Novel Strategies for Disrupting Cancer-Cell Functions with Mitochondria-Targeted Antitumor Drug–Loaded Nanoformulations

References

• Chan DC. Fusion and fission: interlinked processes critical for mitochondrial health. Annu Rev Genet. 2012;46:265–287. doi:10.1146/annurev-genet-110410-132529
   PubMed Web of Science ®Google Scholar
• Hoitzing H, Johnston IG, Jones NS. What is the function of mitochondrial networks? A theoretical assessment of hypotheses and proposal for future research. Bioessays. 2015;37(6):687–700. doi:10.1002/bies.201400188
   PubMedGoogle Scholar
• Rai PK, Russell OM, Lightowlers RN, Turnbull DM. Potential compounds for the treatment of mitochondrial disease. Br Med Bull. 2015;116:5–18. doi:10.1093/bmb/ldv046
   PubMed Web of Science ®Google Scholar
• Xia MF, Zhang YZ, Jin K, Lu ZT, Zeng Z, Xiong W. Communication between mitochondria and other organelles: a brand‑new perspective on mitochondria in cancer. Cell Biosci. 2019;9:27. doi:10.1186/s13578-019-0289-8
   PubMedGoogle Scholar
• Gorman GS, Chinnery PF, DiMauro S, et al. Mitochondrial diseases. Nat Rev Dis Primers. 2016;2(1):1–22. doi:10.1038/nrdp.2016.80
   Google Scholar
• Solaini G, Sgarbi G, Baracca A. Oxidative phosphorylation in cancer cells. Biochim Biophys Acta. 2011;1807(6):534–542. doi:10.1016/j.bbabio.2010.09.003
   PubMedGoogle Scholar
• Ahn CS, Metallo CM. Mitochondria as biosynthetic factories for cancer proliferation. Cancer Metab. 2015;3(1):1–10. doi:10.1186/s40170-015-0128-2
   PubMedGoogle Scholar
• Herst P, Berridge M. Plasma membrane electron transport: a new target for cancer drug development. Curr Mol Med. 2006;6:895–904. doi:10.2174/156652406779010777
   PubMedGoogle Scholar
• Vyas S, Zaganjor E, Haigis MC. Mitochondria and cancer. Cell. 2016;166:555–566. doi:10.1016/j.cell.2016.07.002
   PubMed Web of Science ®Google Scholar
• Zong WX, Rabinowitz JD, White E. Mitochondria and cancer. Mol Cell. 2016;61(5):667–676. doi:10.1016/j.molcel.2016.02.011
   PubMed Web of Science ®Google Scholar
• Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol. 1927;8(6):519–530. doi:10.1085/jgp.8.6.519
   PubMedGoogle Scholar
• Reichert AS, Neupert W. Mitochondriomics or what makes us breathe. Trends Genet. 2004;20(11):555–562. doi:10.1016/j.tig.2004.08.012
   PubMedGoogle Scholar
• Wallace DC. Mitochondria and cancer. Nat Rev Cancer. 2012;12(10):685–698. doi:10.1038/nrc3365
   PubMed Web of Science ®Google Scholar
• Hasnat M, Yuan Z, Naveed M, et al. Drp1-associated mitochondrial dysfunction and mitochondrial autophagy: a novel mechanism in triptolide-induced hepatotoxicity. Cell Biol Toxicol. 2019;35:267–280. doi:10.1007/s10565-018-9447-8
   PubMed Web of Science ®Google Scholar
• Cipolat S, de Brito M, Dal Zilio B, Scorrano L. OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc Natl Acad Sci U S A. 2004;101:15927–15932. doi:10.1073/pnas.0407043101
   PubMed Web of Science ®Google Scholar
• Chen H, Chomyn A, Chan DC. Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J Biol Chem. 2005;280:26185–26192. doi:10.1074/jbc.M503062200
   PubMed Web of Science ®Google Scholar
• Guha M, Avadhani NG. Mitochondrial retrograde signaling at the crossroads of tumor bioenergetics, genetics and epigenetics. Mitochondrion. 2013;13:577–591. doi:10.1016/j.mito.2013.08.007
   PubMed Web of Science ®Google Scholar
• Tu C, Zeng Z, Qi P, et al. Identification of genomic alterations in nasopharyngeal carcinoma and nasopharyngeal carcinoma-derived Epstein-Barr virus by whole-genome sequencing. Carcinogenesis. 2018;39:1517–1528. doi:10.1093/carcin/bgy108
   PubMedGoogle Scholar
• Guo C, Sun L, Chen X, Zhang D. Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural Regen Res. 2013;8:2003–2014. doi:10.3969/j.issn.1673-5374.2013.21.009
   PubMed Web of Science ®Google Scholar
• Rigoulet M, Yoboue ED, Devin A. Mitochondrial ROS generation and its regulation: mechanisms involved in H2O2 signaling. Antioxid Redox Signal. 2010;14:459–468. doi:10.1089/ars.2010.3363
   PubMedGoogle Scholar
• Shimizu S, Kanaseki T, Mizushima N, et al. Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nat Cell Biol. 2004;6:1221–1228. doi:10.1038/ncb1192
   PubMed Web of Science ®Google Scholar
• Maiuri MC, Zalckvar E, Kimchi A, et al. Selfeating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol. 2007;8:741–752. doi:10.1038/nrm2239
   PubMed Web of Science ®Google Scholar
• Dewson RM, Kluck RM. Mechanisms by which Bak and Bax permeabilise mitochondria during apoptosis. J Cell Sci. 2009;122:2801–2808. doi:10.1242/jcs.038166
   PubMed Web of Science ®Google Scholar
• Wallace DC. Mitochondrial diseases in man and mouse. Science. 1999;283(5407):1482–1488. doi:10.1126/science.283.5407.1482
   PubMed Web of Science ®Google Scholar
• Kumari S, Badana AK, G MM, et al. Reactive oxygen species: a key constituent in cancer survival. Biomark Insights. 2018;13:1177271918755391. doi:10.1177/1177271918755391
   Web of Science ®Google Scholar
• Galvan DL, Green NH, Danesh FR. The hallmarks of mito-chondrial dysfunction in chronic kidney disease. Kidney Int. 2017;92(5):1051–1057. doi:10.1016/j.kint.2017.05.034
   PubMed Web of Science ®Google Scholar
• Sena LA, Chandel NS. Physiological roles of mitochondrial reactive oxygen species. Mol Cell. 2012;48(2):158–167. doi:10.1016/j.molcel.2012.09.025
   PubMed Web of Science ®Google Scholar
• Arakawa S, Nakanomyo I, Kudo-Sakamoto Y, Akazawa H, Komuro I, Shimizu S. Identification of a novel compound that inhibits both mitochondria-mediated necrosis and apoptosis. Biochem Biophys Res Commun. 2015;467(4):1006–1011. doi:10.1016/j.bbrc.2015.10.022
   PubMedGoogle Scholar
• Shimizu S, Narita M, Tsujimoto Y, Tsujimoto Y. Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochon-drial channel VDAC. Nature. 1999;399(6735):483–487. doi:10.1038/20959
   PubMed Web of Science ®Google Scholar
• Christofferson DE, Yuan J. Necroptosis as an alternative form of programmed cell death. Curr Opin Cell Biol. 2010;22(2):263–268. doi:10.1016/j.ceb.2009.12.003
   PubMed Web of Science ®Google Scholar
• Gaude E, Frezza C. Defects in mitochondrial metabolism and cancer. Cancer Metab. 2014;2:1–9. doi:10.1186/2049-3002-2-10
   PubMedGoogle Scholar
• Muzza M, Colombo C, Cirello V, Perrino M, Vicentini L, Fugazzola L. Oxidative stress and the subcellular localization of the te-lomerase reverse transcriptase (TERT) in papillary thyroid cancer. Mol Cell Endocrinol. 2016;431:54–61. doi:10.1016/j.mce.2016.05.005
   PubMedGoogle Scholar
• Giampazolias E, Tait SW. Mitochondria and the hallmarks of cancer. Fed Eur Biochem Soc J. 2016;283:803–814.
   PubMed Web of Science ®Google Scholar
• Basak NP, Banerjee S. Mitochondrial dependency in progression of acute myeloid leukemia. Mitochondrion. 2015;21:41–48. doi:10.1016/j.mito.2015.01.006
   PubMed Web of Science ®Google Scholar
• Porporato PE, Filigheddu N, Pedro JMB, Kroemer G, Galluzzi L. Mitochondrial metabolism and cancer. Cell Res. 2018;28:265–280. doi:10.1038/cr.2017.155
   PubMed Web of Science ®Google Scholar
• Ashton TM, McKenna WG, Kunz-Schughart LA, Higgins GS. Oxidative phosphorylation as an emerging target in cancer therapy. Clin Cancer Res. 2018;24:2482–2490. doi:10.1158/1078-0432.CCR-17-3070
   PubMed Web of Science ®Google Scholar
• Griguer CE, Oliva CR, Gillespie GY. Glucose metabolism heterogeneity in human and mouse malignant glioma cell lines. J Neuro Oncol. 2005;74:123–133. doi:10.1007/s11060-004-6404-6
   PubMed Web of Science ®Google Scholar
• Guppy M, Leedman P, Zu XL, Russell V. Contribution by dierent fuels and metabolic pathways to the total ATP turnover of proliferating MCF-7 breast cancer cells. Biochem J. 2002;364:309–315. doi:10.1042/bj3640309
   PubMed Web of Science ®Google Scholar
• Hirpara J, Eu JQ, Tan JKM, et al. Metabolic reprogramming of oncogene-addicted cancer cells to OXPHOS as a mechanism of drug resistance. Redox Biol. 2019;25:101076. doi:10.1016/j.redox.2018.101076
   PubMed Web of Science ®Google Scholar
• Eng C, Kiuru M, Fernandez MJ, Aaltonen LA. A role for mitochondrial enzymes in inherited neoplasia and beyond. Nat Rev Cancer. 2003;3:193–202. doi:10.1038/nrc1013
   PubMed Web of Science ®Google Scholar
• Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360:765–773. doi:10.1056/NEJMoa0808710
   PubMed Web of Science ®Google Scholar
• Todisco S, Convertini P, Iacobazzi V, Infantino V. TCA cycle rewiring as emerging metabolic signature of hepatocellular carcinoma. Cancers. 2019;12:68. doi:10.3390/cancers12010068
   PubMed Web of Science ®Google Scholar
• Dekker LJM, Wu S, Jurriens C, et al. Metabolic changes related to the idh1 mutation in gliomas preserve TCA-cycle activity: an investigation at the protein level. Fed Am Soc Exp Biol J. 2020;3646–3657.
   PubMedGoogle Scholar
• Gorrini C, Harris IS, Mak TW. Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov. 2013;12:931–947. doi:10.1038/nrd4002
   PubMed Web of Science ®Google Scholar
• Bezawork-Geleta A, Rohlena J, Dong L, Pacak K, Neuzil J. Mitochondrial complex II: at the crossroads. Trends Biochem Sci. 2017;42:312–325. doi:10.1016/j.tibs.2017.01.003
   PubMed Web of Science ®Google Scholar
• Hecht F, Pessoa CF, Gentile LB, Rosenthal D, Carvalho DP, Fortunato RS. The role of oxidative stress on breast cancer development and therapy. Tumour Biol. 2016;37:4281–4291. doi:10.1007/s13277-016-4873-9
   PubMedGoogle Scholar
• Valko M, Rhodes CJ, Moncol JM, Mazur M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact. 2006;160:1–40.
   PubMed Web of Science ®Google Scholar
• Zhang J, Wang X, Vikash V, et al. ROS and ROS-mediated cellular signaling. Oxidative Med Cell Longev. 2016;2016:4350965. doi:10.1155/2016/4350965
   PubMed Web of Science ®Google Scholar
• Grandemange S, Herzig S, Martinou JC. Mitochondrial dynamics and cancer. Semin Cancer Biol. 2009;19:50–56. doi:10.1016/j.semcancer.2008.12.001
   PubMed Web of Science ®Google Scholar
• Anderson GR, Wardell SE, Cakir M, et al. Dysregulation of mitochondrial dynamics proteins are a targetable feature of human tumors. Nat Commun. 2018;9:1677. doi:10.1038/s41467-018-04033-x
   PubMedGoogle Scholar
• Yu MF, Nguyen ND, Huang YQ, et al. Mitochondrial fusion exploits a therapeutic vulnerability of pancreatic cancer. J Clin Investig Insight. 2019;4:e126915.
   Google Scholar
• Simula L, Nazio F, Campello S. The mitochondrial dynamics in cancer and immune-surveillance. Semin Cancer Biol. 2017;47:29–42. doi:10.1016/j.semcancer.2017.06.007
   PubMedGoogle Scholar
• Tanwar DK, Parker DJ, Gupta P, et al. Crosstalk between the mitochondrial fission protein, Drp1, and the cell cycle is identified across various cancer types and can impact survival of epithelial ovarian cancer patients. Oncotarget. 2016;7:60021–60037. doi:10.18632/oncotarget.11047
   PubMedGoogle Scholar
• Qian W, Choi S, Gibson GA, Watkins SC, Bakkenist CJ, Van Houten B. Mitochondrial hyperfusion induced by loss of the fission protein Drp1 causes atm-dependent g2/m arrest and aneuploidy through DNA replication stress. J Cell Sci. 2012;125:5745–5757. doi:10.1242/jcs.109769
   PubMed Web of Science ®Google Scholar
• Zhao J, Zhang J, Yu M, et al. Mitochondrial dynamics regulates migration and invasion of breast cancer cells. Oncogene. 2013;32:4814–4824. doi:10.1038/onc.2012.494
   PubMed Web of Science ®Google Scholar
• Wan YY, Zhang JF, Yang ZJ, et al. Involvement of Drp1 in hypoxia-induced migration of human glioblastoma u251 cells. Oncol Rep. 2014;32:619–626.
   PubMed Web of Science ®Google Scholar
• Maycotte P, Marin-Hernandez A, Goyri-Aguirre M, Anaya-Ruiz M, Reyes-Leyva J, Cortes-Hernandez P. Mitochondrial dynamics and cancer. Tumour Biol. 2017;39:1010428317698391. doi:10.1177/1010428317698391
   Google Scholar
• Leboucher GP, Tsai YC, Yang M, et al. Stress-induced phosphorylation and proteasomal degradation of Mitofusin 2 facilitates mitochondrial fragmentation and apoptosis. Mol Cell. 2012;47:547–557. doi:10.1016/j.molcel.2012.05.041
   PubMed Web of Science ®Google Scholar
• Gammage PA, Frezza C. Mitochondrial DNA: the overlooked oncogenome? BMC Biol. 2019;17(1). doi:10.1186/s12915-019-0668-y
   PubMedGoogle Scholar
• Jakupciak JP, Maragh S, Markowitz ME, et al. Performance of mitochondrial DNA mutations detecting early stage cancer. BMC Cancer. 2008;8:285. doi:10.1186/1471-2407-8-285
   PubMed Web of Science ®Google Scholar
• Habano W, Nakamura S, Sugai T. Microsatellite instability in the mitochondrial DNA of colorectal carcinomas: evidence for mismatch repair systems in mitochondrial genome. Oncogene. 1998;17(15):1931–1937. doi:10.1038/sj.onc.1202112
   PubMed Web of Science ®Google Scholar
• Mithani SK, Smith IM, Zhou S, et al. Mitochondrial resequencing arrays detect tumor-specific mutations in salivary rinses of patients with head and neck cancer. Clin Cancer Res. 2007;13(24):7335–7340. doi:10.1158/1078-0432.CCR-07-0220
   PubMedGoogle Scholar
• Jones JB, Song JJ, Hempen PM, Parmigiani G, Hruban RH, Kern SE. Detection of mitochondrial DNA mutations in pancreatic cancer offers a “mass”-ive advantage over detection of nuclear DNA mutations. Cancer Res. 2001;61(4):1299–1304.
   PubMed Web of Science ®Google Scholar
• Liu VW, Shi HH, Cheung AN, et al. High incidence of somatic mitochondrial DNA mutations in human ovarian carcinomas. Cancer Res. 2001;61(16):5998–6001.
   PubMed Web of Science ®Google Scholar
• Habano W, Sugai T, Nakamura SI, Uesugi N, Yoshida T, Sasou S. Microsatellite instability and mutation of mitochondrial and nuclear DNA in gastric carcinoma. Gastroenterology. 2000;118(5):835–841. doi:10.1016/S0016-5085(00)70169-7
   PubMed Web of Science ®Google Scholar
• Parrella P, Xiao Y, Fliss M, et al. Detection of mitochondrial DNA mutations in primary breast cancer and fine-needle aspirates. Cancer Res. 2001;61(20):7623–7626.
   PubMed Web of Science ®Google Scholar
• Moraes CT, DiMauro S, Zeviani M, et al. Mitochondrial DNA deletions in progressive external ophthalmoplegian and Kearns-Sayre syndrome. N Engl J Med. 1989;320(20):1293–1299. doi:10.1056/NEJM198905183202001
   PubMed Web of Science ®Google Scholar
• Errichiello E, Venesio T. Mitochondrial DNA variations in tumors: drivers or passengers? Mitochondrial DNA New Insights. 2018.
   Google Scholar
• Zhang L. Heme Biology: Heme Acts as a Versatile Signaling Molecule Regulating Diverse Biological Processes. 2nd ed. Hackensack, NJ, USA: World scientific; 2020:1–6.
   Google Scholar
• Hooda J, Cadinu D, Alam MM, et al. Enhanced heme function and mitochondrial respiration promote the progression of lung cancer cells. PLoS One. 2013;8(5):e63402. doi:10.1371/journal.pone.0063402
   PubMed Web of Science ®Google Scholar
• Hooda J, Shah A, Zhang L. Heme, an essential nutrient from dietary proteins, critically impacts diverse physiological and pathological processes. Nutrients. 2014;6:1080–1102. doi:10.3390/nu6031080
   PubMed Web of Science ®Google Scholar
• Dong L, Neuzil J. Targeting mitochondria as an anticancer strategy. Cancer Commun (Lond Engl). 2019;39:63. doi:10.1186/s40880-019-0412-6
   PubMedGoogle Scholar
• Rohlenova K, Sachaphibulkij K, Stursa J, et al. Selective disruption of respiratory supercomplexes as a new strategy to suppress her2high breast cancer. Antioxid Redox Signal. 2017;26:84–103. doi:10.1089/ars.2016.6677
   PubMedGoogle Scholar
• Dong LF, Jameson VJ, Tilly D, et al. Mitochondrial targeting of alpha-tocopheryl succinate enhances its pro-apoptotic ecacy: a new paradigm for eective cancer therapy. Free Radic Biol Med. 2011;50:1546–1555. doi:10.1016/j.freeradbiomed.2011.02.032
   PubMed Web of Science ®Google Scholar
• Huang Q, Chen Z, Cheng P, et al. LYRM2 directly regulates complex I activity to support tumor growth in colorectal cancer by oxidative phosphorylation. Cancer Lett. 2019;455:36–47. doi:10.1016/j.canlet.2019.04.021
   PubMedGoogle Scholar
• Lim SC, Carey KT, McKenzie M. Anti-cancer analogues me-143 and me-344 exert toxicity by directly inhibiting mitochondrial NADH: ubiquinone oxidoreductase (complex I). Am J Cancer Res. 2015;5:689–701.
   PubMed Web of Science ®Google Scholar
• DeBerardinis RJ, Mancuso A, Daikhin E, et al. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci USA. 2007;104:19345–19350. doi:10.1073/pnas.0709747104
   PubMed Web of Science ®Google Scholar
• Yen K, Travins J, Wang F, et al. Ag-221, a first-in-class therapy targeting acute myeloid leukemia harboring oncogenic IDH2 mutations. Cancer Discov. 2017;7:478–493. doi:10.1158/2159-8290.CD-16-1034
   PubMed Web of Science ®Google Scholar
• Luengo A, Gui DY, Vander Heiden MG. Targeting metabolism for cancer therapy. Cell Chem Biol. 2017;24:1161–1180.
   PubMed Web of Science ®Google Scholar
• Anderson NM, Mucka P, Kern JG, Feng H. The emerging role and targetability of the TCA cycle in cancer metabolism. Protein Cell. 2018;9:216–237. doi:10.1007/s13238-017-0451-1
   PubMed Web of Science ®Google Scholar
• Han H, Jain AD, Truica MI, et al. Small-molecule MYC inhibitors suppress tumor growth and enhance immunotherapy. Cancer Cell. 2019;36:483–497.e15. doi:10.1016/j.ccell.2019.10.001
   PubMed Web of Science ®Google Scholar
• O’Dwyer PJ, Alonso MT, Leyland-Jones B. Acivicin: a new glutamine antagonist in clinical trials. J Clin Oncol. 1984;2:1064–1071. doi:10.1200/JCO.1984.2.9.1064
   PubMedGoogle Scholar
• Senft D, Ronai ZA. Regulators of mitochondrial dynamics in cancer. Curr Opin Cell Biol. 2016;39:43–52. doi:10.1016/j.ceb.2016.02.001
   PubMed Web of Science ®Google Scholar
• Peiris-Pages M, Bonuccelli G, Sotgia F, Lisanti MP. Mitochondrial fission as a driver of stemness in tumor cells: mDIVI1 inhibits mitochondrial function, cell migration and cancer stem cell (csc) signalling. Oncotarget. 2018;9:13254–13275. doi:10.18632/oncotarget.24285
   PubMedGoogle Scholar
• Pan L, Zhou L, Yin W, Bai J, Liu R. miR-125a induces apoptosis, metabolism disorder and migration impairment in pancreatic cancer cells by targeting Mfn2-related mitochondrial fission. Int J Oncol. 2018;53:124–136. doi:10.3892/ijo.2018.4380
   PubMed Web of Science ®Google Scholar
• Pan L, Zhou L, Yin W, Bai J, Liu R, Pan L. LATS2 promotes apoptosis in non-small cell lung cancer A549 cells via triggering m-dependent mitochondrial fission and activating the JNK signaling pathway. Biomed Pharmacother. 2019;109:679–689. doi:10.1016/j.biopha.2018.10.097
   PubMedGoogle Scholar
• Tang H, Peng S, Dong Y, et al. MARCH5 overexpression contributes to tumor growth and metastasis and associates with poor survival in breast cancer. Cancer Manag Res. 2019;11:201–215. doi:10.2147/CMAR.S190694
   PubMed Web of Science ®Google Scholar
• Zhang X, Han S, Zhou H, et al. TIMM50 promotes tumor progression via ERK signaling and predicts poor prognosis of non-small cell lung cancer patients. Mol Carcinog. 2019;58:767–776. doi:10.1002/mc.22969
   PubMedGoogle Scholar
• Liu D, Angelova A, Liu J, et al. Self-assembly of mitochondria-specific peptide amphiphiles amplifying lung cancer cell death through targeting the VDAC1-hexokinase-II complex. J Mater Chem B. 2019;7:4706–4716. doi:10.1039/C9TB00629J
   PubMed Web of Science ®Google Scholar
• Hu W, Tian H, Yue W, et al. Rotenone induces apoptosis in human lung cancer cells by regulating autophagic flux. IUBMB Life. 2016;68:388–393. doi:10.1002/iub.1493
   PubMed Web of Science ®Google Scholar
• DeWaal D, Nogueira V, Terry AR, et al. Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin. Nat Commun. 2018;9:446; Correction in 2018, 9, 2539.
   Google Scholar
• Nath K, Guo L, Nancolas B, et al. Mechanism of antineoplastic activity of lonidamine. Biochim Biophys Acta. 2016;1866:151–162. doi:10.1016/j.bbcan.2016.08.001
   PubMed Web of Science ®Google Scholar
• Hocsak E, Szabo V, Kalman N, et al. PARP inhibition protects mitochondria and reduces ROS production via PARP-1-ATF4-MKP-1-MAPK retrograde pathway. Free Radic Biol Med. 2017;108:770–784. doi:10.1016/j.freeradbiomed.2017.04.018
   PubMed Web of Science ®Google Scholar
• Ren YJ, Wang XH, Ji C, et al. Silencing of NAC1 expression induces cancer cells oxidative stress in hypoxia and potentiates the therapeutic activity of elesclomol. Front Pharm. 2017;8:804. doi:10.3389/fphar.2017.00804
   PubMedGoogle Scholar
• Pignanelli C, Ma D, Noel M, et al. Selective targeting of cancer cells by oxidative vulnerabilities with novel curcumin analogs. Sci Rep. 2017;7:1105. doi:10.1038/s41598-017-01230-4
   PubMed Web of Science ®Google Scholar
• Kuo ML, Lee MB, Tang M, et al. PYCR1 and PYCR2 interact and collaborate with RRM2B to protect cells from overt oxidative stress. Sci Rep. 2016;6:18846. doi:10.1038/srep18846
   PubMedGoogle Scholar
• Queiroz EA, Puukila S, Eichler R, et al. Metformin induces apoptosis and cell cycle arrest mediated by oxidative stress, AMPK and FOXO3a in MCF-7 breast cancer cells. PLoS One. 2014;9:e98207. doi:10.1371/journal.pone.0098207
   PubMed Web of Science ®Google Scholar
• Sassi N, Mattarei A, Azzolini M, et al. Mitochondria-targeted resveratrol derivatives act as cytotoxic pro-oxidants. Curr Pharm Des. 2014;20:172–179. doi:10.2174/13816128113199990034
   PubMed Web of Science ®Google Scholar
• Zhang C, Liu Z, Bunker E, et al. Sorafenib targets the mitochondrial electron transport chain complexes and ATP synthase to activate the PINK1-Parkin pathway and modulate cellular drug response. J Biol Chem. 2017;292:15105–15120. doi:10.1074/jbc.M117.783175
   PubMed Web of Science ®Google Scholar
• Mou J, Lin T, Huang F, Shi J, Chen H. A new green titania with enhanced NIR absorption for mitochondria-targeted cancer therapy. Theranostics. 2017;7:1531–1542. doi:10.7150/thno.17247
   PubMedGoogle Scholar
• Belzacq AS, El Hamel C, Vieira HL, et al. Adenine nucleotide translocator mediates the mitochondrial membrane permeabilization induced by lonidamine, arsenite and CD437. Oncogene. 2001;20:7579–7587. doi:10.1038/sj.onc.1204953
   PubMed Web of Science ®Google Scholar
• Jan CI, Tsai MH, Chiu CF, Huang YP, Liu CJ, Chang NW. Fenofibrate suppresses oral tumorigenesis via reprogramming metabolic processes: potential drug repurposing for oral cancer. Int J Biol Sci. 2016;12:786–798. doi:10.7150/ijbs.13851
   PubMedGoogle Scholar
• Shteinfer-Kuzmine A, Amsalem Z, Arif T, Zooravlov A, Shoshan-Barmatz V. Selective induction of cancer cell death by VDAC1-based peptides and their potential use in cancer therapy. Mol Oncol. 2018;12:1077–1103. doi:10.1002/1878-0261.12313
   PubMedGoogle Scholar
• Kadavakollu S, Stailey C, Kunapareddy CS, White S. Clotrimazole as a cancer drug: a short review. Med Chem. 2014;4:722–724.
   Google Scholar
• Bromberg JF, Wrzeszczynska MH, Devgan G, et al. Stat3 as an oncogene. Cell. 1999;98:295–303. doi:10.1016/S0092-8674(00)81959-5
   PubMed Web of Science ®Google Scholar
• Fichera GA, Fichera M, Milone G. Antitumoural activity of a cytotoxic peptide of Lactobacillus casei peptidoglycan and its interaction with mitochondrial-bound hexokinase. Anti Cancer Drugs. 2016;27:609–619. doi:10.1097/CAD.0000000000000367
   PubMedGoogle Scholar
• Li W, Zheng M, Wu S, et al. Benserazide, a dopadecarboxylase inhibitor, suppresses tumor growth by targeting hexokinase 2. J Exp Clin Cancer Res. 2017;36:58. doi:10.1186/s13046-017-0530-4
   PubMedGoogle Scholar
• Sun X, Zhang L. MicroRNA-143 suppresses oral squamous cell carcinoma cell growth, invasion and glucose metabolism through targeting hexokinase 2. Biosci Rep. 2017;37:BSR20160404. doi:10.1042/BSR20160404
   PubMed Web of Science ®Google Scholar
• Lu P, Bruno BJ, Rabenau M, Lim CS. Delivery of drugs and macromolecules to the mitochondria for cancer therapy. J Control Release. 2016;240:38–51. doi:10.1016/j.jconrel.2015.10.023
   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;102315.
   Google Scholar
• Dairkee SH, Hackett AJ. Differentialretentionofrhodamine123by breast carcinoma and normal human mammary tissue. Breast Cancer Res Treat. 1991;18:57–61. doi:10.1007/BF01975444
   PubMed Web of Science ®Google Scholar
• Cortes LA, Castro L, Pesce B, et al. Novel gallate triphenylphosphonium derivatives with potent antichagasic activity. PLoS One. 2015;10:e0136852. doi:10.1371/journal.pone.0136852
   PubMed Web of Science ®Google Scholar
• Wang H, Xu W. Mito-methyl coumarin, a novel mitochondria-targeted drug with great antitumor potential was synthesized. Biochem Biophys Res Commun. 2017;489:1–7. doi:10.1016/j.bbrc.2017.05.116
   PubMedGoogle Scholar
• Zielonka J, Joseph J, Sikora A, et al. Mitochondria-targeted triphenylphosphonium-based compounds: syntheses, mechanisms of action, and therapeutic and diagnostic applications. Chem Rev. 2017;117(15):10043–10120. doi:10.1021/acs.chemrev.7b00042
   PubMed Web of Science ®Google Scholar
• Millard M, Gallagher JD, Olenyuk BZ, Neamati N. A selective mitochondrial-targeted chlorambucil with remarkable cytotoxicity in breast and pancreatic cancers. J Med Chem. 2013;56:9170–9179. doi:10.1021/jm4012438
   PubMed Web of Science ®Google Scholar
• Christman JE, Miller DS, Coward P, Smith LH, Teng NN. Study of the selective cytotoxic properties of cationic, lipophilic mitochondrial-specific compounds in gynecologic malignancies. Gynecol Oncol. 1990;39:72–79. doi:10.1016/0090-8258(90)90402-7
   PubMedGoogle Scholar
• Weissig V, Lasch J, Erdos G, Meyer HW, Rowe TC, Hughes J. DQAsomes: a novel potential drug and gene delivery system made from dequalinium TM. Pharm Res. 1998;15:334–337. doi:10.1023/A:1011991307631
   PubMed Web of Science ®Google Scholar
• Song YF, Liu DZ, Cheng Y, et al. Dual subcellular compartment delivery of doxorubicin to overcome drug resistant and enhance antitumor activity. Sci Rep. 2015;5:16125. doi:10.1038/srep16125
   PubMed Web of Science ®Google Scholar
• He H, Li DW, Yang LY, et al. A novel bifunctional mitochondria-targeted anticancer agent with high selectivity for cancer cells. Sci Rep. 2015;5:13543. doi:10.1038/srep13543
   PubMed Web of Science ®Google Scholar
• Horton KL, Stewart KM, Fonseca SB, Guo Q, Kelley SO. Mitochondria-penetrating peptides. Chem Biol. 2008;15:375–382. doi:10.1016/j.chembiol.2008.03.015
   PubMed Web of Science ®Google Scholar
• Szeto HH. Mitochondria-targeted cytoprotective peptides for ischemia-reperfusion injury. Antioxid Redox Signal. 2008;10:601–619. doi:10.1089/ars.2007.1892
   PubMed Web of Science ®Google Scholar
• Szeto HH, Birk AV. Serendipity and the discovery of novel compounds that restore mitochondrial plasticity. Clin Pharmacol Ther. 2014;96(6):672–683. doi:10.1038/clpt.2014.174
   PubMed Web of Science ®Google Scholar
• Jiang L, Li L, He X, et al. Overcoming drug-resistant lung cancer by paclitaxel loaded dual-functional liposomes with mitochondria targeting and pH-response. Biomaterials. 2015;52:126–139. doi:10.1016/j.biomaterials.2015.02.004
   PubMed Web of Science ®Google Scholar
• Li L, Geisler I, Chmielewski J, et al. Cationic amphiphilic polyproline helix P11LRR targets intracellular mitochondria. J Control Release. 2010;142(2):259–266. doi:10.1016/j.jconrel.2009.10.012
   PubMedGoogle Scholar
• Sibrian-Vazquez M, Nesterova IV, Jensen TJ, Vicente MGH. Mitochondria targeting by guanidine-and biguanidine-porphyrin photosensitizers. Bioconjug Chem. 2008;19:705–713. doi:10.1021/bc700393u
   PubMed Web of Science ®Google Scholar
• Battogtokh G, Choi YS, Kang DS, et al. Mitochondria-targeting drug conjugates for cytotoxic, anti-oxidizing and sensing purposes: current strategies and future perspectives. Acta Pharmaceutica Sinica B. 2018;8(6):862–880. doi:10.1016/j.apsb.2018.05.006
   PubMed Web of Science ®Google Scholar
• Luengo A, Sullivan LB, Vander Heiden MG. Understanding the complex-I-ty of metformin action: limiting mitochondrial respiration to improve cancer therapy. BMC Biol. 2014;12(1):1–4. doi:10.1186/s12915-014-0082-4
   PubMedGoogle Scholar
• Fantin VR, Berardi MJ, Scorrano L, Korsmeyer SJ, Leder P. A novel mitochondrio-toxic small molecule that selectively inhibits tumor cell growth. Cancer Cell. 2002;2:29–42. doi:10.1016/S1535-6108(02)00082-X
   PubMed Web of Science ®Google Scholar
• Tee TT, Cheah YH, Hawariah LPA. F16, a fraction from Eurycoma longifolia jack extract, induces apoptosis via a caspase-9-independent manner in MCF-7 cells. Anticancer Res. 2007;27(5A):3425–3430.
   PubMed Web of Science ®Google Scholar
• Lampidis TJ, Hasin Y, Weiss MJ, Chen LB. Selective killing of carcinoma cells “in vitro” bylipophilic-cationic compounds: a cellular basis. Biomed Pharmacother. 1985;39:220–226.
   PubMed Web of Science ®Google Scholar
• Baracca A, Sgarbi G, Solaini G, Lenaz G. Rhodamine 123 as a probe of mitochondrial membrane potential: evaluation of proton flux through F(0) during ATP synthesis. Biochim Biophys Acta. 2003;1606:137–146. doi:10.1016/S0005-2728(03)00110-5
   PubMed Web of Science ®Google Scholar
• Antonenko YN, Avetisyan AV, Cherepanov DA, et al. Derivatives of rhodamine 19 as mild mitochondria-targeted cationic uncouplers. J Biol Chem. 2011;286:17831–17840. doi:10.1074/jbc.M110.212837
   PubMed Web of Science ®Google Scholar
• Antonenko YN, Avetisyan AV, Bakeeva LE, et al. Mitochondria-targeted plastoquinone derivatives a stools to interrupt execution of the aging program.1. Cationic plastoquinone derivatives: synthesis and in vitro studies. Biochem (Mosc). 2008;73:1273–1287. doi:10.1134/S0006297908120018
   PubMed Web of Science ®Google Scholar
• Han M, Vakili MR, Soleymani Abyaneh H, Molavi O, Lai R, Lavasanifar A. Mitochondrial delivery of doxorubicin via triphenylphosphine modification for overcoming drug resistance in MDA-MB-435/DOX cells. Mol Pharm. 2014;11:2640–2649. doi:10.1021/mp500038g
   PubMed Web of Science ®Google Scholar
• Wu S, Cao Q, Wang X, Cheng K, Cheng Z. Design, synthesis and biological evaluation of mitochondria targeting theranostic agents. Chem Commun (Camb). 2014a;50:8919–8922. doi:10.1039/C4CC03296A
   PubMed Web of Science ®Google Scholar
• Hu QL, Gao M, Feng GX, Liu B. Mitochondria-targeted cancer therapy using a light-up probe with aggregation-induced-emission characteristics. Angew Chem Int Edt. 2014;53:14225–14229. doi:10.1002/anie.201408897
   PubMed Web of Science ®Google Scholar
• Chen WH, Xu XD, Luo GF, et al. Dual-targeting pro-apoptotic peptide for programmed cancer cell death via specific mitochondria damage. Sci Rep. 2013;3:3468. doi:10.1038/srep03468
   PubMed Web of Science ®Google Scholar
• Lei W, Xie J, Hou Y, et al. Mitochondriatargeting properties and photodynamic activities of porphyrin derivatives bearing cationic pendant. J Photochem Photobiol B. 2010;98:167–171. doi:10.1016/j.jphotobiol.2009.12.003
   PubMedGoogle Scholar
• Chamberlain GR, Tulumello DV, Kelley SO. Targeted delivery of doxorubicin to mitochondria. ACS Chem Biol. 2013;8:1389–1395. doi:10.1021/cb400095v
   PubMed Web of Science ®Google Scholar
• Fonseca SB, Pereira MP, Mourtada R, et al. Rerouting chlorambucil to mitochondria combats drug deactivation and resistance in cancer cells. Chem Biol. 2011;18:445–453. doi:10.1016/j.chembiol.2011.02.010
   PubMed Web of Science ®Google Scholar
• Wisnovsky SP, Wilson JJ, Radford RJ, et al. Targeting mitochondrial DNA with a platinum-based anticancer agent. Chem Biol. 2013;20:1323–1328. doi:10.1016/j.chembiol.2013.08.010
   PubMedGoogle Scholar
• Agemy L, Friedmann-Morvinski D, Kotamraju VR, et al. Targeted nanoparticle enhanced proapoptotic peptide as potential therapy for glioblastoma. Proc Natl Acad Sci USA. 2011;108:17450–17455. doi:10.1073/pnas.1114518108
   PubMed Web of Science ®Google Scholar
• Zhang S, Yang L, Ling X, et al. Tumor mitochondria-targeted photodynamic therapy with a translocator protein (TSPO)-specific photosensitizer. Acta Biomater. 2015;28:160–170. doi:10.1016/j.actbio.2015.09.033
   PubMedGoogle Scholar
• Li J, Lu J, Zhou Y. Mitochondrial-targeted molecular imaging in cardiac disease. BioMed Res Int. 2017;2017.
   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
• Wongrakpanich A, Geary SM, Joiner ML, Anderson ME, Salem AK. Mitochondria-targeting particles. Nanomedicine. 2014;9(16):2531–2543. doi:10.2217/nnm.14.161
   PubMed Web of Science ®Google Scholar
• Pathak RK, Kolishetti N, Dhar S. Targeted nanoparticles in mitochondrial medicine. Wiley Interdisciplin Rev. 2015;7(3):315–329.
   Google Scholar
• Liu CG, Han YH, Kankala RK, Wang SB, Chen AZ. Subcellular performance of nanoparticles in cancer therapy. Int J Nanomed. 2020;15:675. doi:10.2147/IJN.S226186
   PubMed Web of Science ®Google Scholar
• Oladimeji O, Akinyelu J, Singh M. Nanomedicines for subcellular targeting: the mitochondrial perspective. Curr Med Chem. 2020;27(33):5480–5509. doi:10.2174/0929867326666191125092111
   PubMed Web of Science ®Google Scholar
• Zhang S, Li J, Lykotrafitis G, Bao G, Suresh S. Sizedependent endocytosis of nanoparticles. Adv Mater. 2009;21:419–424. doi:10.1002/adma.200801393
   PubMed Web of Science ®Google Scholar
• Lu F, Wu SH, Hung Y, Mou CY. Size effect on cell uptake in well-suspended, uniform mesoporous silica nanoparticles. Small. 2009;5:1408–1413. doi:10.1002/smll.200900005
   PubMed Web of Science ®Google Scholar
• Jiang W, Kim BYS, Rutka JT, Chan WCW. Nanoparticle mediated cellular response is size-dependent. Nat Nanotechnol. 2008;3:145–150. doi:10.1038/nnano.2008.30
   PubMed Web of Science ®Google Scholar
• Khan AA, Allemailem KS, Almatroodi SA, Almatroudi A, Rahmani AH. Recent strategies towards the surface modification of liposomes: an innovative approach for different clinical applications. 3 Biotech. 2020c;10(4):1–15. doi:10.1007/s13205-020-2144-3
   PubMedGoogle Scholar
• Guo F, Yu M, Wang J, et al. The mitochondria-targeted and IR780-regulated theranosomes for imaging and enhanced photodynamic/photothermal therapy. RSC Adv. 2016;6(14):11070–11076. doi:10.1039/C5RA19521G
   Web of Science ®Google Scholar
• Boddapati SV, D’Souza GG, Erdogan S, et al. Organelle- targeted nanocarriers: specific delivery of liposomal ceramide to mitochondria enhances its cytotoxicity in vitro and in vivo. Nano Lett. 2008;8(8):2559–2563. doi:10.1021/nl801908y
   PubMed Web of Science ®Google Scholar
• Katagiri K, Ariga K, Kikuchi J-I. Preparation of organic- inorganic hybrid vesicle “cerasome” derived from artificial lipid with alkoxysilyl head. Chem Lett. 1999;28(7):661–662. doi:10.1246/cl.1999.661
   Google Scholar
• Wang Y, Wang B, Liao H, et al. Liposomal nanohybrid cerasomes for mitochondria-targeted drug delivery. J Mater Chem B. 2015;3(36):7291–7299. doi:10.1039/C5TB01197C
   PubMedGoogle Scholar
• Yamada Y, Akita H, Kamiya H, et al. MITO-Porter: a liposome-based carrier system for delivery of macromolecules into mitochondria via membrane fusion. Biochim Biophys Acta. 2008;1778(2):423–432. doi:10.1016/j.bbamem.2007.11.002
   PubMed Web of Science ®Google Scholar
• Yamada Y, Nakamura K, Abe J, et al. Mitochondrial delivery of Coenzyme Q10 via systemic administration using a MITO-Porter prevents ischemia/reperfusion injury in the mouse liver. J Control Release. 2015;213:86–95. doi:10.1016/j.jconrel.2015.06.037
   PubMed Web of Science ®Google Scholar
• Khalil IA, Kogure K, Futaki S, et al. High density of octaarginine stimulates macropinocytosis leading to efficient intracellular trafficking for gene expression. J Biol Chem. 2006;281(6):3544–3551. doi:10.1074/jbc.M503202200
   PubMed Web of Science ®Google Scholar
• Yasuzaki Y, Yamada Y, Harashima H. Mitochondrial matrix delivery using MITO-Porter, a liposome-based carrier that specifies fusion with mitochondrial membranes. Biochem Biophys Res Commun. 2010;397(2):181–186. doi:10.1016/j.bbrc.2010.05.070
   PubMed Web of Science ®Google Scholar
• Yamada Y, Furukawa R, Yasuzaki Y, et al. Dual function MITO-Porter, a nano carrier integrating both efficient cytoplasmic delivery and mitochondrial macromolecule delivery. Mol Ther. 2011;19(8):1449–1456. doi:10.1038/mt.2011.99
   PubMed Web of Science ®Google Scholar
• Yamada Y, Harashima H. Delivery of bioactive molecules to the mitochondrial genome using a membrane-fusing, liposome-based carrier, DF-MITO-Porter. Biomaterials. 2012;33(5):1589–1595. doi:10.1016/j.biomaterials.2011.10.082
   PubMed Web of Science ®Google Scholar
• Yamada Y, Harashima H. Enhancement in selective mitochondrial association by direct modification of a mitochondrial targeting signal peptide on a liposomal based nanocarrier. Mitochondrion. 2013;13(5):526–532. doi:10.1016/j.mito.2012.09.001
   PubMed Web of Science ®Google Scholar
• Kawamura E, Yamada Y, Harashima H. Mitochondrial targeting functional peptides as potential devices for the mitochondrial delivery of a DF-MITO-Porter. Mitochondrion. 2013;13(6):610–614. doi:10.1016/j.mito.2013.08.010
   PubMedGoogle Scholar
• Wang Z, Guo W, Kuang X, Hou S, Liu H. Nanopreparations for mitochondria targeting drug delivery system: current strategies and future prospective. Asian J Pharm Sci. 2017;12(6):498–508. doi:10.1016/j.ajps.2017.05.006
   PubMedGoogle Scholar
• Garcia-Perez EG, Sancho P, Sancho P, Sancho P. Dequalinium induces human leukemia cell death by affecting the redox balance. Leuk Res. 2011;35:1395–1401. doi:10.1016/j.leukres.2011.03.012
   PubMedGoogle Scholar
• Zupancic S, Kocbek P, Zariwala MG, et al. Design and development of novel mitochondrial targeted nanocarriers, DQAsomes for curcumin inhalation. Mol Pharm. 2014;11(7):2334–2345. doi:10.1021/mp500003q
   PubMedGoogle Scholar
• D’Souza GGM, Rammohan R, Cheng S-M, et al. DQAsome mediated delivery of plasmid DNA toward mitochondria in living cells. J Control Release. 2003;92(1–2):189–197. doi:10.1016/S0168-3659(03)00297-9
   PubMed Web of Science ®Google Scholar
• Vaidya B, Paliwal R, Rai S, et al. Cell-selective mitochondrial targeting: a new approach for cancer therapy. Cancer Ther. 2009;7:141–148.
   Google Scholar
• D’Souza GG, Boddapati SV, Weissig V. Mitochondrial leader sequence–plasmid DNA conjugates delivered into mammalian cells by DQAsomes co-localize with mitochondria. Mitochondrion. 2005;5(5):352–358. doi:10.1016/j.mito.2005.07.001
   PubMed Web of Science ®Google Scholar
• Weissig V, Lizano C, Torchilin VP. Selective DNA release from DQAsome/DNA complexes at mitochondria-like membranes. Drug Deliv. 2000;7(1):1–5. doi:10.1080/107175400266722
   PubMed Web of Science ®Google Scholar
• Kamaly N, Xiao Z, Valencia PM, et al. Targeted polymeric therapeutic nanoparticles: design, development and clinical translation. Chem Soc Rev. 2012;41(7):2971–3010.
   PubMed Web of Science ®Google Scholar
• Mulik RS, Monkkonen J, Juvonen RO, et al. ApoE3 mediated polymeric nanoparticles containing curcumin: apoptosis induced in vitro anticancer activity against neuroblastoma cells. Int J Pharm. 2012;437(1–2):29–41. doi:10.1016/j.ijpharm.2012.07.062
   PubMed Web of Science ®Google Scholar
• Marrache S, Dhar S. Engineering of blended nanoparticle platform for delivery of mitochondria-acting therapeutics. Proc Natl Acad Sci USA. 2012;109:16288–16293. doi:10.1073/pnas.1210096109
   PubMed Web of Science ®Google Scholar
• Yue C, Yang Y, Zhang C, et al. ROS-responsive mitochondria targeting blended nanoparticles: chemo- and photodynamic synergistic therapy for lung cancer with on-demand drug release upon irradiation with a single light source. Theranostics. 2016;6(13):2352–2366. doi:10.7150/thno.15433
   PubMedGoogle Scholar
• Hou J, Yu X, Shen Y, et al. Triphenyl phosphine functionalized chitosan nanoparticles enhanced antitumor efficiency through targeted delivery of doxorubicin to mitochondria. Nanoscale Res Lett. 2017;12(1):158. doi:10.1186/s11671-017-1931-1
   PubMedGoogle Scholar
• Khatun Z, Choi YS, Kim YG, et al. A bioreducible poly(ethylene glycol)-triphenylphosphonium conjugate as a bioactivable mitochondria-targeting nano-carrier. Biomacromolecules. 2017;18(4):1074–1085. doi:10.1021/acs.biomac.6b01324
   PubMedGoogle Scholar
• Mignani S, El Brahmi N, Eloy L, et al. Anticancer copper(II) phosphorus dendrimers are potent proapoptotic Bax activators. Eur J Med Chem. 2017;132:142–156. doi:10.1016/j.ejmech.2017.03.035
   PubMed Web of Science ®Google Scholar
• Lopez-Lazaro M. How many times should we screen a chemical library to discover an anticancer drug? Drug Discov Today. 2015;20:167–169. doi:10.1016/j.drudis.2014.12.006
   PubMedGoogle Scholar
• Gorzkiewicz M, Klajnert-Maculewicz B. Dendrimers as nanocarriers for nucleoside analogues. Eur J Pharm Biopharm. 2017;114:43–56. doi:10.1016/j.ejpb.2016.12.030
   PubMed Web of Science ®Google Scholar
• Franiak-Pietryga I, Ziemba B, Sikorska H, et al. Maltotriose-modified poly (propylene imine) Glycodendrimers as a potential novel platform in the treatment of chronic lymphocytic Leukemia. A proof-of-concept pilot study in the animal model of CLL. Toxicol Appl Pharmacol. 2020;403:115139. doi:10.1016/j.taap.2020.115139
   PubMed Web of Science ®Google Scholar
• Tomalia DA, Reyna LA, Svenson S. Dendrimers as multi-purpose nanodevices for oncology drug delivery and diagnostic imaging. Biochem Soc Trans. 2007;35:61–67. doi:10.1042/BST0350061
   PubMed Web of Science ®Google Scholar
• Shao N, Su Y, Hu J, Zhang J, Zhang H, Cheng Y. Comparison of generation 3 polyamidoamine dendrimer and generation 4 polypropylenimine dendrimer on drug loading, complex structure, release behavior, and cytotoxicity. Int J Nanomed. 2011;6:3361–3372. doi:10.2147/IJN.S27028
   PubMed Web of Science ®Google Scholar
• Pedziwiatr-Werbicka E, Ferenc M, Zaborski M, Gabara B, Klajnert B, Bryszewska M. Characterization of complexes formed by polypropylene imine dendrimers and anti-HIV oligonucleotides. Colloids Surf B Biointerfaces. 2011;83:360–366. doi:10.1016/j.colsurfb.2010.12.008
   PubMed Web of Science ®Google Scholar
• Bumb A, Brechbiel MW, Choyke P. Macromolecular and dendrimer-based magnetic resonance contrast agents. Acta Radiol. 2010;51:751–767. doi:10.3109/02841851.2010.491091
   PubMed Web of Science ®Google Scholar
• Franiak-Pietryga I, Ziolkowska E, Ziemba B, et al. Glycodendrimer PPI as a potential drug in chronic lymphocytic leukaemia. The influence of glycodendrimer on apoptosis in in vitro B-CLL cells defined by microarrays. Anti Cancer Agents Med Chem. 2017;17(1):102–114.
   PubMed Web of Science ®Google Scholar
• Mukherjee SP, Lyng FM, Garcia A, Davoren M, Byrne HJ. Mechanistic studies of in vitro cytotoxicity of poly(amidoamine) dendrimers in mammalian cells. Toxicol Appl Pharmacol. 2010;248:259–268. doi:10.1016/j.taap.2010.08.016
   PubMed Web of Science ®Google Scholar
• Franiak-Pietryga I, Ziółkowska E, Ziemba B, et al. The influence of maltotriose-modified poly (propylene imine) dendrimers on the chronic lymphocytic leukemia cells in vitro: dense shell G4 PPI. Mol Pharm. 2013;10(6):2490–2501. doi:10.1021/mp400142p
   PubMed Web of Science ®Google Scholar
• Kubeil M, Stephan H, Pietzsch H-J, et al. Sugar-decorated dendritic nanocarriers: encapsulation and release of the octahedral rhenium cluster complex [Re6S8(OH)6]4−. Chem Asian J. 2010;5:2507–2514. doi:10.1002/asia.201000284
   PubMed Web of Science ®Google Scholar
• Xiong Z, Shen M, Shi X. Dendrimer-based strategies for cancer therapy: recent advances and future perspectives. Sci China Mater. 2018;61(11):1387–1403. doi:10.1007/s40843-018-9271-4
   Google Scholar
• Choi YS, Cho TS, Kim JM, Han SW, Kim SK. Amine terminated G-6 PAMAM dendrimer and its interaction with DNA probed by Hoechst 33258. Biophys Chem. 2006;121:142–149. doi:10.1016/j.bpc.2006.01.005
   PubMed Web of Science ®Google Scholar
• Biswas S, Dodwadkar NS, Piroyan A, Torchilin VP. Surface conjugation of triphenylphosphonium to target poly(amidoamine) dendrimers to mitochondria. Biomaterials. 2012;33:4773–4782. doi:10.1016/j.biomaterials.2012.03.032
   PubMed Web of Science ®Google Scholar
• Wang X, Shao N, Zhang Q, Cheng Y. Mitochondrial targeting dendrimer allows efficient and safe gene delivery. J Mater Chem B. 2014;2:2546–2553. doi:10.1039/C3TB21348J
   PubMed Web of Science ®Google Scholar
• Battigelli A, Russier J, Venturelli E, et al. Peptide-based carbon nanotubes for mitochondrial targeting. Nanoscale. 2013;5:9110–9117. doi:10.1039/c3nr02694a
   PubMed Web of Science ®Google Scholar
• Yoong SL, Wong BS, Zhou QL, et al. Enhanced cytotoxicity to cancer cells by mitochondria-targeting MWCNTs containing platinum(IV) prodrug of cisplatin. Biomaterials. 2014;35:748–759. doi:10.1016/j.biomaterials.2013.09.036
   PubMed Web of Science ®Google Scholar
• Xu J, Xu P, Li Z, et al. Oxidative stress and apoptosis induced by hydroxyapatite nanoparticles in C6 cells. J Biomed Mater Res A. 2012;100A(3):738–745. doi:10.1002/jbm.a.33270
   Google Scholar
• Sun Y, Chen Y, Ma X, et al. Mitochondria-targeted hydroxyapatite nanoparticles for selective growth inhibition of lung cancer in vitro and in vivo. ACS Appl Mater Interfaces. 2016;8(39):25680–25690. doi:10.1021/acsami.6b06094
   PubMed Web of Science ®Google Scholar
• Xiong H, Du S, Ni J, et al. Mitochondria and nuclei dualtargeted heterogeneous hydroxyapatite nanoparticles for enhancing therapeutic efficacy of doxorubicin. Biomaterials. 2016;94:70–83. doi:10.1016/j.biomaterials.2016.04.004
   PubMed Web of Science ®Google Scholar
• Sharma A, Goyal AK, Rath G. Recent advances in metal nanoparticles in cancer therapy. J Drug Target. 2018;26(8):617–632. doi:10.1080/1061186X.2017.1400553
   PubMed Web of Science ®Google Scholar
• Zhang X, Chibli H, Mielke R, et al. Ultrasmall golddoxorubicin conjugates rapidly kill apoptosis-resistant cancer cells. Bioconjug Chem. 2011;22(2):235. doi:10.1021/bc100374p
   PubMedGoogle Scholar
• Mkandawire MM, Lakatos M, Springer A, et al. Induction of apoptosis in human cancer cells by targeting mitochondria with gold nanoparticles. Nanoscale. 2015;7(24):10634–10640. doi:10.1039/C5NR01483B
   PubMed Web of Science ®Google Scholar
• Ma X, Wang X, Zhou M, et al. A mitochondria-targeting gold peptide nanoassembly for enhanced cancer-cell killing. Adv Healthc Mater. 2013;2(12):1638–1643. doi:10.1002/adhm.201300037
   PubMed Web of Science ®Google Scholar
• Federici G, Shaw BJ, Handy RD. Toxicity of titanium dioxide nanoparticles to rainbow trout (Oncorhynchus mykiss): gill injury, oxidative stress, and other physiological effects. Aquat Toxicol. 2007;84(4):415–430. doi:10.1016/j.aquatox.2007.07.009
   PubMed Web of Science ®Google Scholar
• Periasamy VS, Athinarayanan J, Al-Hadi AM, Juhaimi FA, Mahmoud MH, Alshatwi AA. Identification of titanium dioxide nanoparticles in food products: induce intracellular oxidative stress mediated by TNF and CYP1A genes in human lung fibroblast cells. Environ Toxicol Pharmacol. 2015;39(1):176–186. doi:10.1016/j.etap.2014.11.021
   PubMedGoogle Scholar
• Wu J, Sun J, Xue Y. Involvement of JNK and P53 activation in G2/M cell cycle arrest and apoptosis induced by titanium dioxide nanoparticles in neuron cells. Toxicol Lett. 2010;199(3):269–276. doi:10.1016/j.toxlet.2010.09.009
   PubMed Web of Science ®Google Scholar
• Cui Y, Gong X, Duan Y, et al. Hepatocyte apoptosis and its molecular mechanisms in mice caused by titanium dioxide nanoparticles. J Hazard Mater. 2010;183(1–3):874–880. doi:10.1016/j.jhazmat.2010.07.109
   PubMedGoogle Scholar
• Zhang L, Gu FX, Chan JM, Wang AZ, Langer RS, Farokhzad OC. Nanoparticles in medicine: therapeutic applications and developments. Clin Pharmacol Ther. 2008;83(5):761–769. doi:10.1038/sj.clpt.6100400
   PubMed Web of Science ®Google Scholar
• Ahamed M, Posgai R, Gorey TJ, Nielsen M, Hussain SM, Rowe JJ. Silver nanoparticles induced heat shock protein 70, oxidative stress and apoptosis in Drosophila melanogaster. Toxicol Appl Pharmacol. 2010;242(3):263–269. doi:10.1016/j.taap.2009.10.016
   PubMed Web of Science ®Google Scholar
• Kim HR, Kim MJ, Lee SY, Oh SM, Chung KH. Genotoxic effects of silver nanoparticles stimulated by oxidative stress in human normal bronchial epithelial (BEAS-2B) cells. Mutat Res. 2011;726(2):129–135. doi:10.1016/j.mrgentox.2011.08.008
   PubMed Web of Science ®Google Scholar
• Piao MJ, Kang KA, Lee IK, et al. Silver nanoparticles induce oxidative cell damage in human liver cells through inhibition of reduced glutathione and induction of mitochondria-involved apoptosis. Toxicol Lett. 2011;201(1):92–100. doi:10.1016/j.toxlet.2010.12.010
   PubMed Web of Science ®Google Scholar
• Ranjbar A, Ataie Z, Khajavi F, Ghasemi H. Effects of silver nanoparticle (Ag NP) on oxidative stress biomarkers in rat. Nanomed J. 2014;1(3):205–210.
   Google Scholar
• Berk M, Kapczinski F, Andreazza AC, et al. Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors. Neurosci Biobehav Rev. 2011;35(3):804–817. doi:10.1016/j.neubiorev.2010.10.001
   PubMed Web of Science ®Google Scholar
• Xue Y, Wang J, Huang Y, et al. Comparative cytotoxicity and apoptotic pathways induced by nanosilver in human liver HepG2 and L02 cells. Human Exp Toxicol. 2018;960327118769718.
   Google Scholar
• Li J, Zhang B, Chang X, et al. Silver nanoparticles modulate mitochondrial dynamics and biogenesis in HepG2 cells. Environ Pollut. 2020;256:113430. doi:10.1016/j.envpol.2019.113430
   PubMed Web of Science ®Google Scholar
• Sharma V, Shukla RK, Saxena N, Parmar D, Das M, Dhawan A. DNA damaging potential of zinc oxide nanoparticles in human epidermal cells. Toxicol Lett. 2009;185(3):211–218. doi:10.1016/j.toxlet.2009.01.008
   PubMed Web of Science ®Google Scholar
• Sharma V, Anderson D, Dhawan A. Zinc oxide nanoparticles induce oxidative stress and genotoxicity in human liver cells (HepG2). J Biomed Nanotechnol. 2011;7(1):98–99. doi:10.1166/jbn.2011.1220
   PubMed Web of Science ®Google Scholar
• Ahamed M, Akhtar MJ, Raja M, et al. ZnO nanorod-induced apoptosis in human alveolar adenocarcinoma cells via p53, survivin and bax/bcl-2 pathways: role of oxidative stress. Nanomedicine. 2011;7(6):904–913. doi:10.1016/j.nano.2011.04.011
   PubMed Web of Science ®Google Scholar
• Sharma V, Anderson D, Dhawan A. Zinc oxide nanoparticles induce oxidative DNA damage and ROS-triggered mitochondria mediated apoptosis in human liver cells (HepG2). Apoptosis. 2012;17(8):852–870. doi:10.1007/s10495-012-0705-6
   PubMed Web of Science ®Google Scholar
• Park YH, Bae HC, Kim J, Jeong SH, Yang SI, Son SW. Zinc oxide nanoparticles induce HIF-1alpha protein stabilization through increased reactive oxygen species generation from electron transfer chain complex III of mitochondria. J Dermatol Sci. 2018;91(1):104–107. doi:10.1016/j.jdermsci.2018.03.010
   PubMed Web of Science ®Google Scholar
• Zhao X, Ren X, Zhu R, Luo Z, Ren B. Zinc oxide nanoparticles induce oxidative DNA damage and ROS-triggered mitochondria-mediated apoptosis in zebrafish embryos. Aquat Toxicol. 2016;180:56–70. doi:10.1016/j.aquatox.2016.09.013
   PubMed Web of Science ®Google Scholar
• Li Y, Li F, Zhang L, et al. Zinc oxide nanoparticles induce mitochondrial biogenesis impairment and cardiac dysfunction in human iPSC-derived cardiomyocytes. Int J Nanomed. 2020;15:2669. doi:10.2147/IJN.S249912
   PubMed Web of Science ®Google Scholar
• Rahman MM, Khan SB, Aslam Jamal MF, Aisiri AM. Iron oxide nanoparticles. In: Rahman M, editor. Nanomaterials. England: InTech; 2011.
   Google Scholar
• Naqvi S, Samim M, Abdin M, et al. Concentration-dependent toxicity of iron oxide nanoparticles mediated by increased oxidative stress. Int J Nanomedicine. 2010;5:983–989. doi:10.2147/IJN.S13244
   PubMed Web of Science ®Google Scholar
• Zhu MT, Wang Y, Feng WY, et al. Oxidative stress and apoptosis induced by iron oxide nanoparticles in cultured human umbilical endothelial cells. J Nanosci Nanotechnol. 2010;10(12):8584–8590. doi:10.1166/jnn.2010.2488
   PubMedGoogle Scholar
• Guo R, Peng H, Tian Y, Shen S, Yang W. Mitochondria‐targeting magnetic composite nanoparticles for enhanced phototherapy of cancer. Small. 2016;12(33):4541–4552. doi:10.1002/smll.201601094
   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;11:777e90. doi:10.1089/ars.2008.2270
   Google Scholar
• Jin J, Mullen TD, Hou Q, et al. AMPK inhibitor compound C stimulates ceramide production and promotes Bax redistribution and apoptosis in MCF-7 breast carcinoma cells. J Lipid Res. 2009;50:2389e97. doi:10.1194/jlr.M900119-JLR200
   Google Scholar
• Mahmoudi M, Simchi A, Vali H, et al. Cytotoxicity and cell cycle effects of bare and polyvinyl alcohol coated iron oxide nanoparticles in mouse fibroblasts. Adv Eng Mater. 2009;11:B243e50. doi:10.1002/adem.200990035
   Google Scholar
• Yu Y, Wang ZH, Zhang L, et al. Mitochondrial targeting topotecan-loaded liposomes for treating drug-resistant breast cancer and inhibiting invasive metastases of melanoma. Biomaterials. 2012;33:1808–1820. doi:10.1016/j.biomaterials.2011.10.085
   PubMed Web of Science ®Google Scholar
• Zhou J, Zhao WY, Ma X, et al. The anticancer efficacy of paclitaxel liposomes modified with mitochondrial targeting conjugate in resistant lung cancer. Biomaterials. 2013;34:3626–3638. doi:10.1016/j.biomaterials.2013.01.078
   PubMed Web of Science ®Google Scholar
• Zhang C, Liu Z, Zheng Y, et al. Glycyrrhetinic acid functionalized graphene oxide for mitochondria targeting and cancer treatment in vivo. Small. 2018;14:1703306. doi:10.1002/smll.201703306
   Web of Science ®Google Scholar
• Wei Y, Zhou F, Zhang D, Chen Q, Xing D. A graphene oxide based smart drug delivery system for tumor mitochondria-targeting photodynamic therapy. Nanoscale. 2016;8:3530–3538. doi:10.1039/C5NR07785K
   PubMed Web of Science ®Google Scholar
• Cho DY, Cho H, Kwon K, et al. Triphenylphosphonium-conjugated poly(+-caprolactone)- based self-assembled nanostructures as nanosized drugs and drug delivery carriers for mitochondria-targeting synergistic anticancer drug delivery. Adv Funct Mater. 2015;25:5479–5491. doi:10.1002/adfm.201501422
   Google Scholar
• Tan Y, Zhu Y, Zhao Y, et al. Mitochondrial alkaline pH-responsive drug release mediated by celastrol loaded glycolipidlike micelles for cancer therapy. Biomaterials. 2018;154:169–181. doi:10.1016/j.biomaterials.2017.07.036
   PubMed Web of Science ®Google Scholar
• Bae Y, Jung MK, Lee S, et al. Dequalinium-based functional nanosomes show increased mitochondria targeting and anticancer effect. Eur J Pharm Biopharm. 2018;124:104–115. doi:10.1016/j.ejpb.2017.12.013
   PubMedGoogle Scholar
• Bae Y, Jung MK, Song SJ, et al. Functional nanosome for enhanced mitochondria-targeted gene delivery and expression. Mitochondrion. 2017;37:27–40. doi:10.1016/j.mito.2017.06.005
   PubMed Web of Science ®Google Scholar
• Lee JH, Kim KY, Jin H, et al. Self-assembled coumarin nanoparticle in aqueous solution as selective mitochondrial-targeting drug delivery system. ACS Appl Mater Interfaces. 2018;10:3380–3391. doi:10.1021/acsami.7b17711
   PubMed Web of Science ®Google Scholar
• Zhang Y, Zhang C, Chen J, et al. Trackable mitochondria-targeting nanomicellar loaded with doxorubicin for overcoming drug resistance. ACS Appl Mater Interfaces. 2017;9:25152–25163. doi:10.1021/acsami.7b07219
   PubMed Web of Science ®Google Scholar
• Zhang Z, Zhou L, Zhou Y, et al. Mitophagy induced by nanoparticle-peptide conjugates enabling an alternative intracellular trafficking route. Biomaterials. 2015b;65:56–65. doi:10.1016/j.biomaterials.2015.06.029
   PubMed Web of Science ®Google Scholar
• He H, Wang J, Wang H, et al. Enzymatic cleavage of branched peptides for targeting mitochondria. J Am Chem Soc. 2018;140:1215–1218. doi:10.1021/jacs.7b11582
   PubMedGoogle Scholar
• Mallick A, More P, Ghosh S, et al. Dual drug conjugated nanoparticle for simultaneous targeting of mitochondria and nucleus in cancer cells. ACS Appl Mater Interfaces. 2015;7:7584–7598. doi:10.1021/am5090226
   PubMed Web of Science ®Google Scholar
• Liu Y, Zhang X, Zhou M, Nan X, Chen X, Zhang X. Mitochondrial-targeting lonidamine-doxorubicin nanoparticles for synergistic chemotherapy to conquer drug resistance. ACS Appl Mater Interfaces. 2017;9:43498–43507. doi:10.1021/acsami.7b14577
   PubMed Web of Science ®Google Scholar
• Haynes B, Zhang Y, Liu F, et al. Gold nanoparticle conjugated Rad6 inhibitor induces cell death in triple negative breast cancer cells by inducing mitochondrial dysfunction and PARP-1 hyperactivation: synthesis and characterization. Nanomedicine. 2016;12:745–757. doi:10.1016/j.nano.2015.10.010
   PubMed Web of Science ®Google Scholar
• Young K, Jin H, Park J, et al. Mitochondria-targeting self-assembled nanoparticles derived from triphenylphosphonium-conjugated cyanostilbene enable site-specific imaging and anticancer drug delivery. Nano Res. 2018;11:1082. doi:10.1007/s12274-017-1728-7
   Google Scholar
• Liu HN, Guo NN, Wang TT, et al. Mitochondrial targeted doxorubicin-triphenylphosphonium delivered by hyaluronic acid modified and pH responsive nanocarriers to breast tumor: in vitro and in vivo studies. Mol Pharm. 2018;15:882–891. doi:10.1021/acs.molpharmaceut.7b00793
   PubMed Web of Science ®Google Scholar
• Parveen S, Misra R, Sahoo SK. Nanoparticles: a boon to drug delivery, therapeutics, diagnostics and imaging. Nanomedicine. 2012;8(2):147–166. doi:10.1016/j.nano.2011.05.016
   PubMed Web of Science ®Google Scholar
• Gnach A, Lipinski T, Bednarkiewicz A, Rybka J, Capobianco JA. Upconverting nanoparticles: assessing the toxicity. Chem Soc Rev. 2015;44(6):1561–1584. doi:10.1039/C4CS00177J
   PubMed Web of Science ®Google Scholar
• Glancy D, Zhang Y, Wu JL, Ouyang B, Ohta S, Chan WC. Characterizing the protein corona of sub-10 nm nanoparticles. J Control Release. 2019;304:102–110. doi:10.1016/j.jconrel.2019.04.023
   PubMedGoogle Scholar
• De Jong WH, Hagens WI, Krystek P, et al. Particle size-dependent organ distribution of gold nanoparticles after intravenous administration. Biomaterials. 2008;29(12):1912–1919. doi:10.1016/j.biomaterials.2007.12.037
   PubMed Web of Science ®Google Scholar
• Khanna P, Ong C, Bay BH, Baeg GH. Nanotoxicity: an interplay of oxidative stress, inflammation and cell death. Nanomaterials. 2015;5(3):1163–1180. doi:10.3390/nano5031163
   Web of Science ®Google Scholar
• Albanese A, Tang PS, Chan WC. The effect of nanoparticle size, shape, and surface chemistry on biological systems. Annu Rev Biomed Eng. 2012;14:1–6. doi:10.1146/annurev-bioeng-071811-150124
   PubMed Web of Science ®Google Scholar
• Tomsa AM, Alexa AL, Junie ML, et al. Oxidative stress as a potential target in acute kidney injury. PeerJ. 2019;7:e8046. doi:10.7717/peerj.8046
   PubMedGoogle Scholar
• Zuberek M, Grzelak A. Nanoparticles-caused oxidative imbalance. Adv Exp Med Biol. 2018;1048:85–98.
   PubMed Web of Science ®Google Scholar
• Hare JI, Lammers T, Ashford MB, et al. Challenges and strategies in anti-cancer nanomedicine development: an industry perspective. Adv Drug Deliv Rev. 2017;108:25–38. doi:10.1016/j.addr.2016.04.025
   PubMed Web of Science ®Google Scholar
• Bobo D, Robinson KJ, Islam J, et al. Nanoparticle-based medicines: a review of FDA-approved materials and clinical trials to date. Pharm Res. 2016;33:2373–2387. doi:10.1007/s11095-016-1958-5
   PubMed Web of Science ®Google Scholar
• Ju R, Guo L, Li J, et al. Carboxyamidotriazole inhibits oxidative phosphorylation in cancer cells and exerts synergistic anti-cancer effect with glycolysis inhibition. Cancer Lett. 2016;370(2):232–241. doi:10.1016/j.canlet.2015.10.025
   PubMed Web of Science ®Google Scholar
• Wilk A, Wyczechowska D, Zapata A, et al. Molecular mechanisms of fenofibrate-induced metabolic ca-tastrophe and glioblastoma cell death. Mol Cell Biol. 2015;35(1):182–198. doi:10.1128/MCB.00562-14
   PubMedGoogle Scholar
• Jordan BF, Sonveaux P. Targeting tumor perfusion and oxygenation to improve the outcome of anticancer therapy. Front Pharmacol. 2012;3:94. doi:10.3389/fphar.2012.00094
   PubMed Web of Science ®Google Scholar
• Levitsky DO, Dembitsky VM. Anti-breast cancer agents derived from plants. Nat Prod Bioprospect. 2014. doi:10.1007/s13659-014-0048-9
   PubMedGoogle Scholar
• Zhou Z, Zhu C, Cai Z, et al. Betulin induces cytochrome c release and apoptosis in colon cancer cells via NOXA. Oncol Lett. 2018;15(5):7319–7327. doi:10.3892/ol.2018.8183
   PubMed Web of Science ®Google Scholar
• Porporato PE, Payen VL, Perez-Escuredo J, et al. A mitochondrial switch pro-motes tumor metastasis. Cell Rep. 2014;8(3):754–766. doi:10.1016/j.celrep.2014.06.043
   PubMed Web of Science ®Google Scholar
• Liou G-Y, Döppler H, DelGiorno Kathleen E, et al. Mutant KRas-induced mitochondrial oxidative stress in acinar cells upregulates EGFR signaling to drive formation of pancreatic precancerous lesions. Cell Rep. 2016;14(10):2325–2336. doi:10.1016/j.celrep.2016.02.029
   PubMed Web of Science ®Google Scholar
• Dheeraj A, Agarwal C, Schlaepfer IR, et al. A novel approach to target hypoxic cancer cells via combining beta-oxidation inhibitor etomoxir with radiation. Hypoxia. 2018;6:23–33. doi:10.2147/HP.S163115
   PubMed Web of Science ®Google Scholar
• Venkataramanaa NK, Venkatesh PK, Dwarakanath BS, Vani S. Protective effect on normal brain tissue during a combination-al therapy of 2-deoxy-d-glucose and hypofractionated irradiation in malignant gliomas. Asian J Neurosurg. 2013;8(1):9–14. doi:10.4103/1793-5482.110274
   PubMedGoogle Scholar
• El Sayed SM, Mohamed WG, Seddik MA, et al. Safety and outcome of treatment of metastatic melanoma using 3-bromopyruvate: a concise literature review and case study. Chin J Cancer. 2014;33(7):356–364. doi:10.5732/cjc.013.10111
   PubMedGoogle Scholar
• Zhong B, Shi D, Wu F, et al. Dynasore suppresses cell proliferation, migration, and invasion and enhances the antitumor capacity of cis-platin via STAT3 pathway in osteosarcoma. Cell Death Dis. 2019;10(10):687. doi:10.1038/s41419-019-1917-2
   PubMedGoogle Scholar
• Angulo-Molina A, Reyes-Leyva J, Lopez-Malo A, Hernandez J. The role of alpha tocopheryl succinate (alpha-TOS) as a poten-tial anticancer agent. Nutr Cancer. 2014;66(2):167–176. doi:10.1080/01635581.2014.863367
   PubMed Web of Science ®Google Scholar