A Triple Combination of Metformin, Acetylsalicylic Acid, and Oseltamivir Phosphate Impacts Tumour Spheroid Viability and Upends Chemoresistance in Triple-Negative Breast Cancer

References

• ZeichnerSB, TerawakiH, GogineniK. A review of systemic treatment in metastatic triple-negative breast cancer. Breast Cancer (Auckl). 2016;10:25–36. doi:10.4137/BCBCR.S3278327042088
   PubMed Web of Science ®Google Scholar
• SambiM, QorriB, HarlessW, SzewczukMR. Therapeutic options for metastatic breast cancer In: AhmadA, editor. Breast Cancer Metastasis and Drug Resistance: Challenges and Progress. Vol. 2 2 ed Switzerland AG: Springer, Cham; 2019:131–172
   Google Scholar
• BaselgaJ, GomezP, GreilR, et al. Randomized Phase II study of the anti-epidermal growth factor receptor monoclonal antibody cetuximab with cisplatin versus cisplatin alone in patients with metastatic triple-negative breast cancer. J Clin Oncol. 2013;31:2586–2592. doi:10.1200/JCO.2012.46.240823733761
   PubMed Web of Science ®Google Scholar
• LiedtkeC, MazouniC, HessKR, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol. 2008;26:1275–1281. doi:10.1200/JCO.2007.14.414718250347
   PubMed Web of Science ®Google Scholar
• RodlerE, KordeL, GralowJ. Current treatment options in triple negative breast cancer. Breast Dis. 2010;32:99–122. doi:10.3233/BD-2010-030421778572
   PubMedGoogle Scholar
• CostaRLB, GradisharWJ. Triple-negative breast cancer: current practice and future directions. J Oncol Pract. 2017;13:301–303. doi:10.1200/JOP.2017.02333328489982
   PubMed Web of Science ®Google Scholar
• GoldvaserH, RibnikarD, MajeedH, OcanaA, AmirE. Absolute benefit from adjuvant chemotherapy in contemporary clinical trials: a systemic review and meta-analysis. Cancer Treat Rev. 2018;71:68–75. doi:10.1016/j.ctrv.2018.10.01030366201
   PubMed Web of Science ®Google Scholar
• SambiM, HaqS, SamuelV, et al. Alternative therapies for metastatic breast cancer: multimodal approach targeting tumor cell heterogeneity. Breast Cancer (Dove Med Press). 2017;9:85–93. doi:10.2147/bctt.s13083828280388
   PubMed Web of Science ®Google Scholar
• LehmannBD, PietenpolJA. Clinical implications of molecular heterogeneity in triple negative breast cancer. Breast. 2015;24(Suppl 2):S36–S40. doi:10.1016/j.breast.2015.07.00926253813
   PubMed Web of Science ®Google Scholar
• WangJ, ShiM, LingR, et al. Adjuvant chemotherapy and radiotherapy in triple-negative breast carcinoma: a prospective randomized controlled multi-center trial. Radiother Oncol. 2011;100:200–204. doi:10.1016/j.radonc.2011.07.00721852010
   PubMed Web of Science ®Google Scholar
• LeoneA, Di GennaroE, BruzzeseF, AvalloneA, BudillonA. New perspective for an old antidiabetic drug: metformin as anticancer agent. Cancer Treat Res. 2014;159:355–376. doi:10.1007/978-3-642-38007-5_2124114491
   PubMedGoogle Scholar
• HanahanD, WeinbergRA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–674. doi:10.1016/j.cell.2011.02.01321376230
   PubMed Web of Science ®Google Scholar
• KasznickiJ, SliwinskaA, DrzewoskiJ. Metformin in cancer prevention and therapy. Ann Transl Med. 2014;2. doi:10.3978/j.issn.2305-5839.2014.06.01.
   PubMedGoogle Scholar
• LiuB, FanZ, EdgertonSM, et al. Metformin induces unique biological and molecular responses in triple negative breast cancer cells. Cell Cycle. 2009;8:2031–2040. doi:10.4161/cc.8.13.881419440038
   PubMed Web of Science ®Google Scholar
• RyabayaO, ProkofievaA, AkasovR, et al. Metformin increases antitumor activity of MEK inhibitor binimetinib in 2D and 3D models of human metastatic melanoma cells. Biomed Pharmacother. 2019;109:2548–2560. doi:10.1016/j.biopha.2018.11.10930551515
   PubMed Web of Science ®Google Scholar
• JiangMJ, DaiJJ, GuDN, HuangQ, TianL. Aspirin in pancreatic cancer: chemopreventive effects and therapeutic potentials. Biochim Biophys Acta. 2016;1866:163–176. doi:10.1016/j.bbcan.2016.08.00227567928
   PubMed Web of Science ®Google Scholar
• VaneJR, BottingRM. The mechanism of action of aspirin. Thromb Res. 2003;110:255–258. doi:10.1016/s0049-3848(03)00379-714592543
   PubMed Web of Science ®Google Scholar
• MontinariMR, MinelliS, De CaterinaR. The first 3500years of aspirin history from its roots - A concise summary. Vascul Pharmacol. 2019;113:1–8. doi:10.1016/j.vph.2018.10.00830391545
   PubMed Web of Science ®Google Scholar
• MimeaultM, BrandRE, SassonAA, BatraSK. Recent advances on the molecular mechanisms involved in pancreatic cancer progression and therapies. Pancreas. 2005;31:301–316. doi:10.1097/01.mpa.0000175893.04660.1b16258363
   PubMed Web of Science ®Google Scholar
• OkamiJ, YamamotoH, FujiwaraY, et al. Overexpression of cyclooxygenase-2 in carcinoma of the pancreas. Clin Cancer Res. 1999;5:2018–2024.10473081
   PubMed Web of Science ®Google Scholar
• SarkarFH, BanerjeeS, LiY. Pancreatic cancer: pathogenesis, prevention and treatment. Toxicol Appl Pharmacol. 2007;224:326–336. doi:10.1016/j.taap.2006.11.00717174370
   PubMed Web of Science ®Google Scholar
• MahdiEJ. Aspirin and its related non-steroidal anti-inflammatory drugs. Libyan J Med. 2013;8:21569. doi:10.3402/ljm.v8i0.21569
   PubMed Web of Science ®Google Scholar
• ZhangX, FengY, LiuX, et al. Beyond a chemopreventive reagent, aspirin is a master regulator of the hallmarks of cancer. J Cancer Res Clin Oncol. 2019;145:1387–1403. doi:10.1007/s00432-019-02902-631037399
   PubMed Web of Science ®Google Scholar
• YueW, YangCS, DiPaolaRS, TanXL. Repurposing of metformin and aspirin by targeting AMPK-mTOR and inflammation for pancreatic cancer prevention and treatment. Cancer Prev Res (Phila). 2014;7:388–397. doi:10.1158/1940-6207.CAPR-13-033724520038
   PubMed Web of Science ®Google Scholar
• De MonteA, BrunettiD, CattinL, et al. Metformin and aspirin treatment could lead to an improved survival rate for Type 2 diabetic patients with stage II and III colorectal adenocarcinoma relative to non-diabetic patients. Mol Clin Oncol. 2018;8:504–512. doi:10.3892/mco.2018.155429456855
   PubMed Web of Science ®Google Scholar
• YueW, ZhengX, LinY, et al. Metformin combined with aspirin significantly inhibit pancreatic cancer cell growth in vitro and in vivo by suppressing anti-apoptotic proteins Mcl-1 and Bcl-2. Oncotarget. 2015;6:21208–21224. doi:10.18632/oncotarget.412626056043
   PubMed Web of Science ®Google Scholar
• AmaralMEA, NeryLR, LeiteCE, de Azevedo JuniorWF, CamposMM. Pre-clinical effects of metformin and aspirin on the cell lines of different breast cancer subtypes. Invest New Drugs. 2018;36:782–796. doi:10.1007/s10637-018-0568-y29392539
   PubMed Web of Science ®Google Scholar
• OrecchioniS, ReggianiF, TalaricoG, et al. The biguanides metformin and phenformin inhibit angiogenesis, local and metastatic growth of breast cancer by targeting both neoplastic and microenvironment cells. Int J Cancer. 2015;136:E534–E544. doi:10.1002/ijc.2919325196138
   PubMed Web of Science ®Google Scholar
• AmithSR, JayanthP, FranchukS, et al. Neu1 desialylation of sialyl alpha-2,3-linked beta-galactosyl residues of TOLL-like receptor 4 is essential for receptor activation and cellular signaling. Cell Signal. 2010;22:314–324. doi:10.1016/j.cellsig.2009.09.03819796680
   PubMed Web of Science ®Google Scholar
• AbdulkhalekS, SzewczukMR. Neu1 sialidase and matrix metalloproteinase-9 cross-talk regulates nucleic acid-induced endosomal TOLL-like receptor-7 and −9 activation, cellular signaling and pro-inflammatory responses. Cell Signal. 2013;25:2093–2105. doi:10.1016/j.cellsig.2013.06.01023827939
   PubMed Web of Science ®Google Scholar
• O’SheaLK, AbdulkhalekS, AllisonS, NeufeldRJ, SzewczukMR. Therapeutic targeting of Neu1 sialidase with oseltamivir phosphate (Tamiflu(R)) disables cancer cell survival in human pancreatic cancer with acquired chemoresistance. Onco Targets Ther. 2014;7:117–134. doi:10.2147/ott.s5534424470763
   PubMed Web of Science ®Google Scholar
• AbdulkhalekS, GeenOD, BrodhagenL, et al. Transcriptional factor snail controls tumor neovascularization, growth and metastasis in mouse model of human ovarian carcinoma. Clin Transl Med. 2014;3:28. doi:10.1186/s40169-014-0028-z26932374
   PubMedGoogle Scholar
• HaxhoF, AllisonS, AlghamdiF, et al. Oseltamivir phosphate monotherapy ablates tumor neovascularization, growth, and metastasis in mouse model of human triple-negative breast adenocarcinoma. Breast Cancer (Dove Med Press). 2014;6:191–203. doi:10.2147/BCTT.S7466325525387
   PubMedGoogle Scholar
• GilmourAM, AbdulkhalekS, ChengTS, et al. A novel epidermal growth factor receptor-signaling platform and its targeted translation in pancreatic cancer. Cell Signal. 2013;25:2587–2603. doi:10.1016/j.cellsig.2013.08.00823993964
   PubMed Web of Science ®Google Scholar
• HaxhoF, NeufeldRJ, SzewczukMR. Neuraminidase-1: a novel therapeutic target in multistage tumorigenesis. Oncotarget. 2016;7:40860–40881. doi:10.18632/oncotarget.839627029067
   PubMedGoogle Scholar
• Allison LoganS, BrissendenAJ, SzewczukMR, NeufeldRJ. Combinatorial and sequential delivery of gemcitabine and oseltamivir phosphate from implantable poly(d,l-lactic-co-glycolic acid) cylinders disables human pancreatic cancer cell survival. Drug Des Devel Ther. 2017;11:2239–2250. doi:10.2147/DDDT.S137934
   PubMed Web of Science ®Google Scholar
• AkasovR, GilevaA, Zaytseva-ZotovaD, et al. 3D in vitro co-culture models based on normal cells and tumor spheroids formed by cyclic RGD-peptide induced cell self-assembly. Biotechnol Lett. 2017;39:45–53. doi:10.1007/s10529-016-2218-927659030
   PubMed Web of Science ®Google Scholar
• MikhailAS, EetezadiS, AllenC. Multicellular tumor spheroids for evaluation of cytotoxicity and tumor growth inhibitory effects of nanomedicines in vitro: a comparison of docetaxel-loaded block copolymer micelles and Taxotere®. PLoS One. 2013;8:e62630. doi:10.1371/journal.pone.006263023626842
   PubMed Web of Science ®Google Scholar
• AkasovR, Zaytseva-ZotovaD, BurovS, et al. Formation of multicellular tumor spheroids induced by cyclic RGD-peptides and use for anticancer drug testing in vitro. Int J Pharm. 2016;506:148–157. doi:10.1016/j.ijpharm.2016.04.00527107900
   PubMed Web of Science ®Google Scholar
• AkasovR, HaqS, HaxhoF, et al. Sialylation transmogrifies human breast and pancreatic cancer cells into 3D multicellular tumor spheroids using cyclic RGD-peptide induced self-assembly. Oncotarget. 2016;7:66119–66134. doi:10.18632/oncotarget.1186827608845
   PubMedGoogle Scholar
• GuertlerA, KraemerA, RoesslerU, et al. The WST survival assay: an easy and reliable method to screen radiation-sensitive individuals. Radiat Prot Dosimetry. 2011;143:487–490. doi:10.1093/rpd/ncq51521183542
   PubMed Web of Science ®Google Scholar
• MenyhartO, Harami-PappH, SukumarS, et al. Guidelines for the selection of functional assays to evaluate the hallmarks of cancer. Biochim Biophys Acta. 2016;1866:300–319. doi:10.1016/j.bbcan.2016.10.00227742530
   PubMed Web of Science ®Google Scholar
• ZhangY, LiuL, FanP, et al. Aspirin counteracts cancer stem cell features, desmoplasia and gemcitabine resistance in pancreatic cancer. Oncotarget. 2015;6:9999–10015. doi:10.18632/oncotarget.317125846752
   PubMedGoogle Scholar
• LuoQ, HuD, HuS, YanM, SunZ, ChenF. In vitro and in vivo anti-tumor effect of metformin as a novel therapeutic agent in human oral squamous cell carcinoma. BMC Cancer. 2012;12:517. doi:10.1186/1471-2407-12-51723151022
   PubMed Web of Science ®Google Scholar
• BrennanBJ, DaviesB, Cirrincione-DallG, et al. Safety, tolerability, and pharmacokinetics of intravenous oseltamivir: single- and multiple-dose Phase I studies with healthy volunteers. Antimicrob Agents Chemother. 2012;56:4729–4737. doi:10.1128/aac.00200-1222733065
   PubMed Web of Science ®Google Scholar
• YinMJ, YamamotoY, GaynorRB. The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature. 1998;396:77–80. doi:10.1038/239489817203
   PubMed Web of Science ®Google Scholar
• WilcockC, BaileyCJ. Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica. 1994;24:49–57. doi:10.3109/004982594090432208165821
   PubMed Web of Science ®Google Scholar
• GoodsellDS. The molecular perspective: tamoxifen and the estrogen receptor. Stem Cells. 2002;20:267–268. doi:10.1634/stemcells.20-3-26712004085
   PubMed Web of Science ®Google Scholar
• MannaS, HolzMK. Tamoxifen action in ER-negative breast cancer. Sign Transduct Insights. 2016;5:1–7. doi:10.4137/STI.S2990126989346
   PubMedGoogle Scholar
• O’ReillyEA, GubbinsL, SharmaS, et al. The fate of chemoresistance in triple negative breast cancer (TNBC). BBA Clin. 2015;3:257–275. doi:10.1016/j.bbacli.2015.03.00326676166
   PubMed Web of Science ®Google Scholar
• Al-MahmoodS, SapiezynskiJ, GarbuzenkoOB, MinkoT. Metastatic and triple-negative breast cancer: challenges and treatment options. Drug Deliv Transl Res. 2018;8:1483–1507. doi:10.1007/s13346-018-0551-329978332
   PubMed Web of Science ®Google Scholar
• RibattiD, NicoB, RuggieriS, TammaR, SimoneG, MangiaA. Angiogenesis and antiangiogenesis in triple-negative breast cancer. Transl Oncol. 2016;9:453–457. doi:10.1016/j.tranon.2016.07.00227751350
   PubMed Web of Science ®Google Scholar
• RobertNJ, DiérasV, GlaspyJ, et al. RIBBON-1: randomized, double-blind, placebo-controlled, Phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2–negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011;29:1252–1260. doi:10.1200/JCO.2010.28.098221383283
   PubMed Web of Science ®Google Scholar
• CreightonCJ, LiX, LandisM, et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci U S A. 2009;106:13820–13825. doi:10.1073/pnas.090571810619666588
   PubMed Web of Science ®Google Scholar
• SheridanC, KishimotoH, FuchsRK, et al. CD44+/CD24- breast cancer cells exhibit enhanced invasive properties: an early step necessary for metastasis. Breast Cancer Res. 2006;8:R59. doi:10.1186/bcr161017062128
   PubMed Web of Science ®Google Scholar
• AbrahamBK, FritzP, McClellanM, HauptvogelP, AthelogouM, BrauchH. Prevalence of CD44+/CD24-/low cells in breast cancer may not be associated with clinical outcome but may favor distant metastasis. Clin Cancer Res. 2005;11:1154–1159.15709183
   PubMed Web of Science ®Google Scholar
• ChuteJP, MuramotoGG, WhitesidesJ, et al. Inhibition of aldehyde dehydrogenase and retinoid signaling induces the expansion of human hematopoietic stem cells. Proc Natl Acad Sci. 2006;103:11707. doi:10.1073/pnas.060380610316857736
   PubMed Web of Science ®Google Scholar
• LiW, MaH, ZhangJ, ZhuL, WangC, YangY. Unraveling the roles of CD44/CD24 and ALDH1 as cancer stem cell markers in tumorigenesis and metastasis. Sci Rep. 2017;7:13856. doi:10.1038/s41598-017-14364-229062075
   PubMed Web of Science ®Google Scholar
• BieleckaZF, Maliszewska-OlejniczakK, SafirIJ, SzczylikC, CzarneckaAM. Three-dimensional cell culture model utilization in cancer stem cell research. Biol Rev. 2016. doi:10.1111/brv.12293
   PubMed Web of Science ®Google Scholar
• LinX, LiJ, YinG, et al. Integrative analyses of gene expression and DNA methylation profiles in breast cancer cell line models of tamoxifen-resistance indicate a potential role of cells with stem-like properties. Breast Cancer Res. 2013;15:R119. doi:10.1186/bcr358824355041
   PubMed Web of Science ®Google Scholar
• NotasG, PelekanouV, KampaM, et al. Tamoxifen induces a pluripotency signature in breast cancer cells and human tumors. Mol Oncol. 2015;9:1744–1759. doi:10.1016/j.molonc.2015.05.00826115764
   PubMed Web of Science ®Google Scholar
• GutierrezMC, DetreS, JohnstonS, et al. Molecular changes in tamoxifen-resistant breast cancer: relationship between estrogen receptor, HER-2, and p38 mitogen-activated protein kinase. J Clin Oncol. 2005;23:2469–2476. doi:10.1200/jco.2005.01.17215753463
   PubMed Web of Science ®Google Scholar
• SeyfriedTN, FloresRE, PoffAM, D’AgostinoDP. Cancer as a metabolic disease: implications for novel therapeutics. Carcinogenesis. 2014;35:515–527. doi:10.1093/carcin/bgt48024343361
   PubMed Web of Science ®Google Scholar
• BizjakM, MalavasicP, PirkmajerS, PavlinM. Comparison of the effects of metformin on MDA-MB-231 breast cancer cells in a monolayer culture and in tumor spheroids as a function of nutrient concentrations. Biochem Biophys Res Commun. 2019;515:296–302. doi:10.1016/j.bbrc.2019.05.09031146913
   PubMed Web of Science ®Google Scholar
• LinR-Z, ChangH-Y. Recent advances in three-dimensional multicellular spheroid culture for biomedical research. Biotechnol J. 2008;3:1172–1184. doi:10.1002/biot.20070022818566957
   PubMedGoogle Scholar
• VarnerJA, ChereshDA. Integrins and cancer. Curr Opin Cell Biol. 1996;8:724–730. doi:10.1016/S0955-0674(96)80115-38939661
   PubMed Web of Science ®Google Scholar
• YiY, ChenD, AoJ, et al. Metformin promotes AMP-activated protein kinase-independent suppression of DeltaNp63alpha protein expression and inhibits cancer cell viability. J Biol Chem. 2017;292:5253–5261. doi:10.1074/jbc.M116.76914128193839
   PubMed Web of Science ®Google Scholar
• LorizioW, WuAHB, BeattieMS, et al. Clinical and biomarker predictors of side effects from tamoxifen. Breast Cancer Res Treat. 2012;132:1107–1118. doi:10.1007/s10549-011-1893-422207277
   PubMed Web of Science ®Google Scholar
• BaneshiMR, WarnerP, AndersonN, EdwardsJ, CookeTG, BartlettJMS. Tamoxifen resistance in early breast cancer: statistical modelling of tissue markers to improve risk prediction. Br J Cancer. 2010;102:1503–1510. doi:10.1038/sj.bjc.660562720461093
   PubMed Web of Science ®Google Scholar
• RothwellPM, WilsonM, ElwinCE, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet. 2010;376:1741–1750. doi:10.1016/s0140-6736(10)61543-720970847
   PubMed Web of Science ®Google Scholar
• RothwellPM, WilsonM, PriceJF, BelchJF, MeadeTW, MehtaZ. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet. 2012;379:1591–1601. doi:10.1016/s0140-6736(12)60209-822440947
   PubMed Web of Science ®Google Scholar
• HosonoK, EndoH, TakahashiH, et al. Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial. Cancer Prev Res (Phila). 2010;3:1077–1083. doi:10.1158/1940-6207.Capr-10-018620810669
   PubMed Web of Science ®Google Scholar
• HigurashiT, HosonoK, TakahashiH, et al. Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: a multicentre double-blind, placebo-controlled, randomised Phase 3 trial. Lancet Oncol. 2016;17:475–483. doi:10.1016/s1470-2045(15)00565-326947328
   PubMed Web of Science ®Google Scholar
• PetreraM, PaleariL, ClavarezzaM, et al. The ASAMET trial: a randomized, phase II, double-blind, placebo-controlled, multicenter, 2 × 2 factorial biomarker study of tertiary prevention with low-dose aspirin and metformin in stage I-III colorectal cancer patients. BMC Cancer. 2018;18:1210. doi:10.1186/s12885-018-5126-730514262
   PubMed Web of Science ®Google Scholar
• ChenWY, HolmesMD. Role of aspirin in breast cancer survival. Curr Oncol Rep. 2017;19:48. doi:10.1007/s11912-017-0605-628597105
   PubMed Web of Science ®Google Scholar
• ChenC, ZhaoS, KarnadA, FreemanJW. The biology and role of CD44 in cancer progression: therapeutic implications. J Hematol Oncol. 2018;11:64. doi:10.1186/s13045-018-0605-529747682
   PubMed Web of Science ®Google Scholar
• Ortiz-MonteroP, Liu-BordesWY, Londono-VallejoA, VernotJP. CD24 expression and stem-associated features define tumor cell heterogeneity and tumorigenic capacities in a model of carcinogenesis. Cancer Manag Res. 2018;10:5767–5784. doi:10.2147/CMAR.S17665430510447
   PubMed Web of Science ®Google Scholar
• KwonMJ, HanJ, SeoJH, et al. CD24 overexpression is associated with poor prognosis in luminal A and triple-negative breast cancer. PLoS One. 2015;10:e0139112. doi:10.1371/journal.pone.013911226444008
   PubMed Web of Science ®Google Scholar
• GinestierC, HurMH, Charafe-JauffretE, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell. 2007;1:555–567. doi:10.1016/j.stem.2007.08.01418371393
   PubMed Web of Science ®Google Scholar
• VassalliG. Aldehyde dehydrogenases: not just markers, but functional regulators of stem cells. Stem Cells Int. 2019;2019:3904645. doi:10.1155/2019/390464530733805
   PubMed Web of Science ®Google Scholar
• KozovskaZ, PatsaliasA, BajzikV, et al. ALDH1A inhibition sensitizes colon cancer cells to chemotherapy. BMC Cancer. 2018;18:656. doi:10.1186/s12885-018-4572-629902974
   PubMed Web of Science ®Google Scholar
• ShiP, LiuW, WangH, et al. Metformin suppresses triple-negative breast cancer stem cells by targeting KLF5 for degradation. Cell Discov. 2017;3:17010. doi:10.1038/celldisc.2017.1028480051
   PubMed Web of Science ®Google Scholar
• SahaS, MukherjeeS, KhanP, et al. Aspirin suppresses the acquisition of chemoresistance in breast cancer by disrupting an NFkappaB-IL6 signaling axis responsible for the generation of cancer stem cells. Cancer Res. 2016;76:2000–2012. doi:10.1158/0008-5472.CAN-15-136026842876
   PubMed Web of Science ®Google Scholar
• ShiY. Caspase activation, inhibition, and reactivation: a mechanistic view. Protein Sci. 2004;13:1979–1987. doi:10.1110/ps.0478980415273300
   PubMed Web of Science ®Google Scholar