Alkylating anticancer agents and their relations to microRNAs

Abstract

Alkylating agents represent an important class of anticancer drugs. The occurrence and emergence of tumor resistance to the treatment with alkylating agents denotes a severe problem in the clinics. A detailed understanding of the mechanisms of activity of alkylating drugs is essential in order to overcome drug resistance. In particular, the role of non-coding microRNAs concerning alkylating drug activity and resistance in various cancers is highlighted in this review. Both synthetic and natural alkylating agents, which are approved for cancer therapy, are discussed concerning their interplay with microRNAs.

Keywords

Alkylating agents / microRNA / anticancer agents / DNA / drug resistance

References

[1] Smith SL.War! What is it good for? Mustard gas medicine..CMAJ2017;189:E321-2 PMCID:PMC5325736

[2] Ralhan R.Alkylating agents and cancer therapy..Expert Opin Ther Patents2007;17:1061-75

[3] Baker SD,Statkevich P,Alton K.Absorption, metabolism, and excretion of 14C-temozolomide following oral administration to patients with advanced cancer..Clin Cancer Res1999;5:309-17

[4] Bradner WT.Mitomycin C: a clinical update..Cancer Treat Rev2001;27:35-50

[5] Ghosh N,Searcey M.Chemical and biological explorations of the family of CC-1065 and the duocarmycin natural products..Curr Topics Med Chem2009;9:1494-524

[6] Schobert R,Seibt S.Anticancer active illudins: recent developments of a potent alkylating compound class..Curr Med Chem2011;18:790-807

[7] Carter NJ.Trabectedin: a review of its use in soft tissue sarcoma and ovarian cancer..Drugs2010;70:355-76

[8] Guarnieri DJ.MicroRNAs: a new class of gene regulators..Ann Med2008;40:197-208

[9] Bartels DB.MicroRNAs: genomics, biogenesis, mechanism, and function..Cell2004;116:281-98

[10] Wu S,Ding Y,Liang L.Multiple microRNAs modulate p21Cip1/Waf1 expression by directly targeting its 3’ untranslated region..Oncogene2010;29:2302-8

[11] Calin GA.MicroRNA signatures in human cancers..Nat Rev Cancer2006;6:857-66

[12] Mallick R,Yendumuri S.Micro RNAs and lung cancer: biology and prognosis in diagnosis and prognosis..J Carcinog2010;9:8 PMCID:PMC2925280

[13] Rothe F,Chaboteaux C,Kheddoumi N.Global microRNA expression profiling identifies miR-210 associated with tumor proliferation, invasion and poor clinical outcome in breast cancer..PLoS One2011;6:e20980 PMCID:PMC3126805

[14] Shimono Y,Cho RW,Dalerba P.Downregulation of miRNA-200c links breast cancer stem cells with normal cells..Cell2009;138:592-603 PMCID:PMC2731699

[15] Gregory PA,Bert AG.MicroRNAs as regulators of epithelial-mesenchymal transition..Cell Cycle2008;7:3112-8

[16] Biersack B.Interactions between anticancer active platinum complexes and non-coding RNAs/microRNAs..Non-coding RNA Res2017;2:1-17 PMCID:PMC6096430

[17] Su JL,Johansson G.Function and regulation of let-7 microRNAs..MicroRNA2012;1:34-9

[18] Feng YH.Emerging role of microRNA-21 in cancer..Biomed Rep2016;5:395-402 PMCID:PMC5038362

[19] Singh RK,Prasad DN.Therapeutic journey of nitrogen mustards alkylating anticancer agents: historic to future perspectives..Eur J Med Chem2018;151:401-33

[20] Goede V,Fischer K,Hallek M.Past, present and future role of chlorambucil in the treatment of chronic lymphocytic leukemia..Leuk Lymphoma2015;56:1585-92

[21] Zenz T,Edelmann J,Hoth P.Treatment resistance in chronic lymphocytic leukemia: the role of the p53 pathway..Leuk Lymphoma2009;50:510-3

[22] Zenz T,Eldering E,Bühler A.MiR-34a as part of the resistance network in chronic lymphocytic leukemia..Blood2009;113:3801-8

[23] Battistella M,Castro-Vega LJ,Bouhidel F.The high expression of the microRNA 17-92 cluster and its paralogs, and the downregulation of the target gene PTEN, is associated with primary cutaneous B-cell lymphoma progression..J Invest Dermatol2015;135:1659-67

[24] Costales MG,Velagapudi SP,Phinney DG.Small molecule inhibition of microRNA-210 reprograms an oncogenic hypoxic circuit..J Am Chem Soc2017;139:3446-55 PMCID:PMC5810126

[25] Zweegman S.Treatment of myeloma: recent developments..Anticancer Drugs2002;13:339-51

[26] Manier S,Avet-Loiseau H,Shi J.Prognostic role of circulating exosomal miRNAs in multiple myeloma..Blood2017;129:2429-36 PMCID:PMC5409448

[27] Hao M,An G,Yu Z.Suppressing miRNA-15a/16 expression by interleukin-6 enhances drug-resistance in myeloma cells..J Hematol Oncol2011;4:37 PMCID:PMC3189173

[28] Zhao JJ,Hu Y,Wang J.Targeting the miR-221-222/PUMA/BAK/BAX pathway abrogates dexamethasone resistance in multiple myeloma..Cancer Res2015;75:4384-97 PMCID:PMC4609291

[29] Gullá A,Cantafio MEG,Amodio N.A 13 mer LNA-i-miR-221 inhibitor restores drug sensitivity in melphalan-refractory multiple myeloma cells..Clin Cancer Res2015;22:1222-33 PMCID:PMC4775414

[30] Du J,He J,Qu Y.MicroRNA-451 regulates stemness of side population cells via PI3K/Akt/mTOR signaling pathway in multiple myeloma..Oncotarget2015;6:14993-5007 PMCID:PMC4558131

[31] Emadi A,Brodsky RA.Cyclophosphamide and cancer: golden anniversary..Nat Rev Clin Oncol2009;6:638-47

[32] Boddy AV.Metabolism and pharmacokinetics of oxazaphosphorines..Clin Pharmacokinet2000;39:291-304

[33] Zhang J,Chan SY,Zhou S.Insights into oxaphosphorine resistance and possible approaches to its circumvention..Drug Resist Updat2005;8:271-97

[34] Cho WCS.Great potential of microRNAs as predictive and prognostic markers for cancer..Expert Rev Mol Diagn2012;12:315-8

[35] Yu X.New insights into microRNAs involves in drug resistance in diffuse large B cell lymphoma..Am J Transl Res2015;7:2536-42 PMCID:PMC4731655

[36] Yuan WX,Na WN,Yang X.Circulating microRNA-125b and microRNA-130a expression profiles predict chemoresistance to R-CHOP in diffuse large B-cell lymphoma patients..Oncol Lett2016;11:423-32 PMCID:PMC4726930

[37] Alencar AJ,Kozloski GA,Talreja N.MicroRNAs are independent predictors of outcome in diffuse large B-cell lymphoma patients treated with R-CHOP..Clin Cancer Res2011;17:4125-35 PMCID:PMC3117929

[38] Montes-Moreno S,Sanchez-Espiridión B,Rodriguez ME.MiRNA expression in diffuse large B-cell lymphoma treated with chemoimmunotherapy..Blood2011;118:1034-40

[39] Bai H,Deng C,Wang C.MicroRNA-21 regulates the sensitivity of diffuse large B-cell lymphoma cells to the CHOP chemotherapy regimen..Int J Hematol2013;97:223-31

[40] Zheng Z,Zhu Y,Xie X.Prognostic significance of miRNA in patients with diffuse large B-cell lymphoma: a meta-analysis..Cell Physiol Biochem2016;39:1891-904

[41] Berglund M,Amini RM,Thunberg U.High expression of microRNA-200c predicts poor clinical outcome in diffuse large B-cell lymphoma..Oncol Rep2013;29:720-4

[42] Iqbal J,Huang X,Wake L.Global microRNA expression profiling uncovers molecular markers for classification and prognosis in aggressive B-cell lymphoma..Blood2015;125:1137-45 PMCID:PMC4326773

[43] Hedstrom G,Berglund M,Amini RM.Low expression of microRNA-129-5p predicts poor clinical outcome in diffuse large B cell lymphoma (DLBCL)..Int J Hematol2013;97:465-71

[44] Huang H,Yao S,Zhao Y.MicroRNAs are related to rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone resistance in patients with diffuse large B-cell lymphoma..Cancer Transl Med2015;1:6-10

[45] Wu PY,Zhu J,Wang JF.Low expression of microRNA-146b-5p and microRNA-320d predicts poor outcome of large B-cell lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisone..Hum Pathol2014;45:1664-73

[46] Song G,Li J,Liu H.Serum microRNA expression profiling predict response to R-CHOP treatment in diffuse large B cell lymphoma patients..Ann Hematol2014;93:1735-43

[47] Chigrinova E,Shen Y,Chan WC.Integrated profiling of diffuse large B-cell lymphoma with 7q gain..Br J Haematol2011;153:499-503

[48] Salter KH,Walters KS,Anguiano A.An integrated approach t the prediction of chemotherapeutic response in patients with breast cancer..PLoS One2008;3:e1908 PMCID:PMC2270912

[49] Sun G,Liu Y,Wang K.Her-2 expression regulated by downregulation of miR-9 and which affects chemotherapeutic effect in breast cancer..Cancer Gene Ther2017;24:194-202

[50] Gezer U,Igci A,Tiryakioglu D.Abundant circulating microRNAs in breast cancer patients fluctuate considerably during neoadjuvant chemotherapy..Oncol Lett2014;8:845-8 PMCID:PMC4081437

[51] Al-Khanbashi M,Alajmi AM,Al-Riyami M.Tissue and serum miRNA profile in locally advanced breast cancer (LABC) in response to neo-adjuvant chemotherapy (NAC) treatment..PLoS One2016;11:e152032 PMCID:PMC4827834

[52] Hu Y,Yagüe E,Liu J.MiRNA-205 targets VEGFA and FGF2 and regulates resistance to chemotherapeutics in breast cancer..Cell Death Dis2016;7:e2291 PMCID:PMC5108343

[53] Hu H,Cui X,Jiao Y.The overexpression of hypomethylated miR-663 induces chemotherapy resistance in human breast cancer cells by targeting heparin sulfate proteoglycan 2 (HSPG2)..J Biol Chem2013;288:10973-85 PMCID:PMC3630848

[54] Kolacinska A,Fendler W,Morawiec Z.Association of microRNAs and pathogenic response to preoperative chemotherapy in triple negative breast cancer: preliminary report..Mol Biol Rep2014;41:2851-7 PMCID:PMC4013446

[55] García-Vazquez R,García AM,Lara-Medina F.A microRNA signature associated with pathological complete response to novel neoadjuvant therapy regimen in triple-negative breast cancer..Tumor Biol2017;39:1010428317702899

[56] Hubaux R,Cosse JP,Kapoor V.Valproic acid improves second-line regimen of small cell lung carcinoma in preclinical models..ERJ Open Res2015;1:00028-2015 PMCID:PMC5005116

[57] Pan YZ,Yu AM.MicroRNAs regulate CYP3A4 expression via direct and indirect targeting..Drug Metab Dispos2009;37:2112-7 PMCID:PMC2769037

[58] Ravery V,Oudard S,Eymard JC.The use of estramustine phosphate in the modern management of advanced prostate cancer..BJU Int2011;108:1782-6

[59] Wei C,Huang H.Estramustine phosphate induces prostate cancer cell line PC3 apoptosis by down-regulating miR-31 levels..Eur Rev Med Pharmacol Sci2018;22:40-5

[60] Lin X.Re-expression of microRNA-4319 inhibits growth of prostate cancer via Her-2 suppression..Clin Transl Oncol2018;20:1400-7

[61] Teimouri F,Abdollahi M.Efficacy and side effects of dacarbazine in comparison with temozolomide in the treatment of malignant melanoma: a meta-analysis consisting of 1314 patients..Melanoma Res2013;23:381-9

[62] Zhu W,Qian JQ,Shu YQ.Temozolomide for the treatment of brain metastases: a review of 21 clinical trials..World J Clin Oncol2014;5:19-27 PMCID:PMC3920177

[63] Newlands ES,Wedge SR,Brock C.Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials..Cancer Treat Rev1997;23:35-61

[64] Chen YN.Dacarbazine inhibits proliferation of melanoma FEMX-1 cells by up-regulating expression of miRNA-200..Eur Rev Med Pharmacol Sci2017;21:1191-7

[65] Jones K,Keane C,Gandhi MK.Plasma microRNA are disease response biomarkers in classical Hodgkin lymphoma..Clin Cancer Res2013;20:253-64

[66] Shi L,Yang J,Zhang S.MiR-21 protected human glioblastoma U78MG cells from chemotherapeutic drug temozolomide induced apoptosis be decreasing Bax/Bcl-2 ratio and caspase-3 activity..Brain Res2010;1352:255-64

[67] Zhang S,Pan T,Qian C.MicroRNA-21 inhibitor sensitizes human glioblastoma U251 stem cells to chemotherapeutic drug temozolomide..J Mol Neurosci2012;47:346-56

[68] Wong ST,Zhuang JT,Li CH.MicroRNA-21 inhibition enhances in vitro chemosensitivity of temozolomide-resistant glioblastoma cells..Anticancer Res2012;32:2835-41

[69] Gwak HS,Jo GH,Kwak HJ.Silencing of microRNA-21 confers radio-sensitivity through inhibition of the PI3K/AKT pathway and enhancing autophagy in malignant glioma cell lines..PLoS One2012;7:e47449 PMCID:PMC3471817

[70] Comincini S,Palumbo S,Durando F.MicroRNA-17 regulates the expression of ATG7 and modulates the autophagy process, improving the sensitivity to temozolomide and low-dose ionizing radiation treatments in human glioblastoma cells..Cancer Biol Ther2013;14:574-86 PMCID:PMC3742487

[71] Ananta JS,Massoud TF.Nanoparticle-delivered antisense microRNA-21 enhances the effects of temozolomide on glioblastoma..Mol Pharmaceutics2015;12:4509-17

[72] Ujifuku K,Takakura S,Saenko V.MiR-195, miR-455-3p and miR-10a(*) are implicated in acquired temozolomide resistance in glioblastoma multiforme cells..Cancer Lett2010;296:241-8

[73] Tezcan G,Bekar A,Berghoff AS.MicroRNA expression pattern modulates temozolomide response in GBM tumors with cancer stem cells..Cell Mol Neurobiol2014;34:679-92

[74] Cirilo PDR,Corrêa BRS,Furuya TK.MicroRNA-195 acts as an anti-proliferative miRNA in human melanoma cells by targeting prohibitin 1..BMC Cancer2017;17:750 PMCID:PMC5681823

[75] Munoz JL,Rameshwar P.High expression of miR-9 in CD133(+) glioblastoma cells in chemoresistance to temozolomide..J Cancer Stem Cell Res2015;3:e1003 PMCID:PMC4917210

[76] Munoz JL,Ramkissoon SH,Greco SJ.Temozolomide resistance in glioblastoma occurs by miRNA-9-targeted PTCH1, independent of sonic hedgehog level..Oncotarget2015;6:1190-201 PMCID:PMC4359226

[77] Stojcheva N,Sass S,Florea AM.MicroRNA-138 promotes acquired alkylator resistance in glioblastoma by targeting the Bcl-2-interacting mediator BIM..Oncotarget2016;7:12937-50 PMCID:PMC4914333

[78] Han J.MiR-16 modulate temozolomide resistance by regulating BCL-2 in human glioma cells..Int J Clin Exp Pathol2015;8:12698-707 PMCID:PMC4680404

[79] Luo H,Wang S,Qiu W.C-Myc-miR-29c-REV3L signaling pathway drives the acquisition of temozolomide resistance in glioblastoma..Brain2015;138:3654-72

[80] Xiao S,Qiu X,Liu J.MiR-29c contribute to glioma cells temozolomide sensitivity by targeting O6-methylgunine-DNA methyltransferases indirectly..Oncotarget2016;7:50229-38 PMCID:PMC5226579

[81] Xu J,Peng R,Jiang B.MicroRNA-30a increases the chemosensitivity of U251 glioblastoma cells to temozolomide by directly targeting beclin 1 and inhibiting autophagy..Exp Ther Med2018;15:4798-804 PMCID:PMC5952084

[82] Wu H,Cai T,Liao F.MiR-136 modulates glioma cell sensitivity to temozolomide by targeting astrocyte elevated gene-1..Diagn Pathol2014;9:173 PMCID:PMC4195982

[83] Wang L,Jiang CF,Chen Q.MiR-143 acts as a tumor suppressor by targeting N-RAS and enhances temozolomide-induced apoptosis in glioma..Oncotarget2014;5:5416-27 PMCID:PMC4170647

[84] Chen R,Cheng Q,Peng R.MicroRNA-93 promotes the malignant phenotypes of human glioma cells and induces their chemoresistance to temozolomide..Biol Open2016;5:669-77 PMCID:PMC4920179

[85] Shi L,Feng K,Wan Y.MicroRNA-125b-2 confers human glioblastoma stem cell resistance to temozolomide through the mitochondrial pathway of apoptosis..Int J Oncol2012;40:119-29

[86] Chen L,Han L,Zhang C.Downregulation of miR-221/222 sensitizes glioma cells to temozolomide by regulating apoptosis independently of the p53 status..Oncol Rep2012;27:854-60

[87] Zhou X,Zeng A,Jin X.MicroRNA-141-3p promotes glioma cell growth and temozolomide resistance by directly targeting p53..Oncotarget2017;8:71080-94 PMCID:PMC5642619

[88] Peng Y,Chen H,Shao B.Inhibition of microRNA-299-5p sensitizes glioblastoma cells to temozolomide via the MAPK/ERK signaling pathway..Biosci Rep2018;38:BSR20181051 PMCID:PMC6131327

[89] Tian T,Qiu X.MicroRNA-101 reverses temozolomide resistance by inhibition of GSK3b in glioblastoma..Oncotarget2016;7:79584-95 PMCID:PMC5346737

[90] Chen PH,Shih CM,Lin CW.The inhibition of microRNA-128 on IGF-1-activating mTOR signaling involves in temozolomide-induced glioma cell apoptotic death..PLoS One2016;11:e0167096 PMCID:PMC5125683

[91] Chen H,Zheng H.MiR-130a can predict response to temozolomide in patients with glioblastoma multiforme, independently of O6-methylguanine-DANN methyltransferase..J Transl Med2015;13:69 PMCID:PMC4345002

[92] Kushwaha D,Ng K,Nguyen T.A genome-wide miRNA screen revealed miR-603 as a MGMT-regulating miRNA in glioblastomas..Oncotarget2014;5:4026-39 PMCID:PMC4147303

[93] Lee YY,Wang ML,Chiou SH.MicroRNA-142-3p is involved in regulation of MGMT expression in glioblastoma cells..Cancer Management Res2018;10:775-85 PMCID:PMC5903834

[94] Kreth S,Hinske LC,Thon N.In human glioblastomas transcript elongation by alternative polyadenylation and miRNA targeting is a potent mechanism of MGMT silencing..Acta Neuropathol2013;125:671-81

[95] Kouri FM,Daniel WL,Hua Y.MiR-182 integrates apoptosis, growth, and differentiation programs in glioblastoma..Genes Dev2015;29:732-45 PMCID:PMC4387715

[96] Cheng ZX,Wang ZY.MicroRNA-132 induces temozolomide resistance and promotes the formation of cancer stem cell phenotypes by targeting tumor suppressor candidate 3 in glioblastoma..Int J Mol Med2017;40:1307-14 PMCID:PMC5627876

[97] Gao YT,Liu HL.Up-regulation of miR-370-3p restores glioblastoma multiforme sensitivity to temozolomide by influencing MGMT expression..Sci Rep2016;6:32972 PMCID:PMC5011744

[98] Li S,Hu Q,Liu Y.MiR-423-5p contributes to a malignant phenotype and temozolomide chemoresistance in glioblastomas..Neuro Oncol2017;19:55-65 PMCID:PMC5193021

[99] Chen HY,Zhang CB,Zheng HY.MiR-629-3p level significantly predicts prognosis in glioblastoma patients with temozolomide chemotherapy..Curr Signal Transd Ther2014;9:9-14

[100] Li XB,Xu AD,Meng LQ.The microRNA-1268 rs28599926 polymorphism modified diffusely infiltrating astrocytoma risk and prognosis..Int J Clin Exp Med2016;9:21615-24 PMCID:PMC3907808

[101] Chen H,Li X,Liu N.MicroRNA-1294 inhibits the proliferation and enhances the chemosensitivity of temozolomide via the direct targeting of TPX2..Am J Cancer Res2018;8:291-301 PMCID:PMC5835696

[102] Ahir BK,Engelhard HH.MicroRNAs in glioblastoma pathogenesis and therapy: a comprehensive review..Crit Rev Oncol Hematol2017;120:22-33

[103] Quintavalle C,Roscigno G,Diaz-Lagares A.MiR-221/222 target the DNA methyltransferase MGMT in glioma cells..PLoS One2013;8:e74466 PMCID:PMC3798259

[104] Bassiouny AR.Synergistic effect of curcumin on temozolomide inhibition of cancer stem cell-like properties and reduced chemoresistance of glioblastoma C6..J Stem Cell Res Ther2012;2:5

[105] Schepartz SA.Early history and development of the nitrosoureas..Cancer Treat Rep1976;60:647-9

[106] Weiss RB.The nitrosoureas: carmustine (BCNU) and lomustine (CCNU)..Cancer Treat Rev1982;9:313-30

[107] Reithmeier T,Piroth T,Pinsker MO.BCNU for recurrent glioblastoma multiforme: efficacy, toxicity and prognostic factors..BMC Cancer2010;10:30 PMCID:PMC2837009

[108] Kohn KW.Interstrand coss-linking of DNA by 1,3-bis(2-chloroethyl)-1-nitrosourea and other 1-(2-chloroethyl)-1-nitrosoureas..Cancer Res1977;37:1450-4

[109] Panasci LC,Nagourney R,Schein PS.A structure-activity analysis of chemical and biological parameters of chloroethylnitrosoureas in mice..Cancer Res1977;37:2615-8

[110] Winkler JA,Johnson D,Scheck AC.Global microRNA expression analysis in human malignant glioma cells reveals novel miRNA-mediated therapy-resistance mechanisms..Proc Amer Assoc Cancer Res2005;46:Abstract No 5942

[111] Wang GB,Hu J.MiR-21 enhanced glioma cells resistance to carmustine via decreasing Spry2 expression..Eur Rev Med Pharmacol Sci2017;21:5065-71

[112] Sippl C,Bohr L,List M.MiRNA-181d expression significantly affects treatment responses to carmustine wafer implantation..Neurosurgery2018;

[113] Xie Q,Huang Z,Huang L.MicroRNA-221 targeting PI3-K/Akt signaling axis indces cell proliferation and BCNU resistance in human glioblastoma..Neuropathol2014;34:455-64

[114] Anchel M,Robbins WJ.Antibiotic substances from Basidiomycetes. VII. Clitocybe illudens..Proc Natl Acad Sci1950;6:30-6 PMCID:PMC1063187

[115] Crooke ST.Mitomycin C: a review..Cancer Treat Rev1976;3:121-39

[116] Hata T.Mitomycin, a new antibiotic from Streptomyces. II. Description of the strain..J Antibiot1956;9:147-51

[117] Wakaki S,Tomioka K,Kato E.Isolation of new fractions of antitumor mitomycins..Antibiotics Chemother1958;8:228-40

[118] Frank W.Mitomycin C: a evaluation of the Japanese reports..Cancer Chemother Rep1960;9:114-9

[119] Bradner WT.Mitomycin C: a clinical update..Cancer Treat Rev2001;27:35-50

[120] Tomasz M.Mitomycin C: small, fast and deadly (but very selective)..Chem Biol1995;2:575-9

[121] Feist M,Müller JM,Dubiel W.Can hyperthermic intraperitoneal chemotherapy efficiency be improved by blocking the DNA repair factor COP9 signalosome?.Int J Colorectal Dis2014;29:673-80

[122] Xu T,Zhu Z,Liu Y.MicroRNA-31 functions as a tumor suppressor and increases sensitivity to mitomycin-C in urothelial bladder cancer by targeting integrin α5..Oncotarget2016;7:27445-57 PMCID:PMC5053662

[123] Weeraratne SD,Neiss A,Scott DK.MiR-34a confers chemosensitivity through modulation of MAGE-A and p53 in medulloblastoma..Neuro Oncol2011;13:165-75 PMCID:PMC3064629

[124] Sharma S,Ghosh PC.p53-miR-191-SOX4 regulatory loop affects apoptosis in breast cancer..RNA2017;23:1237-46 PMCID:PMC5513068

[125] Mezencev R,Jabbari N.Snail-induced epithelial-to-mesenchymal transition of MCF-7 breast cancer cells: systems analysis of molecular changes and their effect on radiation and drug sensitivity..BMC Cancer2016;16:236 PMCID:PMC4797178

[126] Lee S,Ryu YS,Hong IS.MiR-543 and miR-590-3p regulate human mesenchymal stem cell aging via direct targeting of AIMP3/p18..AGE2014;36:9724 PMCID:PMC4259092

[127] Xu K,Cui D,Shi W.MiR-1915 inhibits Bcl-2 to modulate multidrug resistance by increasing drug-sensitivity in human colorectal carcinoma cells..Mol Carcinogen2013;52:70-8

[128] Tarasov VA,Shin EF,Timoshkina NN.Inheritable changes in miRNAs expression in HeLa cells after X-ray and mitomycin C treatment..Russ J Gen2014;50:798-806

[129] Le VH,Williams RM.Ecteinascidins. A review of the chemistry, biology and clinical utility of potent tetrahydroisoquinoline antitumor antibiotics..Nat Prod Rep2015;32:328-47 PMCID:PMC4806878

[130] Jaspers NG,Kelner MJ,Yamashita YM.Anti-tumour compounds illudin S and irofulven induce DNA lesions ignored by global repair and exclusively processed by transcription- and replication-coupled repair pathways..DNA Repair2002;1:1027-38

[131] Forni C,Virdis E,Simone M.Trabectedin (ET-743) promotes differentiation in myxoid liposarcoma tumors..Mol Cancer Ther2009;8:449-57

[132] Uboldi S,Beltrame L,Marchini S.A systems biology approach to characterize the regulatory networks leading to trabectedin resistance in an in vitro model of myxoid liposarcoma..PLoS One2012;7:e35423 PMCID:PMC3327679

[133] Neia CP,Chiorino G,Aglietta M.Gene and microRNA modulation upon trabectedin treatment in a human intrahepatic cholangiocarcinoma paired patient derived xenograft and cell line..Oncotarget2016;7:86766-80 PMCID:PMC5349952