancer Lett. 2006;237(2):167–179. doi:10.1016/j.canlet.2005.06.007
   PubMed Web of Science ®Google Scholar
• Kolter T, Sandhoff K. Lysosomal degradation of membrane lipids. FEBS Lett. 2010;584(9):1700–1712. doi:10.1016/j.febslet.2009.10.021
   PubMed Web of Science ®Google Scholar
• Fehrenbacher N, Bastholm L, Kirkegaard-Sørensen T, et al. Sensitization to the lysosomal cell death pathway by oncogene-induced down-regulation of lysosome-associated membrane proteins 1 and 2. Cancer Res. 2008;68(16):6623–6633. doi:10.1158/0008-5472.CAN-08-0463
   PubMed Web of Science ®Google Scholar
• Schneede A, Schmidt CK, Hölttä‐Vuori M, et al. Role for LAMP‐2 in endosomal cholesterol transport. J Cell Mol Med. 2011;15(2):280–295. doi:10.1111/j.1582-4934.2009.00973.x
   PubMed Web of Science ®Google Scholar
• Eskelinen EL, Tanaka Y, Saftig P. At the acidic edge: emerging functions for lysosomal membrane proteins. Trends Cell Biol. 2003;13(3):137–145. doi:10.1016/S0962-8924(03)00005-9
   PubMed Web of Science ®Google Scholar
• Kundra R, Kornfeld S. Asparagine-linked oligosaccharides protect Lamp-1 and Lamp-2 from intracellular proteolysis. J Biol Chem. 1999;274(43):31039–31046. doi:10.1074/jbc.274.43.31039
   PubMedGoogle Scholar
• Tian X, Teng J, Chen J. New insights regarding SNARE proteins in autophagosome-lysosome fusion. Autophagy. 2020;24:1–9.
   Google Scholar
• Kleine Balderhaar HJ, Ungermann C. CORVET and HOPS tethering complexes–coordinators of endosome and lysosome fusion. J Cell Sci. 2013;126(6):1307–1316. doi:10.1242/jcs.107805
   PubMedGoogle Scholar
• Settembre C, Fraldi A, Medina DL, Ballabio A. Signals from the lysosome: a control centre for cellular clearance and energy metabolism. Nat Rev Mol Cell Biol. 2013;14(5):283–296. doi:10.1038/nrm3565
   PubMed Web of Science ®Google Scholar
• Roczniak-Ferguson A, Petit CS, Froehlich F, et al. The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci Signal. 2012;5(228):ra42. doi:10.1126/scisignal.2002790
   PubMed Web of Science ®Google Scholar
• Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell. 2017;168(6):960–976. doi:10.1016/j.cell.2017.02.004
   PubMed Web of Science ®Google Scholar
• Hosokawa N, Hara T, Kaizuka T, et al. Nutrient-dependent mTORC1 association with the ULK1–Atg13–FIP200 complex required for autophagy. Mol Biol Cell. 2009;20(7):1981–1991. doi:10.1091/mbc.e08-12-1248
   PubMed Web of Science ®Google Scholar
• Yu L, McPhee CK, Zheng L, et al. Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature. 2010a;465(7300):942–946. doi:10.1038/nature09076
   PubMed Web of Science ®Google Scholar
• Lawrence RE, Zoncu R. The lysosome as a cellular centre for signalling, metabolism and quality control. Nat Cell Biol. 2019;21(2):133–142. doi:10.1038/s41556-018-0244-7
   PubMed Web of Science ®Google Scholar
• Li P, Gu M, Xu H. Lysosomal ion channels as decoders of cellular signals. Trends Biochem Sci. 2019;44(2):110–124. doi:10.1016/j.tibs.2018.10.006
   PubMed Web of Science ®Google Scholar
• Wang ZC, Liu Y, Wang H, Han QK, Lu C. Research on the relationship between artesunate and Raji cell autophagy and apoptosis of Burkitt’s lymphoma and its mechanism. Eur Rev Med Pharmacol Sci. 2017;21(9):2238–2243.
   PubMedGoogle Scholar
• Mindell JA. Lysosomal acidification mechanisms. Annu Rev Physiol. 2012;17(74):69–86. doi:10.1146/annurev-physiol-012110-142317
   Google Scholar
• Cheng X, Shen D, Samie M, Xu H. Mucolipins: intracellular TRPML1–3 channels. FEBS Lett. 2010;584(10):2013–2021. doi:10.1016/j.febslet.2009.12.056
   PubMed Web of Science ®Google Scholar
• Zhang X, Cheng X, Yu L, et al. MCOLN1 is a ROS sensor in lysosomes that regulates autophagy. Nat Commun. 2016a;7(1):1–2.
   Google Scholar
• Medina DL, Di Paola S, Peluso I, et al. Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB. Nat Cell Biol. 2015;17(3):288–299. doi:10.1038/ncb3114
   PubMed Web of Science ®Google Scholar
• Dong XP, Wang X, Shen D, et al. PI(3,5)P2 controls membrane trafficking by direct activation of mucolipin Ca2+ release channels in the endolysosome. Nat Commun. 2010;1(4):38.
   PubMedGoogle Scholar
• Medina DL, Fraldi A, Bouche V, et al. Transcriptional activation of lysosomal exocytosis promotes cellular clearance. Dev Cell. 2011;21(3):421–430. doi:10.1016/j.devcel.2011.07.016
   PubMed Web of Science ®Google Scholar
• Samie M, Wang X, Zhang X, et al. A TRP channel in the lysosome regulates large particle phagocytosis via focal exocytosis. Dev Cell. 2013;26(5):511–524. doi:10.1016/j.devcel.2013.08.003
   PubMed Web of Science ®Google Scholar
• Wang F, Gómez‐Sintes R, Boya P. Lysosomal membrane permeabilization and cell death. Traffic. 2018;19(12):918–931. doi:10.1111/tra.12613
   PubMed Web of Science ®Google Scholar
• Kim YM, Jung CH, Seo M, et al. mTORC1 phosphorylates UVRAG to negatively regulate autophagosome and endosome maturation. Mol Cell. 2015a;57(2):207–218. doi:10.1016/j.molcel.2014.11.013
   PubMed Web of Science ®Google Scholar
• Reddy A, Caler EV, Andrews NW. Plasma membrane repair is mediated by Ca2+-regulated exocytosis of lysosomes. Cell. 2001;106(2):157–169. doi:10.1016/S0092-8674(01)00421-4
   PubMed Web of Science ®Google Scholar
• Naegeli KM, Hastie E, Garde A, et al. Cell invasion in vivo via rapid exocytosis of a transient lysosome-derived membrane domain. Dev Cell. 2017;43(4):403–417. doi:10.1016/j.devcel.2017.10.024
   PubMed Web of Science ®Google Scholar
• Baron R, Neff L, Brown W, Courtoy PJ, Louvard D, Farquhar MG. Polarized secretion of lysosomal enzymes: co-distribution of cation-independent mannose-6-phosphate receptors and lysosomal enzymes along the osteoclast exocytic pathway. J Cell Biol. 1988;106(6):1863–1872. doi:10.1083/jcb.106.6.1863
   PubMed Web of Science ®Google Scholar
• Wu H, Carvalho P, Voeltz GK. Here, there, and everywhere: the importance of ER membrane contact sites. Science. 2018;361:6401. doi:10.1126/science.aan5835
   Google Scholar
• Friedman JR, DiBenedetto JR, West M, Rowland AA, Voeltz GK, Hegde RS. Endoplasmic reticulum–endosome contact increases as endosomes traffic and mature. Mol Biol Cell. 2013;24(7):1030–1040. doi:10.1091/mbc.e12-10-0733
   PubMed Web of Science ®Google Scholar
• Dong R, Saheki Y, Swarup S, Lucast L, Harper JW, De Camilli P. Endosome-ER contacts control actin nucleation and retromer function through VAP-dependent regulation of PI4P. Cell. 2016;166(2):408–423. doi:10.1016/j.cell.2016.06.037
   PubMedGoogle Scholar
• Wilhelm LP, Wendling C, Védie B, et al. STARD 3 mediates endoplasmic reticulum‐to‐endosome cholesterol transport at membrane contact sites. EMBO J. 2017;36(10):1412–1433. doi:10.15252/embj.201695917
   PubMedGoogle Scholar
• Glunde K, Guggino SE, Solaiyappan M, Pathak AP, Ichikawa Y, Bhujwalla ZM. Extracellular acidification alters lysosomal trafficking in human breast cancer cells. Neoplasia. 2003;5(6):533–545. doi:10.1016/S1476-5586(03)80037-4
   PubMed Web of Science ®Google Scholar
• Don AS, Hsiao JH, Bleasel JM, Couttas TA, Halliday GM, Kim WS. Altered lipid levels provide evidence for myelin dysfunction in multiple system atrophy. Acta Neuropathol Commun. 2014;2(1):1–4. doi:10.1186/s40478-014-0150-6
   PubMedGoogle Scholar
• Petersen NH, Olsen OD, Groth-Pedersen L, et al. Transformation-associated changes in sphingolipid metabolism sensitize cells to lysosomal cell death induced by inhibitors of acid sphingomyelinase. Cancer Cell. 2013;24(3):379–393. doi:10.1016/j.ccr.2013.08.003
   PubMed Web of Science ®Google Scholar
• Zhitomirsky B, Assaraf YG. Lysosomes as mediators of drug resistance in cancer. Drug Resist Updat. 2016;24:23–33. doi:10.1016/j.drup.2015.11.004
   PubMed Web of Science ®Google Scholar
• Jamora M, Fuchs E, Fuchs E. Sticky business: orchestrating cellular signals at adherens junctions. Cell. 2003;112(4):535–548. doi:10.1016/S0092-8674(03)00108-9
   PubMedGoogle Scholar
• Mousavi SA, Brech A, Berg T, Kjeken R. Phosphoinositide 3-kinase regulates maturation of lysosomes in rat hepatocytes. Biochem J. 2003;372(3):861–869. doi:10.1042/bj20021136
   PubMedGoogle Scholar
• Madge LA, Li JH, Choi J, Pober JS. Inhibition of phosphatidylinositol 3-kinase sensitizes vascular endothelial cells to cytokine-initiated cathepsin-dependent apoptosis. J Biol Chem. 2003;278(23):21295–21306. doi:10.1074/jbc.M212837200
   PubMed Web of Science ®Google Scholar
• Kimmelman AC, White E. Autophagy and tumor metabolism. Cell Metab. 2017;25(5):1037–1043. doi:10.1016/j.cmet.2017.04.004
   PubMed Web of Science ®Google Scholar
• Di Malta C, Siciliano D, Calcagni A, et al. Transcriptional activation of RagD GTPase controls mTORC1 and promotes cancer growth. Science. 2017;356(6343):1188–1192. doi:10.1126/science.aag2553
   PubMed Web of Science ®Google Scholar
• Li X, Rydzewski N, Hider A, et al. A molecular mechanism to regulate lysosome motility for lysosome positioning and tubulation. Nat Cell Biol. 2016;18(4):404–417. doi:10.1038/ncb3324
   PubMed Web of Science ®Google Scholar
• Bian B, Mongrain S, Cagnol S, et al. Cathepsin B promotes colorectal tumorigenesis, cell invasion, and metastasis. Mol Carcinog. 2016;55(5):671–687. doi:10.1002/mc.22312
   PubMed Web of Science ®Google Scholar
• Ibrahim SA, El-Ghonaimy EA, Hassan H, et al. Hormonal-receptor positive breast cancer: IL-6 augments invasion and lymph node metastasis via stimulating cathepsin B expression. J Adv Res. 2016;7(5):661–670. doi:10.1016/j.jare.2016.06.007
   PubMed Web of Science ®Google Scholar
• Small DM, Burden RE, Jaworski J, et al. Cathepsin S from both tumor and tumor‐associated cells promote cancer growth and neovascularization. Int J Cancer Res. 2013;133(9):2102–2112. doi:10.1002/ijc.28238
   Web of Science ®Google Scholar
• Silverman GA, Bartuski AJ, Çataltepe S, et al. SCCA1 and SCCA2 are proteinase inhibitors that map to the serpin cluster at 18q21.3. Tumor Biol. 1998;19(6):480–487. doi:10.1159/000030041
   PubMedGoogle Scholar
• Kirkegaard T, Roth AG, Petersen NH, et al. Hsp70 stabilizes lysosomes and reverts Niemann–Pick disease-associated lysosomal pathology. Nature. 2010;463(7280):549–553. doi:10.1038/nature08710
   PubMed Web of Science ®Google Scholar
• Gyrd-Hansen M, Nylandsted J, Jattela M. Heat shock protein 70 promotes cancer cell viability by safeguarding lysosomal integrity. Cell Cycle. 2004;3(12):1484–1485. doi:10.4161/cc.3.12.1287
   PubMed Web of Science ®Google Scholar
• Liu N, Raja SM, Zazzeroni F, et al. NF‐κB protects from the lysosomal pathway of cell death. EMBO J. 2003;22(19):5313–5322. doi:10.1093/emboj/cdg510
   PubMed Web of Science ®Google Scholar
• Halaby R. Role of lysosomes in cancer therapy. Res Rep Biol. 2015;28(6):147–155. doi:10.2147/RRB.S83999
   Google Scholar
• Dielschneider RF, Henson ES, Gibson SB. Lysosomes as oxidative targets for cancer therapy. In: Oxidative Medicine and Cellular Longevity. 2017:2017.
   Google Scholar
• Amaravadi R, Kimmelman AC, White E. Recent insights into the function of autophagy in cancer. Genes Dev. 2016;30(17):1913–1930. doi:10.1101/gad.287524.116
   PubMed Web of Science ®Google Scholar
• Levy JM, Towers CG, Thorburn A. Targeting autophagy in cancer. Nat Rev Cancer. 2017;17(9):528–542. doi:10.1038/nrc.2017.53
   PubMed Web of Science ®Google Scholar
• Commisso C, Davidson SM, Soydaner-Azeloglu RG, et al. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature. 2013;497(7451):633–637. doi:10.1038/nature12138
   PubMed Web of Science ®Google Scholar
• Xie J, Wang X, Proud CG. mTOR inhibitors in cancer therapy. F1000Research. 2016;5:2078. doi:10.12688/f1000research.9207.1
   Google Scholar
• Maycotte P, Aryal S, Cummings CT, Thorburn J, Morgan MJ, Thorburn A. Chloroquine sensitizes breast cancer cells to chemotherapy independent of autophagy. Autophagy. 2012;8(2):200–212. doi:10.4161/auto.8.2.18554
   PubMed Web of Science ®Google Scholar
• Towers CG, Thorburn A. Targeting the lysosome for cancer therapy. Cancer Discov. 2017;7(11):1218–1220. doi:10.1158/2159-8290.CD-17-0996
   PubMed Web of Science ®Google Scholar
• Boya P, Kroemer G. Lysosomal membrane permeabilization in cell death. Oncogene. 2008;27(50):6434–6451. doi:10.1038/onc.2008.310
   PubMed Web of Science ®Google Scholar
• Yu F, Chen Z, Wang B, et al. The role of lysosome in cell death regulation. Tumor Biol. 2016;37(2):1427–1436. doi:10.1007/s13277-015-4516-6
   PubMedGoogle Scholar
• Ostenfeld MS, Fehrenbacher N, Høyer-Hansen M, Thomsen C, Farkas T, Jäättelä M. Effective tumor cell death by σ-2 receptor ligand siramesine involves lysosomal leakage and oxidative stress. Cancer Res. 2005;65(19):8975–8983. doi:10.1158/0008-5472.CAN-05-0269
   PubMed Web of Science ®Google Scholar
• Mena S, Rodriguez ML, Ponsoda X, Estrela JM, Jäättela M, Ortega AL. Pterostilbene-induced tumor cytotoxicity: a lysosomal membrane permeabilization-dependent mechanism. PLoS One. 2012;7(9):e44524. doi:10.1371/journal.pone.0044524
   PubMed Web of Science ®Google Scholar
• Chen QY, Shi JG, Yao QH, et al. Lysosomal membrane permeabilization is involved in curcumin-induced apoptosis of A549 lung carcinoma cells. Mol Cell Biochem. 2012;359(1):389–398. doi:10.1007/s11010-011-1033-9
   PubMedGoogle Scholar
• Sukhai MA, Prabha S, Hurren R, et al. Lysosomal disruption preferentially targets acute myeloid leukemia cells and progenitors. J Clin Invest. 2012;123(1):315–328.
   PubMedGoogle Scholar
• Terman A, Kurz T, Gustafsson B, Brunk UT. Lysosomal labilization. IUBMB Life. 2006;58(9):531–539. doi:10.1080/15216540600904885
   PubMedGoogle Scholar
• Boya P, Gonzalez-Polo RA, Poncet D, et al. Mitochondrial membrane permeabilization is a critical step of lysosome-initiated apoptosis induced by hydroxychloroquine. Oncogene. 2003b;22(25):3927–3936. doi:10.1038/sj.onc.1206622
   PubMed Web of Science ®Google Scholar
• Boya P, Andreau K, Poncet D, et al. Lysosomal membrane permeabilization induces cell death in a mitochondrion-dependent fashion. J Exp Med. 2003a;197(10):1323–1334. doi:10.1084/jem.20021952
   PubMed Web of Science ®Google Scholar
• Paris C, Bertoglio J, Breard J. Lysosomal and mitochondrial pathways in miltefosine-induced apoptosis in U937 cells. Apoptosis. 2007;12(7):1257–1267. doi:10.1007/s10495-007-0052-1
   PubMedGoogle Scholar
• Feldstein AE, Werneburg NW, Li Z, Bronk SF, Gores GJ. Bax inhibition protects against free fatty acid-induced lysosomal permeabilization. Am J Physiol. 2006;290(6):G1339–46. doi:10.1152/ajpgi.00509.2005
   Google Scholar
• Gyrd-Hansen M, Farkas T, Fehrenbacher N, et al. Apoptosome-independent activation of the lysosomal cell death pathway by caspase-9. Mol Cell Biol. 2006;26(21):7880–7891. doi:10.1128/MCB.00716-06
   PubMedGoogle Scholar
• Werneburg NW, Guicciardi ME, Bronk SF, Gores GJ. Tumor necrosis factor-α-associated lysosomal permeabilization is cathepsin B dependent. Am J Physiol. 2002;283(4):G947–56. doi:10.1152/ajpgi.00151.2002
   Google Scholar
• Groth-Pedersen L, Ostenfeld MS, Høyer-Hansen M, Nylandsted J, Jäättelä M. Vincristine induces dramatic lysosomal changes and sensitizes cancer cells to lysosome-destabilizing siramesine. Cancer Res. 2007;67(5):2217–2225. doi:10.1158/0008-5472.CAN-06-3520
   PubMed Web of Science ®Google Scholar
• Ichinose S, Usuda J, Hirata T, et al. Lysosomal cathepsin initiates apoptosis, which is regulated by photodamage to Bcl-2 at mitochondria in photodynamic therapy using a novel photosensitizer, ATX-s10 (Na). Int J Oncol. 2006;29(2):349–355.
   PubMedGoogle Scholar
• Trincheri NF, Nicotra G, Follo C, Castino R, Isidoro C. Resveratrol induces cell death in colorectal cancer cells by a novel pathway involving lysosomal cathepsin D. Carcinogenesis. 2007;28(5):922–931. doi:10.1093/carcin/bgl223
   PubMed Web of Science ®Google Scholar
• Heinrich M, Neumeyer J, Jakob M, et al. Cathepsin D links TNF-induced acid sphingomyelinase to Bid-mediated caspase-9 and-3 activation. Cell Death Differ. 2004;11(5):550–563. doi:10.1038/sj.cdd.4401382
   PubMed Web of Science ®Google Scholar
• Li N, Zheng Y, Chen W, et al. Adaptor protein LAPF recruits phosphorylated p53 to lysosomes and triggers lysosomal destabilization in apoptosis. Cancer Res. 2007;67(23):11176–11185. doi:10.1158/0008-5472.CAN-07-2333
   PubMed Web of Science ®Google Scholar
• Paquet C, Sane AT, Beauchemin M, Bertrand R. Caspase-and mitochondrial dysfunction-dependent mechanisms of lysosomal leakage and cathepsin B activation in DNA damage-induced apoptosis. Leukemia. 2005;19(5):784–791. doi:10.1038/sj.leu.2403717
   PubMedGoogle Scholar
• Hamilton RF Jr, Thakur SA, Holian A. Silica binding and toxicity in alveolar macrophages. Free Radic Biol Med. 2007;44(7):1246–1258. doi:10.1016/j.freeradbiomed.2007.12.027
   PubMedGoogle Scholar
• Yan CH, Liang ZQ, Gu ZL, Yang YP, Reid P, Qin ZH. Contributions of autophagic and apoptotic mechanisms to CrTX-induced death of K562 cells. Toxicon. 2006;47(5):521–530. doi:10.1016/j.toxicon.2006.01.010
   PubMedGoogle Scholar
• Bao H, Zhang Q, Zhu Z, et al. BHX, a novel pyrazoline derivative, inhibits breast cancer cell invasion by reversing the epithelial-mesenchymal transition and down-regulating Wnt/-catenin signaling. Sci Rep. 2017;7:9153. doi:10.1038/s41598-017-09655-7
   PubMedGoogle Scholar
• O'Brien MA, Kirby R. Apoptosis: A review of pro‐apoptotic and anti‐apoptotic pathways and dysregulation in disease. J Vet Emerg Crit Care (San Antonio). 2008;18(6):572–585.
   Google Scholar
• Zaman S, Wang R, Gandhi V. Targeting the apoptosis pathway in hematologic malignancies. Leuk Lymphoma. 2014;55:1980–1992. doi:10.3109/10428194.2013.855307
   PubMed Web of Science ®Google Scholar
• Lopez J, Tait SWG. Mitochondrial apoptosis: killing cancer using the enemy within. Br J Cancer. 2015;112(6):957–962. doi:10.1038/bjc.2015.85
   PubMed Web of Science ®Google Scholar
• Villa-Pulgarín JA, Gajate C, Botet J, et al. Mitochondria and lipid raft-located FoF1-ATP synthase as major therapeutic targets in the antileishmanial and anticancer activities of ether lipid edelfosine. PLoS Negl Trop Dis. 2017;11(8):e0005805. doi:10.1371/journal.pntd.0005805
   PubMedGoogle Scholar
• Pfeffer CM, Singh AT. Apoptosis: a target for anticancer therapy. Int J Mol Sci. 2018;19(2):448.
   PubMed Web of Science ®Google Scholar
• Oberle C, Huai J, Reinheckel T, et al. Lysosomal membrane permeabilization and cathepsin release is a Bax/Bak-dependent, amplifying event of apoptosis in fibroblasts and monocytes. Cell Death Differ. 2010;17(7):1167–1178. doi:10.1038/cdd.2009.214
   PubMed Web of Science ®Google Scholar
• Dielschneider RF, Eisenstat H, Mi S, et al. Lysosomotropic agents selectively target chronic lymphocytic leukemia cells due to altered sphingolipid metabolism. Leukemia. 2016;30(6):1290–1300. doi:10.1038/leu.2016.4
   PubMedGoogle Scholar
• Zang Y, Beard RL, Chandraratna RA, Kang JX. Evidence of a lysosomal pathway for apoptosis induced by the synthetic retinoid CD437 in human leukemia HL-60 cells. Cell Death Differ. 2001;8(5):477–485. doi:10.1038/sj.cdd.4400843
   PubMed Web of Science ®Google Scholar
• Azad MB, Chen Y, Gibson SB. Regulation of autophagy by reactive oxygen species (ROS): implications for cancer progression and treatment. Antioxid Redox Signal. 2009;11(4):777–790. doi:10.1089/ars.2008.2270
   PubMed Web of Science ®Google Scholar
• Chen Y, Henson ES, Xiao W, et al. Tyrosine kinase receptor EGFR regulates the switch in cancer cells between cell survival and cell death induced by autophagy in hypoxia. Autophagy. 2016;12(6):1029–1046. doi:10.1080/15548627.2016.1164357
   PubMed Web of Science ®Google Scholar
• Hasegawa J, Maejima I, Iwamoto R, Yoshimori T. Selective autophagy: lysophagy. Methods. 2015;15(75):128–132. doi:10.1016/j.ymeth.2014.12.014
   Google Scholar
• Klionsky DJ, Abdel-Aziz AK, Abdelfatah S, et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy. 2021;20:1–382.
   Google Scholar
• Liu Y, Shoji-Kawata S, Sumpter RM, et al. Autosis is a Na+, K+-ATPase–regulated form of cell death triggered by autophagy-inducing peptides, starvation, and hypoxia–ischemia. Proc Natl Acad Sci U S A. 2013;110(51):20364–20371. doi:10.1073/pnas.1319661110
   PubMed Web of Science ®Google Scholar
• Morel E, Mehrpour M, Botti J, et al. Autophagy: a Druggable Process. Annu Rev Pharmacol Toxicol. 2017;57(1):375–398. doi:10.1146/annurev-pharmtox-010716-104936
   PubMed Web of Science ®Google Scholar
• Jin F, Wang Y, Li M, et al. MiR-26 enhances chemosensitivity and promotes apoptosis of hepatocellular carcinoma cells through inhibiting autophagy. Cell Death Dis. 2017;8(1):e2540. doi:10.1038/cddis.2016.461
   PubMedGoogle Scholar
• Xiong L, Liu Z, Ouyang G, et al. Autophagy inhibition enhances photocytotoxicity of Photosan-II in human colorectal cancer cells. Oncotarget. 2017;8(4):6419–6432. doi:10.18632/oncotarget.14117
   PubMedGoogle Scholar
• Redmann M, Benavides GA, Berryhill TF, et al. Inhibition of autophagy with bafilomycin and chloroquine decreases mitochondrial quality and bioenergetic function in primary neurons. Redox Biol. 2017;11:73–81. doi:10.1016/j.redox.2016.11.004
   PubMed Web of Science ®Google Scholar
• Ganguli A, Choudhury D, Datta S, Bhattacharya S, Chakrabarti G. Inhibition of autophagy by chloroquine potentiates synergistically anti-cancer property of artemisinin by promoting ROS dependent apoptosis. Biochimie. 2014;1(107):338–349. doi:10.1016/j.biochi.2014.10.001
   Google Scholar
• Cheng C, Wang T, Song Z, et al. Induction of autophagy and autophagy‐dependent apoptosis in diffuse large B‐cell lymphoma by a new antimalarial artemisinin derivative, SM 1044. Cancer Med. 2018;7(2):380–396. doi:10.1002/cam4.1276
   PubMedGoogle Scholar
• Zhou GZ, Zhang SN, Zhang L, Sun GC, Chen XB. A synthetic curcumin derivative hydrazinobenzoylcurcumin induces autophagy in A549 lung cancer cells. Pharm Biol. 2014;52(1):111–116. doi:10.3109/13880209.2013.816971
   PubMed Web of Science ®Google Scholar
• Tiwari RV, Parajuli P, Sylvester PW. Synergistic anticancer effects of combined γ-tocotrienol and oridonin treatment is associated with the induction of autophagy. Mol Cell Biochem. 2015;408(1):123–137. doi:10.1007/s11010-015-2488-x
   PubMedGoogle Scholar
• Basile V, Belluti S, Ferrari E, et al. bis-Dehydroxy-Curcumin triggers mitochondrial-associated cell death in human colon cancer cells through ER-stress induced autophagy. PLoS One. 2013;8(1):e53664. doi:10.1371/journal.pone.0053664
   PubMedGoogle Scholar
• Jia G, Kong R, Ma ZB, et al. The activation of c-Jun NH 2-terminal kinase is required for dihydroartemisinin-induced autophagy in pancreatic cancer cells. J Exp Clin Cancer Res. 2014;33(1):1. doi:10.1186/1756-9966-33-8
   PubMedGoogle Scholar
• Feng X, Li L, Jiang H, Jiang K, Jin Y, Zheng J. Dihydroartemisinin potentiates the anticancer effect of cisplatin via mTOR inhibition in cisplatin-resistant ovarian cancer cells: involvement of apoptosis and autophagy. Biochem Biophys Res Commun. 2014;444(3):376–381. doi:10.1016/j.bbrc.2014.01.053
   PubMed Web of Science ®Google Scholar
• Du XX, Li YJ, Wu CL, et al. Initiation of apoptosis, cell cycle arrest and autophagy of esophageal cancer cells by dihydroartemisinin. Biomed Pharmacother. 2013;67(5):417–424. doi:10.1016/j.biopha.2013.01.013
   PubMed Web of Science ®Google Scholar
• Zhang ZS, Wang J, Shen YB, et al. Dihydroartemisinin increases temozolomide efficacy in glioma cells by inducing autophagy. Oncol Lett. 2015a;10(1):379–383. doi:10.3892/ol.2015.3183
   PubMed Web of Science ®Google Scholar
• Wang Z, Hu W, Zhang JL, Wu XH, Zhou HJ. Dihydroartemisinin induces autophagy and inhibits the growth of iron-loaded human myeloid leukemia K562 cells via ROS toxicity. FEBS Open Bio. 2012;2(1):103–112. doi:10.1016/j.fob.2012.05.002
   PubMed Web of Science ®Google Scholar
• Shi X, Wang L, Li X, et al. Dihydroartemisinin induces autophagy-dependent death in human tongue squamous cell carcinoma cells through DNA double-strand break-mediated oxidative stress. Oncotarget. 2017;8(28):45981. doi:10.18632/oncotarget.17520
   PubMedGoogle Scholar
• Qu W, Xiao J, Zhang H, et al. B19, a novel monocarbonyl analogue of curcumin, induces human ovarian cancer cell apoptosis via activation of endoplasmic reticulum stress and the autophagy signaling pathway. Int J Biol Sci. 2013;9(8):766. doi:10.7150/ijbs.5711
   PubMed Web of Science ®Google Scholar
• Chen K, Shou LM, Lin F, et al. Artesunate induces G2/M cell cycle arrest through autophagy induction in breast cancer cells. Anticancer Drugs. 2014;25(6):652–662. doi:10.1097/CAD.0000000000000089
   PubMedGoogle Scholar
• Berte N, Lokan S, Eich M, Kim E, Kaina B. Artesunate enhances the therapeutic response of glioma cells to temozolomide by inhibition of homologous recombination and senescence. Oncotarget. 2016;7(41):67235. doi:10.18632/oncotarget.11972
   PubMedGoogle Scholar
• Jiang F, Zhou JY, Zhang D, Liu MH, Chen YG. Artesunate induces apoptosis and autophagy in HCT116 colon cancer cells, and autophagy inhibition enhances the artesunate-induced apoptosis. Int J Mol Med. 2018;42(3):1295–1304.
   PubMed Web of Science ®Google Scholar
• Boridy S, Le PU, Petrecca K, Maysinger D. Celastrol targets proteostasis and acts synergistically with a heat-shock protein 90 inhibitor to kill human glioblastoma cells. Cell Death Dis. 2014;5(5):e1216. doi:10.1038/cddis.2014.182
   PubMed Web of Science ®Google Scholar
• Lee HW, Jang KS, Choi HJ, Jo A, Cheong JH, Chun KH. Celastrol inhibits gastric cancer growth by induction of apoptosis and autophagy. BMB Rep. 2014a;47(12):697. doi:10.5483/BMBRep.2014.47.12.069
   PubMedGoogle Scholar
• Li HY, Zhang J, Sun LL, et al. Celastrol induces apoptosis and autophagy via the ROS/JNK signaling pathway in human osteosarcoma cells: an in vitro and in vivo study. Cell Death Dis. 2015;6(1):e1604. doi:10.1038/cddis.2014.543
   PubMedGoogle Scholar
• Guo J, Xu B, Han Q, et al. Ferroptosis: a novel anti-tumor action for cisplatin. Cancer Res Treat. 2018;50(2):445. doi:10.4143/crt.2016.572
   PubMed Web of Science ®Google Scholar
• Veldhoen RA, Banman SL, Hemmerling DR, et al. The chemotherapeutic agent paclitaxel inhibits autophagy through two distinct mechanisms that regulate apoptosis. Oncogene. 2013;32(6):736–746. doi:10.1038/onc.2012.92
   PubMed Web of Science ®Google Scholar
• Xi G, Hu X, Wu B, et al. Autophagy inhibition promotes paclitaxel-induced apoptosis in cancer cells. Cancer Lett. 2011;307(2):141–148. doi:10.1016/j.canlet.2011.03.026
   PubMed Web of Science ®Google Scholar
• Zou SH, Du X, Lin H, Wang PC, Li M. Paclitaxel inhibits the progression of cervical cancer by inhibiting autophagy via lncRNARP11-381N20. 2. Eur Rev Med Pharmacol Sci. 2018;22(10):3010–3017.
   PubMedGoogle Scholar
• Tomas‐Hernández S, Blanco J, Rojas C, et al. Resveratrol potently counteracts quercetin starvation‐induced autophagy and sensitizes HepG2 cancer cells to apoptosis. Mol Nutr Food Res. 2018;62(5):1700610. doi:10.1002/mnfr.201700610
   Google Scholar
• Fu Y, Chang H, Peng X, et al. Resveratrol inhibits breast cancer stem-like cells and induces autophagy via suppressing Wnt/β-catenin signaling pathway. PLoS One. 2014;9(7):e102535. doi:10.1371/journal.pone.0102535
   PubMed Web of Science ®Google Scholar
• Garcia-Zepeda SP, García-Villa E, Díaz-Chávez J, Hernández-Pando R, Gariglio P. Resveratrol induces cell death in cervical cancer cells through apoptosis and autophagy. Eur J Cancer Prev. 2013;22(6):577–584. doi:10.1097/CEJ.0b013e328360345f
   PubMed Web of Science ®Google Scholar
• Fan Y, Chiu JF, Liu J, et al. Resveratrol induces autophagy-dependent apoptosis in HL-60 cells. BMC Cancer. 2018;18(1):1. doi:10.1186/s12885-018-4504-5
   PubMedGoogle Scholar
• Selvaraj S, Sun Y, Sukumaran P, Singh BB. Resveratrol activates autophagic cell death in prostate cancer cells via downregulation of STIM1 and the mTOR pathway. Mol Carcinog. 2016;55(5):818–831. doi:10.1002/mc.22324
   PubMed Web of Science ®Google Scholar
• Puissant A, Robert G, Fenouille N, et al. Resveratrol promotes autophagic cell death in chronic myelogenous leukemia cells via JNK-mediated p62/SQSTM1 expression and AMPK activation. Cancer Res. 2010;70(3):1042–1052. doi:10.1158/0008-5472.CAN-09-3537
   PubMed Web of Science ®Google Scholar
• Back JH, Zhu Y, Calabro A, et al. Resveratrol‐mediated downregulation of Rictor attenuates autophagic process and suppresses UV‐induced skin carcinogenesis. Photochem Photobiol. 2012;88(5):1165–1172. doi:10.1111/j.1751-1097.2012.01097.x
   PubMed Web of Science ®Google Scholar
• Liu Q, Fang Q, Ji S, Han Z, Cheng W, Zhang H. Resveratrol-mediated apoptosis in renal cell carcinoma via the p53/AMP-activated protein kinase/mammalian target of rapamycin autophagy signaling pathway. Mol Med Rep. 2018;17(1):502–508.
   PubMedGoogle Scholar
• Mendes VI, Bartholomeusz GA, Ayres M, Gandhi V, Salvador JA. Synthesis and cytotoxic activity of novel A-ring cleaved ursolic acid derivatives in human non-small cell lung cancer cells. Eur J Med Chem. 2016;10(123):317–331. doi:10.1016/j.ejmech.2016.07.045
   Google Scholar
• Xavier CP, Lima CF, Pedro DF, Wilson JM, Kristiansen K, Pereira-Wilson C. Ursolic acid induces cell death and modulates autophagy through JNK pathway in apoptosis-resistant colorectal cancer cells. J Nutr Biochem. 2013;24(4):706–712. doi:10.1016/j.jnutbio.2012.04.004
   PubMedGoogle Scholar
• Leng S, Hao Y, Du D, et al. Ursolic acid promotes cancer cell death by inducing Atg5‐dependent autophagy. Int J Cancer Res. 2013;133(12):2781–2790.
   PubMed Web of Science ®Google Scholar
• Lewinska A, Adamczyk-Grochala J, Kwasniewicz E, Deregowska A, Wnuk M. Ursolic acid-mediated changes in glycolytic pathway promote cytotoxic autophagy and apoptosis in phenotypically different breast cancer cells. Apoptosis. 2017;22(6):800–815. doi:10.1007/s10495-017-1353-7
   PubMed Web of Science ®Google Scholar
• Shen S, Zhang Y, Zhang R, Tu X, Gong X. Ursolic acid induces autophagy in U87MG cells via ROS-dependent endoplasmic reticulum stress. Chem Biol Interact. 2014;218:28–41. doi:10.1016/j.cbi.2014.04.017
   PubMedGoogle Scholar
• Shin SW, Kim SY, Park JW. Autophagy inhibition enhances ursolic acid-induced apoptosis in PC3 cells. Biochim Biophys Acta Mol Cell Res. 2012;1823(2):451–457. doi:10.1016/j.bbamcr.2011.10.014
   Google Scholar
• Wu CC, Huang YF, Hsieh CP, Chueh PJ, Chen YL. Combined use of zoledronic acid augments ursolic acid-induced apoptosis in human osteosarcoma cells through enhanced oxidative stress and autophagy. Molecules. 2016;21(12):1640. doi:10.3390/molecules21121640
   PubMed Web of Science ®Google Scholar
• Jung J, Seo J, Kim J, Kim JH. Ursolic acid causes cell death in PC-12 cells by inducing apoptosis and impairing autophagy. Anticancer Res. 2018;38(2):847–853.
   PubMedGoogle Scholar
• Lin YC, Lin JF, Wen SI, et al. Chloroquine and hydroxychloroquine inhibit bladder cancer cell growth by targeting basal autophagy and enhancing apoptosis. Kaohsiung J Med Sci. 2017;33(5):215–223. doi:10.1016/j.kjms.2017.01.004
   PubMed Web of Science ®Google Scholar
• Frieboes HB, Huang JS, Yin WC, McNally LR. Chloroquine-mediated cell death in metastatic pancreatic adenocarcinoma through inhibition of autophagy. JOP J Pancreas. 2014;15(2):189–197.
   PubMedGoogle Scholar
• Wang T, Goodall ML, Gonzales P, et al. Synthesis of improved lysomotropic autophagy inhibitors. J Med Chem. 2015;58(7):3025–3035. doi:10.1021/jm501586m
   PubMedGoogle Scholar
• Tran AT, Ramalinga M, Kedir H, Clarke R, Kumar D. Autophagy inhibitor 3-methyladenine potentiates apoptosis induced by dietary tocotrienols in breast cancer cells. Eur J Nutr. 2015;54(2):265–272. doi:10.1007/s00394-014-0707-y
   PubMedGoogle Scholar
• Jang Y, Rao X, Jiang Q. Gamma-tocotrienol profoundly alters sphingolipids in cancer cells by inhibition of dihydroceramide desaturase and possibly activation of sphingolipid hydrolysis during prolonged treatment. J Nutr Biochem. 2017;1(46):49–56. doi:10.1016/j.jnutbio.2017.04.003
   Google Scholar
• Chu SC, Hsieh YS, Yu CC, Lai YY, Chen PN. Thymoquinone induces cell death in human squamous carcinoma cells via caspase activation-dependent apoptosis and LC3-II activation-dependent autophagy. PLoS One. 2014;9(7):e101579. doi:10.1371/journal.pone.0101579
   PubMedGoogle Scholar
• Pazhouhi M, Sariri R, Rabzia A, Khazaei M. Thymoquinone synergistically potentiates temozolomide cytotoxicity through the inhibition of autophagy in U87MG cell line. Iran J Basic Med Sci. 2016;19(8):890.
   PubMed Web of Science ®Google Scholar
• Chen MC, Lee NH, Hsu HH, et al. Thymoquinone induces caspase-independent, autophagic cell death in CPT-11-resistant lovo colon cancer via mitochondrial dysfunction and activation of JNK and p38. J Agric Food Chem. 2015a;63(5):1540–1546. doi:10.1021/jf5054063
   PubMedGoogle Scholar
• Aoki H, Takada Y, Kondo S, Sawaya R, Aggarwal BB, Kondo Y. Evidence that curcumin suppresses the growth of malignant gliomas in vitro and in vivo through induction of autophagy: role of Akt and extracellular signal-regulated kinase signaling pathways. Mol Pharmacol. 2007;72(1):29–39. doi:10.1124/mol.106.033167
   PubMed Web of Science ®Google Scholar
• Li B, Takeda T, Tsuiji K, et al. Curcumin induces cross-regulation between autophagy and apoptosis in uterine leiomyosarcoma cells. Int J Gynecol Cancer. 2013;23(5):803–808. doi:10.1097/IGC.0b013e31828c9581
   PubMedGoogle Scholar
• Masuelli L, Benvenuto M, Di Stefano E, et al. Curcumin blocks autophagy and activates apoptosis of malignant mesothelioma cell lines and increases the survival of mice intraperitoneally transplanted with a malignant mesothelioma cell line. Oncotarget. 2017;8(21):34405. doi:10.18632/oncotarget.14907
   PubMedGoogle Scholar
• Zhang J, Wang J, Xu J, et al. Curcumin targets the TFEB-lysosome pathway for induction of autophagy. Oncotarget. 2016c;7(46):75659. doi:10.18632/oncotarget.12318
   PubMedGoogle Scholar
• Rainey N, Motte L, Aggarwal BB, Petit PX. Curcumin hormesis mediates a cross-talk between autophagy and cell death. Cell Death Dis. 2015;6(12):e2003. doi:10.1038/cddis.2015.343
   PubMedGoogle Scholar
• Eaton JW, Qian M. Molecular bases of cellular iron toxicity. Free Radic Biol Med. 2002;32(9):833–840. doi:10.1016/S0891-5849(02)00772-4
   PubMed Web of Science ®Google Scholar
• Windelborn JA, Lipton P. Lysosomal release of cathepsins causes ischemic damage in the rat hippocampal slice and depends on NMDA‐mediated calcium influx, arachidonic acid metabolism, and free radical production. J Neurochem. 2008;106(1):56–69. doi:10.1111/j.1471-4159.2008.05349.x
   PubMedGoogle Scholar
• Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060–1072. doi:10.1016/j.cell.2012.03.042
   PubMed Web of Science ®Google Scholar
• Schonberg DL, Miller TE, Wu Q, et al. Preferential iron trafficking characterizes glioblastoma stem-like cells. Cancer Cell. 2015;28(4):441–455. doi:10.1016/j.ccell.2015.09.002
   PubMedGoogle Scholar
• Tang M, Chen Z, Wu D, Chen L. Ferritinophagy/ferroptosis: iron‐related newcomers in human diseases. J Cell Physiol. 2018;233(12):9179–9190. doi:10.1002/jcp.26954
   PubMed Web of Science ®Google Scholar
• Kang R, Xie Y, Zeh HJ, Klionsky DJ, Tang D. Mitochondrial quality control mediated by PINK1 and PRKN: links to iron metabolism and tumor immunity. Autophagy. 2019;15(1):172–173. doi:10.1080/15548627.2018.1526611
   PubMed Web of Science ®Google Scholar
• Dodson M, Castro-Portuguez R, Zhang DD. NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biol. 2019;23:101107. doi:10.1016/j.redox.2019.101107
   PubMed Web of Science ®Google Scholar
• Chen GQ, Benthani FA, Wu J, Liang D, Bian ZX, Jiang X. Artemisinin compounds sensitize cancer cells to ferroptosis by regulating iron homeostasis. Cell Death Differ. 2020;27(1):242–254. doi:10.1038/s41418-019-0352-3
   PubMed Web of Science ®Google Scholar
• Lin R, Zhang Z, Chen L, et al. Dihydroartemisinin (DHA) induces ferroptosis and causes cell cycle arrest in head and neck carcinoma cells. Cancer Lett. 2016;381(1):165–175. doi:10.1016/j.canlet.2016.07.033
   PubMed Web of Science ®Google Scholar
• Du J, Wang T, Li Y, et al. DHA inhibits proliferation and induces ferroptosis of leukemia cells through autophagy dependent degradation of ferritin. Free Radic Biol Med. 2019;1(131):356–369. doi:10.1016/j.freeradbiomed.2018.12.011
   Google Scholar
• Zhu S, Zhang Q, Sun X, et al. HSPA5 regulates ferroptotic cell death in cancer cells. Cancer Res. 2017;77(8):2064–2077. doi:10.1158/0008-5472.CAN-16-1979
   PubMed Web of Science ®Google Scholar
• Lv C, Qu H, Zhu W, et al. Low-dose paclitaxel inhibits tumor cell growth by regulating glutaminolysis in colorectal carcinoma cells. Front Pharmacol. 2017;4(8):244. doi:10.3389/fphar.2017.00244
   Google Scholar
• Giannakakou P, Robey R, Fojo T, Blagosklonny MV. Low concentrations of paclitaxel induce cell type-dependent p53, p21 and G1/G2 arrest instead of mitotic arrest: molecular determinants of paclitaxel-induced cytotoxicity. Oncogene. 2001;20(29):3806–3813. doi:10.1038/sj.onc.1204487
   PubMed Web of Science ®Google Scholar
• Song X, Zhu S, Chen P, et al. AMPK-mediated BECN1 phosphorylation promotes ferroptosis by directly blocking system Xc–activity. Curr Biol. 2018;28(15):2388–2399. doi:10.1016/j.cub.2018.05.094
   PubMed Web of Science ®Google Scholar
• Sehm T, Fan Z, Ghoochani A, et al. Sulfasalazine impacts on ferroptotic cell death and alleviates the tumor microenvironment and glioma-induced brain edema. Oncotarget. 2016;7(24):36021. doi:10.18632/oncotarget.8651
   PubMedGoogle Scholar
• Sun X, Ou Z, Chen R, et al. Activation of the p62‐Keap1‐NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology. 2016;63(1):173–184. doi:10.1002/hep.28251
   PubMed Web of Science ®Google Scholar
• Dixon SJ, Patel DN, Welsch M, et al. Pharmacological inhibition of cystine–glutamate exchange induces endoplasmic reticulum stress and ferroptosis. Elife. 2014;20(3):e02523. doi:10.7554/eLife.02523
   Google Scholar
• Chen L, Li X, Liu L, Yu B, Xue Y, Liu Y. Erastin sensitizes glioblastoma cells to temozolomide by restraining xCT and cystathionine-γ-lyase function. Oncol Rep. 2015b;33(3):1465–1474. doi:10.3892/or.2015.3712
   PubMed Web of Science ®Google Scholar
• Kondratskyi A, Yassine M, Slomianny C, et al. Identification of ML-9 as a lysosomotropic agent targeting autophagy and cell death. Cell Death Dis. 2014;5(4):e1193. doi:10.1038/cddis.2014.156
   PubMedGoogle Scholar
• Sabella S, Carney RP, Brunetti V, et al. A general mechanism for intracellular toxicity of metal-containing nanoparticles. Nanoscale. 2014;6(12):7052–7061. doi:10.1039/c4nr01234h
   PubMed Web of Science ®Google Scholar
• Choi AR, Kim JH, Woo YH, Kim HS, Yoon S. Anti-malarial drugs primaquine and chloroquine have different sensitization effects with anti-mitotic drugs in resistant cancer cells. Anticancer Res. 2016;36(4):1641–1648. doi:10.21873/anticanres.11171
   PubMedGoogle Scholar
• de Jong WH, Borm PJ. Drug delivery and nanoparticles: applications and hazards. Int J Nanomed. 2008;3:133–149. doi:10.2147/IJN.S596
   PubMed Web of Science ®Google Scholar
• Daraio C, Jin S. Synthesis and patterning methods for nanostructures useful for biological applications. In: Daraio C, Jin S, Silva GA, Parpura V, editors. Nanotechnology for Biology and Medicine. New York: Springer; 2012:27–44.
   Google Scholar
• Jain AK, Thareja S. In vitro and in vivo characterization of pharmaceutical nanocarriers used for drug delivery. Artif Cells Nanomed Biotechnol. 2019;47(1):524–539. doi:10.1080/21691401.2018.1561457
   PubMed Web of Science ®Google Scholar
• Chen F, Ehlerding EB, Cai W. Theranostic nanoparticles. J Nucl Med. 2014;55(12):1919–1922. doi:10.2967/jnumed.114.146019
   PubMed Web of Science ®Google Scholar
• Khan AA, Allemailem KS, Almatroudi A, Almatroodi SA, Alsahli MA, Rahmani AH. Novel strategies of third level (organelle-specific) drug targeting: an innovative approach of modern therapeutics. J Drug Deliv Sci Technol. 2020;29:102315.
   Google Scholar
• Allemailem KS, Almatroudi A, Alsahli MA, et al. Novel strategies for disrupting cancer-cell functions with mitochondria-targeted antitumor drug–loaded nanoformulations. Int J Nanomedicine. 2021;16:3907. doi:10.2147/IJN.S303832
   PubMedGoogle Scholar
• Borkowska M, Siek M, Kolygina DV, et al. Targeted crystallization of mixed-charge nanoparticles in lysosomes induces selective death of cancer cells. Nat Nanotechnol. 2020;15(4):331–341. doi:10.1038/s41565-020-0643-3
   PubMed Web of Science ®Google Scholar
• Nasrollahi SA, Taghibiglou C, Azizi E, Farboud ES. Cell‐penetrating peptides as a novel transdermal drug delivery system. Chem Biol Drug Des. 2012;80(5):639–646. doi:10.1111/cbdd.12008
   PubMed Web of Science ®Google Scholar
• Zhong YJ, Shao LH, Li YA. Cathepsin B-cleavable doxorubicin prodrugs for targeted cancer therapy. Int J Oncol. 2013;42(2):373–383. doi:10.3892/ijo.2012.1754
   PubMed Web of Science ®Google Scholar
• Cudic M, Fields GB. Extracellular proteases as targets for drug development. Curr Protein Pept Sci. 2009;10(4):297–307. doi:10.2174/138920309788922207
   PubMed Web of Science ®Google Scholar
• Zhang L, Sheng R, Qin Z. The lysosome and neurodegenerative diseases. Acta Biochim Biophys Sin (Shanghai). 2009a;41(6):437–445. doi:10.1093/abbs/gmp031
   PubMedGoogle Scholar
• Berquin IM, Sloane BF. Cathepsin B expression in human tumors. Adv Exp Med Biol. 1996;389:281–294.
   Google Scholar
• Reinheckel T, Peters C, Krüger A, Turk B, Vasiljeva O. Differential impact of cysteine cathepsins on genetic mouse models of de novo carcinogenesis: cathepsin B as emerging therapeutic target. Front Pharmacol. 2012;11(3):133.
   Google Scholar
• Maiti KK, Jeon OY, Lee WS, et al. Design, synthesis, and membrane‐translocation studies of inositol‐based transporters. Angew Chem Int Ed. 2006;45(18):2907–2912. doi:10.1002/anie.200600312
   PubMed Web of Science ®Google Scholar
• Maiti KK, Lee WS, Takeuchi T, et al. Guanidine‐containing molecular transporters: sorbitol‐based transporters show high intracellular selectivity toward mitochondria. Angew Chem. 2007;119(31):5984–5988. doi:10.1002/ange.200701346
   Google Scholar
• Wender PA, Galliher WC, Goun EA, Jones LR, Pillow TH. The design of guanidinium-rich transporters and their internalization mechanisms. Adv Drug Deliv Rev. 2008;60(4–5):452–472. doi:10.1016/j.addr.2007.10.016
   PubMed Web of Science ®Google Scholar
• Wei P, Zhang L, Lu Y, Man N, Wen L. C60 (Nd) nanoparticles enhance chemotherapeutic susceptibility of cancer cells by modulation of autophagy. Nanotechnology. 2010;21(49):495101. doi:10.1088/0957-4484/21/49/495101
   PubMed Web of Science ®Google Scholar
• Ma X, Wu Y, Jin S, et al. Gold nanoparticles induce autophagosome accumulation through size-dependent nanoparticle uptake and lysosome impairment. ACS Nano. 2011;5(11):8629–8639. doi:10.1021/nn202155y
   PubMed Web of Science ®Google Scholar
• Dekiwadia CD, Lawrie AC, Fecondo JV. Peptide‐mediated cell penetration and targeted delivery of gold nanoparticles into lysosomes. J Pept Sci. 2012;18(8):527–534. doi:10.1002/psc.2430
   PubMed Web of Science ®Google Scholar
• Lee AS. Glucose-regulated proteins in cancer: molecular mechanisms and therapeutic potential. Nat Rev Cancer. 2014b;14(4):263–276. doi:10.1038/nrc3701
   PubMed Web of Science ®Google Scholar
• Lee AS. GRP78 induction in cancer: therapeutic and prognostic implications. Cancer Res. 2007;67(8):3496–3499. doi:10.1158/0008-5472.CAN-07-0325
   PubMed Web of Science ®Google Scholar
• Cuervo AM, Bergamini E, Brunk UT, Dröge W, Ffrench M, Terman A. Autophagy and aging: the importance of maintaining” clean” cells. Autophagy. 2005;1(3):131–140. doi:10.4161/auto.1.3.2017
   PubMed Web of Science ®Google Scholar
• Nesic M, Popović I, Leskovac A, Petković M. Biological activity and binding properties of [Ru (II)(dcbpy) 2 Cl 2] complex to bovine serum albumin, phospholipase A 2 and glutathione. Biometals. 2016;29(5):921–933. doi:10.1007/s10534-016-9964-y
   PubMedGoogle Scholar
• Purushothaman B, Arumugam P, Ju H, Kulsi G, Samson AA, Song JM. Novel ruthenium (II) triazine complex [Ru (bdpta)(tpy)] 2+ co-targeting drug resistant GRP78 and subcellular organelles in cancer stem cells. Eur J Med Chem. 2018;156:747–759. doi:10.1016/j.ejmech.2018.07.048
   PubMed Web of Science ®Google Scholar
• Purushothaman B, Choi J, Park S, et al. Biotin-conjugated PEGylated porphyrin self-assembled nanoparticles co-targeting mitochondria and lysosomes for advanced chemo-photodynamic combination therapy. J Mater Chem B. 2019;7(1):65–79. doi:10.1039/C8TB01923A
   PubMedGoogle Scholar
• Zabner J, Fasbender AJ, Moninger T, Poellinger K, Welsh MJ. J. Biol Chem. 1995;270:18997–19007. doi:10.1074/jbc.270.32.18997
   Web of Science ®Google Scholar
• Wattiaux R, Wattiaux-de Coninck S. Biology of the Lysosome. Lloyd and Mason, editors. New York: Plenum Press; 1996:387.
   Google Scholar
• Kornfeld S. Trafficking of lysosomal enzymes in normal and disease states. J Clin Invest. 1986;77(1):1–6. doi:10.1172/JCI112262
   PubMedGoogle Scholar
• Kornfeld S, Reitman ML, Varki A, Goldberg D, Gabel CA. Steps in the phosphorylation of the high mannose oligosaccharides of lysosomal enzymes. Ciba Found Symp. 1982;92(92):138–156.
   Google Scholar
• Izbicki T, Mazur J, Izbicka E. Epidemiology of neuroblastoma: analysis of a single institution. Anticancer Res. 2003;23(2C):1933–1938.
   PubMedGoogle Scholar
• Schwake M, Schröder B, Saftig P. Lysosomal membrane proteins and their central role in physiology. Traffic. 2013;14(7):739–748. doi:10.1111/tra.12056
   PubMed Web of Science ®Google Scholar
• Biederbick A, Rose S, Elsasser HP. A human intracellular apyrase-like protein, LALP70, localizes to lysosomal/autophagic vacuoles. J Cell Sci. 1999;112(15):2473–2484. doi:10.1242/jcs.112.15.2473
   PubMedGoogle Scholar
• Lloyd-Evans E, Platt FM. Lysosomal Ca2+ homeostasis: role in pathogenesis of lysosomal storage diseases. Cell Calcium. 2011;50(2):200–205. doi:10.1016/j.ceca.2011.03.010
   PubMedGoogle Scholar
• Stern ST, Adiseshaiah PP, Crist RM. Autophagy and lysosomal dysfunction as emerging mechanisms of nanomaterial toxicity. Part Fibre Toxicol. 2012;9(1):1–7. doi:10.1186/1743-8977-9-20
   PubMedGoogle Scholar
• Man N, Chen Y, Zheng F, Zhou W, Wen LP. Induction of genuine autophagy by cationic lipids in mammalian cells. Autophagy. 2010;6(4):449–454. doi:10.4161/auto.6.4.11612
   PubMed Web of Science ®Google Scholar
• Yang K, Lu Y, Xie F, et al. Cationic liposomes induce cell necrosis through lysosomal dysfunction and late-stage autophagic flux inhibition. Nanomedicine. 2016;12(23):3117–3137. doi:10.2217/nnm-2016-0289
   Google Scholar
• Andreichenko K, Shelyuk O, Prylutska S, et al. Effect of multi‐walled iron‐filled carbon nanotubes on ATPase activity and superprecipitation of natural actomyosin. Materwiss Werksttech. 2013;44(2–3):103–106. doi:10.1002/mawe.201300103
   Google Scholar
• Capco DG, Chen Y. Preface. In: Nanomaterial Impacts on Cell Biology and Medicine. NY, USA: Springer; 2014.
   Google Scholar
• Yu KN, Kim JE, Seo HW, et al. Differential toxic responses between pristine and functionalized multiwall nanotubes involve induction of autophagy accumulation in murine lung. J Toxicol Environ Health A. 2013;76(23):1282–1292. doi:10.1080/15287394.2013.850137
   PubMed Web of Science ®Google Scholar
• Sohaebuddin SK, Thevenot PT, Baker D, Eaton JW, Tang L. Nanomaterial cytotoxicity is composition, size, and cell type dependent. Part Fibre Toxicol. 2010;7(1):1–7. doi:10.1186/1743-8977-7-22
   PubMed Web of Science ®Google Scholar
• Sandhoff K, Kolter T, Harzer K. Sphingolipid activator proteins. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, Inc.; 2000:3371–3388.
   Google Scholar
• Wang Y, Grabowski GA, Qi X. Phospholipid vesicle fusion induced by saposin C. Arch Biochem Biophys. 2003;415(1):43–53. doi:10.1016/S0003-9861(03)00219-4
   PubMedGoogle Scholar
• Ran S, Thorpe PE. Phosphatidylserine is a marker of tumor vasculature and a potential target for cancer imaging and therapy. Int J Radiat Oncol Biol Phys. 2002;54(5):1479–1484. doi:10.1016/S0360-3016(02)03928-7
   PubMed Web of Science ®Google Scholar
• Ditaranto-Desimone K, Saito M, Tekirian TL, et al. Neuronal endosomal/lysosomal membrane destabilization activates caspases and induces abnormal accumulation of the lipid secondary messenger ceramide. Brain Res Bull. 2003;59(6):523–531. doi:10.1016/S0361-9230(02)00948-6
   PubMed Web of Science ®Google Scholar
• Hendrich AB, Michalak K. Lipids as a target for drugs modulating multidrug resistance of cancer cells. Curr Drug Targets. 2003;4(1):23–30. doi:10.2174/1389450033347172
   PubMed Web of Science ®Google Scholar
• Thekkedath R, Koshkaryev A, Torchilin VP. Lysosome-targeted octadecyl-rhodamine B-liposomes enhance lysosomal accumulation of glucocerebrosidase in Gaucher’s cells in vitro. Nanomedicine. 2013;8(7):1055–1065. doi:10.2217/nnm.12.138
   PubMed Web of Science ®Google Scholar
• Jiang Y, Huo S, Mizuhara T, et al. The interplay of size and surface functionality on the cellular uptake of sub-10 nm gold nanoparticles. ACS Nano. 2015;9(10):9986–9993. doi:10.1021/acsnano.5b03521
   PubMed Web of Science ®Google Scholar
• Kim B, Han G, Toley BJ, Kim CK, Rotello VM, Forbes NS. Tuning payload delivery in tumour cylindroids using gold nanoparticles. Nat Nanotechnol. 2010;5(6):465–472. doi:10.1038/nnano.2010.58
   PubMed Web of Science ®Google Scholar
• Pillai PP, Kowalczyk B, Pudlo WJ, Grzybowski BA. Electrostatic titrations reveal surface compositions of mixed, on-nanoparticle monolayers comprising positively and negatively charged ligands. J Phys Chem C. 2016;120(7):4139–4144. doi:10.1021/acs.jpcc.5b12599
   Google Scholar
• Zhang ZY, Xu YD, Ma YY, et al. Biodegradable ZnO@ polymer core–shell nanocarriers: pH‐triggered release of doxorubicin in vitro. Angew Chem Int Ed. 2013;52:4127. doi:10.1002/anie.201300431
   PubMed Web of Science ®Google Scholar
• Chu JJ, Ng ML. Interaction of West Nile virus with αvβ3 integrin mediates virus entry into cells. J Biol Chem. 2004;2004(52):54533. doi:10.1074/jbc.M410208200
   Google Scholar
• Domenech M, Marrero-Berrios I, Torres-Lugo M, Rinaldi C. Lysosomal membrane permeabilization by targeted magnetic nanoparticles in alternating magnetic fields. ACS Nano. 2013;7(6):5091–5101. doi:10.1021/nn4007048
   PubMed Web of Science ®Google Scholar
• Yanes RE, Tamanoi F. Development of mesoporous silica nanomaterials as a vehicle for anticancer drug delivery. Ther Deliv. 2012;3(3):389–404. doi:10.4155/tde.12.9
   PubMedGoogle Scholar
• Meng H, Xue M, Xia T, et al. Use of size and a copolymer design feature to improve the biodistribution and the enhanced permeability and retention effect of doxorubicin-loaded mesoporous silica nanoparticles in a murine xenograft tumor model. ACS Nano. 2011;5(5):4131–4144. doi:10.1021/nn200809t
   PubMed Web of Science ®Google Scholar
• Zhu CL, Lu CH, Song XY, Yang HH, Wang XR. Bioresponsive controlled release using mesoporous silica nanoparticles capped with aptamer-based molecular gate. J Am Chem Soc. 2011;133(5):1278–1281. doi:10.1021/ja110094g
   PubMed Web of Science ®Google Scholar
• Lu J, Li Z, Zink JI, Tamanoi F. In vivo tumor suppression efficacy of mesoporous silica nanoparticles-based drug-delivery system: enhanced efficacy by folate modification. Nanomedicine. 2012;8(2):212–220. doi:10.1016/j.nano.2011.06.002
   PubMed Web of Science ®Google Scholar
• Mamaeva V, Rosenholm JM, Bate-Eya LT, et al. Mesoporous silica nanoparticles as drug delivery systems for targeted inhibition of Notch signaling in cancer. Mol Ther. 2011;19(8):1538–1546. doi:10.1038/mt.2011.105
   PubMed Web of Science ®Google Scholar
• Zhao Q, Gong Z, Li Z, et al. Target reprogramming lysosomes of CD8+ T cells by a mineralized metal–organic framework for cancer immunotherapy. Adv Mater. 2021;33(17):2100616. doi:10.1002/adma.202100616
   Google Scholar
• Jaattela M. Multiple cell death pathways as regulators of tumour initiation and progression. Oncogene. 2004;23(16):2746–2756. doi:10.1038/sj.onc.1207513
   PubMed Web of Science ®Google Scholar
• Huang Y, Mao K, Zhang B, Zhao Y. Superparamagnetic iron oxide nanoparticles conjugated with folic acid for dual target-specific drug delivery and MRI in cancer theranostics. Mater Sci Eng C. 2017;70:763–771. doi:10.1016/j.msec.2016.09.052
   PubMed Web of Science ®Google Scholar
• Lee H, Dam DHM, Ha JW, Yue J, Odom TW. Enhanced human epidermal growth factor receptor 2 degradation in breast cancer cells by lysosome-targeting gold nanoconstructs. ACS Nano. 2015;9(10):9859–9867. doi:10.1021/acsnano.5b05138
   PubMed Web of Science ®Google Scholar
• Zeng Y, Yang Z, Luo S, et al. Fast and facile preparation of PEGylated graphene from graphene oxide by lysosome targeting delivery of photosensitizer to efficiently enhance photodynamic therapy. RSC Adv. 2015;5(71):57725–57734. doi:10.1039/C5RA07535A
   Google Scholar
• Yuan X, Xiao F, Zhao H, et al. High-Yield method to fabricate and functionalize DNA nanoparticles from the products of rolling circle amplification. ACS Appl Bio Mater. 2018;1(2):511–519. doi:10.1021/acsabm.8b00238
   PubMedGoogle Scholar
• Zeng L, Gupta P, Chen Y, et al. The development of anticancer ruthenium(ii) complexes: from single molecule compounds to nanomaterials. Chem Soc Rev. 2017;46(19):5771–5804. doi:10.1039/C7CS00195A
   PubMed Web of Science ®Google Scholar
• Cheng W, Liang C, Wang X, et al. A drug-self-gated and tumor microenvironment-responsive mesoporous silica vehicle:“four-in-one” versatile nanomedicine for targeted multidrug-resistant cancer therapy. Nanoscale. 2017;9(43):17063–17073. doi:10.1039/C7NR05450E
   PubMed Web of Science ®Google Scholar
• Gao W, Cao W, Zhang H, Li P, Xu K, Tang B. Targeting lysosomal membrane permeabilization to induce and image apoptosis in cancer cells by multifunctional Au-ZnO hybrid nanoparticles. Chem Commun. 2014;50(60):8117–8120. doi:10.1039/c4cc03793f
   PubMed Web of Science ®Google Scholar
• Xue S, Tan C, Chen M, et al. Tumor-targeted supramolecular nanoparticles self-assembled from a ruthenium-β-cyclodextrin complex and an adamantane-functionalized peptide. Chem Commun. 2017;53:842–845. doi:10.1039/C6CC08296C
   PubMedGoogle Scholar
• Ju E, Chen Z, Li W, et al. Embedding magnetic nanoparticles into coordination polymers to mimic zinc ion transporters for targeted tumor therapy. Chem Commun. 2016;52(85):12598–12601. doi:10.1039/C6CC06467A
   PubMedGoogle Scholar
• Sharma A, Lee M-G, Shi H, et al. Overcoming drug resistance by targeting cancer bioenergetics with an activatable prodrug. Chem. 2018;4(10):2370–2383. doi:10.1016/j.chempr.2018.08.002
   Google Scholar
• Clerc P, Jeanjean P, Hallali N, et al. Targeted magnetic intra-lysosomal hyperthermia produces lysosomal reactive oxygen species and causes caspase-1 dependent cell death. J Control Release. 2018;270:120–134. doi:10.1016/j.jconrel.2017.11.050
   PubMed Web of Science ®Google Scholar
• Leanza L, Biasutto L, Manago A, Gulbins E, Zoratti M, Szabo I. Intracellular ion channels and cancer. Front Physiol. 2013;4:227–233. doi:10.3389/fphys.2013.00227
   PubMedGoogle Scholar
• Gangopadhyay M, Mukhopadhyay SK, Gayathri S, et al. Fluorene–morpholine-based organic nanoparticles: lysosome-targeted pH-triggered two-photon photodynamic therapy with fluorescence switch on-off. J Mater Chem B. 2016;4(10):1862–1868. doi:10.1039/C5TB02563J
   PubMedGoogle Scholar
• Sharma A, Arambula JF, Koo S, et al. Hypoxia-targeted drug delivery. Chem Soc Rev. 2019;48:771–813.
   PubMed Web of Science ®Google Scholar
• Mirshafiee V, Sun B, Chang CH, et al. Toxicological profiling of metal oxide nanoparticles in liver context reveals pyroptosis in kupffer cells and macrophages versus apoptosis in hepatocytes. ACS Nano. 2018;12(4):3836–3852. doi:10.1021/acsnano.8b01086
   PubMed Web of Science ®Google Scholar
• Cerda MB, Batalla M, Anton M, et al. Enhancement of nucleic acid delivery to hard-totransfect human colorectal cancer cells by magnetofection at laminin coated substrates and promotion of the endosomal/lysosomal escape. RSC Adv. 2015;5(72):58345–58354. doi:10.1039/C5RA06562C
   Google Scholar
• Joris F, De Backer L, Van de Vyver T, Bastiancich C, De Smedt SC, Raemdonck K. Repurposing cationic amphiphilic drugs as adjuvants to induce lysosomal siRNA escape in nanogel transfected cells. J Control Release. 2018;269:266–276. doi:10.1016/j.jconrel.2017.11.019
   PubMed Web of Science ®Google Scholar
• Zhou L, Yang T, Wang J, et al. Size-tunable Gd2O3@Albumin nanoparticles conjugating chlorin e6 for magnetic resonance imaging-guided photo-induced therapy. Theranostics. 2017;7(3):764–774. doi:10.7150/thno.15757
   PubMed Web of Science ®Google Scholar
• Berger E, Breznan D, Stals S, et al. Cytotoxicity assessment, inflammatory properties, and cellular uptake of neutraplex lipid-based nanoparticles in THP-1 monocyte-derived macrophages. Nanobiomedicine. 2017;4:1–14. doi:10.1177/1849543517746259
   Google Scholar
• Chen L, She X, Wang T, et al. Overcoming acquired drug resistance in colorectal cancer cells by targeted delivery of 5-FU with EGF grafted hollow mesoporous silica nanoparticles. Nanoscale. 2015;7(33):14080–14092. doi:10.1039/C5NR03527A
   PubMed Web of Science ®Google Scholar
• Guo S, Huang L. Nanoparticles escaping RES and endosome: challenges for siRNA delivery for cancer therapy. J Nanomater. 2011;2011:Article ID 742895.
   Web of Science ®Google Scholar
• Yuan Y, Zhang C, Liu B. A photoactivatable AIE polymer for light-controlled gene delivery: concurrent endo/lysosomal escape and DNA unpacking. Angew Chem Int Ed. 2015;54(39):11419–11423. doi:10.1002/anie.201503640
   PubMed Web of Science ®Google Scholar
• Li L, Sun W, Li L, et al. A pHresponsive sequential-disassembly nanohybrid for mitochondrial targeting. Nanoscale. 2017;9(1):314–325. doi:10.1039/C6NR07004C
   PubMedGoogle Scholar
• Chen G, Wang Y, Xie R, Gong S. Tumor-targeted pH/redox dual-sensitive unimolecular nanoparticles for efficient siRNA delivery. J Control Release. 2017;259:105–114. doi:10.1016/j.jconrel.2017.01.042
   PubMed Web of Science ®Google Scholar
• Wan B, Wang Z, Lv Q, et al. Single-walled carbon nanotubes and graphene oxides induce autophagosome accumulation and lysosome impairment in primarily cultured murine peritoneal macrophages. Toxicol Lett. 2013;221(2):118–127. doi:10.1016/j.toxlet.2013.06.208
   PubMed Web of Science ®Google Scholar
• Ghosh S, Panja P, Dalal C, Jana NR. Arginine-Terminated, chemically designed nanoparticle for direct cell translocation. ACS Appl Bio Mater. 2019;2(1):339–348. doi:10.1021/acsabm.8b00617
   PubMedGoogle Scholar
• Rothbard JB, Jessop TC, Lewis RS, Murray BA, Wender PA. Role of membrane potential and hydrogen bonding in the mechanism of translocation of guanidinium rich peptides into cells. J Am Chem Soc. 2004;126(31):9506–9507. doi:10.1021/ja0482536
   PubMed Web of Science ®Google Scholar
• Cohignac V, Landry MJ, Ridoux A, et al. Carbon nanotubes, but not spherical nanoparticles, block autophagy by a shape-related targeting of lysosomes in murine macrophages. Autophagy. 2018;14(8):1323–1334.
   PubMed Web of Science ®Google Scholar
• Duan J, Yu Y, Li Y, et al. Silica nanoparticles induce autophagy and endothelial dysfunction via the PI3K/Akt/ mTOR signaling pathway. Int J Nanomed. 2014;9:5131–5141. doi:10.2147/IJN.S71074
   PubMed Web of Science ®Google Scholar
• Bossi E, Zanella D, Gornati R, Bernardini G. Cobalt oxide nanoparticles can enter inside the cells by crossing plasma membranes. Sci Rep. 2016;6(1):22254–22263. doi:10.1038/srep22254
   PubMed Web of Science ®Google Scholar
• Wang J, Yu Y, Lu K, et al. Silica nanoparticles induce autophagy dysfunction via lysosomal impairment and inhibition of autophagosome degradation in hepatocytes. Int J Nanomed. 2017;12:809–825. doi:10.2147/IJN.S123596
   PubMed Web of Science ®Google Scholar
• Zhang L, Chen X, Wu J, et al. Palladium nanoparticles induces autophagy and autophagic flux blockade in HeLa cells. RSC Adv. 2018;8(8):4130–4141. doi:10.1039/C7RA11400A
   Google Scholar
• Nakamura S, Yoshimori T. New insights into autophagosome–lysosome fusion. J Cell Sci. 2017;130:1209–1216.
   PubMed Web of Science ®Google Scholar
• Xue X, Wang L, Sato Y, et al. Single single walled carbon nanotubes alleviate autophagic/lysosomal defects in primary glia from a mouse model of Alzheimer’s disease. Nano Lett. 2014;14(9):5110–5117. doi:10.1021/nl501839q
   PubMed Web of Science ®Google Scholar
• Lin J, Alexander-Katz A. Cell membranes open “Doors” for cationic nanoparticles/ biomolecules: insights into uptake kinetics. ASC Nano. 2013;7(12):10799–10808. doi:10.1021/nn4040553
   Google Scholar
• Derivery E, Bartolami E, Matile S, Gonzalez-Gaitan M. Efficient delivery of quantum dots into the cytosol of cells using cell-penetrating poly(disulfide)s. J Am Chem Sci. 2017;139(30):10172–10175. doi:10.1021/jacs.7b02952
   PubMedGoogle Scholar
• Aggarwal P, Hall JB, McLeland CB, Dobrovolskaia MA, McNeil SE. Nanoparticle interaction with plasma proteins as it relates to particle biodistribution, biocompatibility and therapeutic efficacy. Adv Drug Deliv Rev. 2009;61(6):428–437. doi:10.1016/j.addr.2009.03.009
   PubMed Web of Science ®Google Scholar
• Gao Y, Chen Y, Zhan S, Zhang W, Xiong F, Ge W. Comprehensive proteome analysis of lysosomes reveals the diverse function of macrophages in immune responses. Oncotarget. 2017;8(5):7420. doi:10.18632/oncotarget.14558
   PubMedGoogle Scholar
• Casey TM, Meade JL, Hewitt EW. Organelle proteomics: identification of the exocytic machinery associated with the natural killer cell secretory lysosome. Mol Cell Proteomics. 2007;6(5):767–780. doi:10.1074/mcp.M600365-MCP200
   PubMedGoogle Scholar
• Jenkins SJ, Ruckerl D, Cook PC, et al. Local macrophage proliferation, rather than recruitment from the blood, is a signature of Th2 inflammation. Science. 2011;332(6035):1284–1288. doi:10.1126/science.1204351
   PubMed Web of Science ®Google Scholar
• Terenzi A, Pirker C, Keppler BK, Berger W. Anticancer metal drugs and immunogenic cell death. J Inorg Biochem. 2016;1(165):71–79. doi:10.1016/j.jinorgbio.2016.06.021
   Google Scholar
• Zitvogel L, Apetoh L, Ghiringhelli F, André F, Tesniere A, Kroemer G. The anticancer immune response: indispensable for therapeutic success? J Clin Invest. 2008;118(6):1991–2001. doi:10.1172/JCI35180
   PubMed Web of Science ®Google Scholar
• Fedeli C, Segat D, Tavano R, et al. Variations of the corona HDL:albumin ratio determine distinct effects of amorphous SiO2 nanoparticles on monocytes and macrophages in serum. Nanomedicine. 2014;9(16):2481–2497. doi:10.2217/nnm.14.22
   PubMedGoogle Scholar
• Poland CA, Duffin R, Kinloch I, et al. Carbon nanotubes introduced into the abdominal cavity of mice show asbestoslike pathogenicity in a pilot study. Nat Nanotechnol. 2008;3(7):423–428. doi:10.1038/nnano.2008.111
   PubMed Web of Science ®Google Scholar
• Moghimi SM. Chemical camouflage of nanospheres with a poorly reactive surface: towards development of stealth and targetspecific nanocarriers. Biochim Biophys Acta. 2002;1590(1–3):131–139. doi:10.1016/S0167-4889(02)00204-5
   PubMedGoogle Scholar
• Ishida T, Kiwada H. Accelerated blood clearance (ABC) phenomenon upon repeated injection of PEGylated liposomes. Int J Pharm. 2008;354(1–2):56–62. doi:10.1016/j.ijpharm.2007.11.005
   PubMed Web of Science ®Google Scholar
• Mitchell LA, Lauer FT, Burchiel SW, McDonald JD. Mechanisms for how inhaled multiwalled carbon nanotubes suppress systemic immune function in mice. Nat Nanotechnol. 2009;4(7):451–456. doi:10.1038/nnano.2009.151
   PubMed Web of Science ®Google Scholar
• Stinchcombe TE, Socinski MA, Walko CM, et al. Phase I and pharmacokinetic trial of carboplatin and albumin-bound paclitaxel, ABI-007 (Abraxane) on three treatment schedules in patients with solid tumors. Cancer Chemother Pharmacol. 2007;60(5):759–766. doi:10.1007/s00280-007-0423-x
   PubMed Web of Science ®Google Scholar
• Higaki M, Ishihara T, Izumo N, Takatsu M, Mizushima Y. Treatment of experimental arthritis with poly(D, L-lactic/glycolic acid) nanoparticles encapsulating betamethasone sodium phosphate. Ann Rheum Dis. 2005;64(8):1132–1136. doi:10.1136/ard.2004.030759
   PubMed Web of Science ®Google Scholar
• Blum JL, Savin MA, Edelman G, et al. Phase II study of weekly albumin-bound paclitaxel for patients with metastatic breast cancer heavily pretreated with taxanes. Clin Breast Cancer. 2007;7(11):850–856. doi:10.3816/CBC.2007.n.049
   PubMed Web of Science ®Google Scholar
• Lafuente A, Gonza´lez-Carracedo A, Romero A, Esquifino AI. Effect ofcadmiumon lymphocyte subsets distribution in thymus and spleen. J Physiol Biochem. 2003;59(1):43–48. doi:10.1007/BF03179867
   PubMedGoogle Scholar
• Szebeni J, Alving CR, Rosivall L. Animal models of complement-mediated hypersensitivity reactions to liposomes and other lipid-based nanoparticles. J Liposome Res. 2007;17(2):107–117. doi:10.1080/08982100701375118
   PubMed Web of Science ®Google Scholar
• Mottram PL, Leong D, Crimeen-Irwin B, et al. Type 1 and 2 immunity following vaccination is influenced by nanoparticle size: formulation of a model vaccine for respiratory syncytial virus. Mol Pharm. 2007;4(1):73–84. doi:10.1021/mp060096p
   PubMedGoogle Scholar
• Nygaard UC, Hansen JS, Samuelsen M, Alberg T, Marioara CD, Løvik M. Single-walled and multi-walled carbon nanotubes promote allergic immune responses in mice. Toxicol Sci. 2009;109(1):113–123. doi:10.1093/toxsci/kfp057
   PubMed Web of Science ®Google Scholar
• Toyama T, Matsuda H, Ishida I, et al. A case of toxic epidermal necrolysis-like dermatitis evolving from contact dermatitis of the hands associated with exposure to dendrimers. Contact Dermatitis. 2008;59(2):122–123. doi:10.1111/j.1600-0536.2008.01340.x
   PubMedGoogle Scholar
• Huang B, Abraham WD, Zheng Y, et al. Active targeting of chemotherapy to disseminated tumors using nanoparticle- carrying Tcells. Sci Transl Med. 2015;7(291):291ra294. doi:10.1126/scitranslmed.aaa5447
   Google Scholar
• Cheung AS, Zhang DKY, Koshy ST, Mooney DJ. Scaffolds that mimic antigen- presenting cells enable ex vivo expansion of primary T cells. Nat Biotechnol. 2018;36(2):160–169. doi:10.1038/nbt.4047
   PubMedGoogle Scholar
• Rebecca VW, Amaravadi RK. Emerging strategies to effectively target autophagy in cancer. Oncogene. 2016;35(1):1–11. doi:10.1038/onc.2015.99
   PubMed Web of Science ®Google Scholar
• Mahalingam D, Mita M, Sarantopoulos J, et al. Combined autophagy and HDAC inhibition: a phase I safety, tolerability, pharmacokinetic, and pharmacodynamic analysis of hydroxychloroquine in combination with the HDAC inhibitor vorinostat in patients with advanced solid tumors. Autophagy. 2014;10(8):1403–1414. doi:10.4161/auto.29231
   PubMed Web of Science ®Google Scholar
• Rangwala R, Chang YC, Hu J, et al. Combined MTOR and autophagy inhibition: phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma. Autophagy. 2014;10(8):1391–1402. doi:10.4161/auto.29119
   PubMed Web of Science ®Google Scholar
• Barnard RA, Wittenburg LA, Amaravadi RK, Gustafson DL, Thorburn A, Thamm DH. Phase I clinical trial and pharmacodynamic evaluation of combination hydroxy-chloroquine and doxorubicin treatment in pet dogs treated for spontaneously occurring lymphoma. Autophagy. 2014;10(8):1415–1425. doi:10.4161/auto.29165
   PubMed Web of Science ®Google Scholar
• Amaravadi RK, Yu D, Lum JJ, et al. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest. 2007;117(2):326–336. doi:10.1172/JCI28833
   PubMed Web of Science ®Google Scholar
• Bray K, Mathew R, Lau A, et al. Autophagy suppresses RIP kinase-dependent necrosis enabling survival to mTOR inhibition. PLoS One. 2012;7(7):e41831. doi:10.1371/journal.pone.0041831
   PubMed Web of Science ®Google Scholar
• Xie X, White EP, Mehnert JM, Fimia GM. Coordinate autophagy and mTOR pathway inhibition enhances cell death in melanoma. PLoS One. 2013;8(1):e55096. doi:10.1371/journal.pone.0055096
   PubMed Web of Science ®Google Scholar
• Wolpin BM, Rubinson DA, Wang X, et al. Phase II and pharmacodynamic study of autophagy inhibition using hydroxychloroquine in patients with metastatic pancreatic adenocarcinoma. Oncologist. 2014;19(6):637–638. doi:10.1634/theoncologist.2014-0086
   PubMed Web of Science ®Google Scholar
• Amaravadi RKWJ, Winkler JD. Lys05: a new lysosomal autophagy inhibitor. Autophagy. 2012;8(9):1383–1384. doi:10.4161/auto.20958
   PubMed Web of Science ®Google Scholar