Abstract

Despite significant progress in the last few decades in breast cancer biology and the use of different therapeutic strategies, this cancer remains a serious clinical problem. Paclitaxel (PTX) is used to treat breast cancer both as a monotherapy and in combination with other anticancer drugs depending on the severity of the cancer, the presence of metastases and previous therapeutic management. It is characterized by high effectiveness both in early breast cancer and in metastatic breast cancer. Primary or acquired drug resistance of tumour cells to taxanes is a significant clinical problem in the treatment of various histological types of breast cancer. The main problem of resistance of tumour cells is the complexity and multifactorial nature of this phenomenon, which is conditioned by numerous different mechanisms that interact with each other. Among the known mechanisms of breast cancer cells resistance to PTX, the most important are the active removal of the drug from the cell related to the increased activity of ABC family membrane transporters, enhanced drug detoxification by cytochrome P450, CYP3A4/5 and CYP2C8 enzymes, changes within the molecular targets of PTX, microtubule and disorders of microtubule associated protein (MAPs) or apoptosis. This paper presents the latest reports on the mechanisms of drug resistance of breast cancer cells to PTX, pointing to modern strategies to counteract this adverse phenomenon.

References

• 1. Ajabnoor G.M., Crook T., Coley H.M.: Paclitaxel resistance is asso­ciated with switch from apoptotic to autophagic cell death in MCF-7 breast cancer cells. Cell Death Dis., 2012; 3: e260
  Google Scholar
• 2. Alli E., Yang J.M., Ford J.M., Hait W.N.: Reversal of stathmin-me­diated resistance to paclitaxel and vinblastine in human breast car­cinoma cells. Mol. Pharmacol., 2007; 71: 1233–1240
  Google Scholar
• 3. Anreddy N., Gupta P., Kathawala R.J., Patel A., Wurpel J.N., Chen Z.S.: Tyrosine kinase inhibitors as reversal agents for ABC trans­porter mediated drug resistance. Molecules, 2014; 19: 13848–13877
  Google Scholar
• 4. Blanco E., Sangai T., Wu S., Hsiao A., Ruiz-Esparza G.U., Gonzalez­-Delgado C.A., Cara F.E., Granados-Principal S., Evans K.W., Akcakanat A., Wang Y., Do K.A., Meric-Bernstam F., Ferrari M.: Colocalized delivery of rapamycin and paclitaxel to tumors enhances synergistic targe­ting of the PI3K/Akt/mTOR pathway. Mol. Ther., 2014; 22: 1310–1319
  Google Scholar
• 5. Brown R., Curry E., Magnani L., Wilhelm-Benartzi C.S., Borley, J.: Poised epigenetic states and acquired drug resistance in cancer. Nat. Rev. Cancer, 2014; 14: 747–753
  Google Scholar
• 6. Chen Y., Tang Y., Chen S., Nie D.: Regulation of drug resistance by human pregnane X receptor in breast cancer. Cancer Biol. Ther., 2009; 8: 1265–1272
  Google Scholar
• 7. Chen Z., Shi T., Zhang L., Zhu P., Deng M., Huang C., Hu T., Jiang L., Li J.: Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett., 2016; 370: 153–164
  Google Scholar
• 8. Choi Y.H., Yu A.M.: ABC transporters in multidrug resistance and pharmacokinetics, and strategies for drug development. Curr. Pharm. Des., 2014; 20: 793–807
  Google Scholar
• 9. Conde I., Lobo M.V., Zamora J., Pérez J., González F.J., Alba E.,Fraile B., Paniagua R., Arenas M.I.: Human pregnane X receptor isexpressed in breast carcinomas, potential heterodimers formationbetween hPXR and RXR-alpha. BMC Cancer, 2008; 8: 174
  Google Scholar
• 10. Croker A.K., Goodale D., Chu J., Postenka C., Hedley B.D., HessD.A., Allan A.L.: High aldehyde dehydrogenase and expressionof cancer stem cell markers selects for breast cancer cells with enhanced malignant and metastatic ability. J. Cell. Mol. Med., 2009; 13: 2236–2252
  Google Scholar
• 11. Cui S.Y., Wang R., Chen L.B.: MicroRNAs: key players of taxane resistance and their therapeutic potential in human cancers. J. Cell. Mol. Med., 2013; 17: 1207–1217
  Google Scholar
• 12. Dehghankelishadi P., Saadat E., Ravar F., Safavi M., Pordeli M., Gholami M., Dorkoosh F.A.: In vitro and in vivo evaluation of paclita­xel-lapatinib-loaded F127 pluronic micelles. Drug Dev. Ind. Pharm., 2017; 43: 390–398
  Google Scholar
• 13. Duan Z., Li X., Huang H., Yuan W., Zheng S.L., Liu X., Zhang Z., Choy E., Harmon D., Mankin H., Hornicek F.: Synthesis and evalu­ation of (2-(4-methoxyphenyl)-4-quinolinyl)(2-piperidinyl)metha­nol (NSC23925) isomers to reverse multidrug resistance in cancer. J. Med. Chem., 2012; 55: 3113–3121
  Google Scholar
• 14. Fletcher J.I., Williams R.T., Henderson M.J., Norris M.D., Haber M.: ABC transporters as mediators of drug resistance and contribu­tors to cancer cell biology. Drug Resist. Updat., 2016; 26: 1–9
  Google Scholar
• 15. Fracasso P.M., Brady M.F., Moore D.H., Walker J.L., Rose P.G., Le­tvak L., Grogan T.M., McGuire W.P.: Phase II study of paclitaxel and valspodar (PSC 833) in refractory ovarian carcinoma: A gynecologic oncology group study. J. Clin. Oncol., 2001; 19: 2975–2982
  Google Scholar
• 16. Hansen S.N., Westergaard D., Thomsen M.B., Vistesen M., Do K.N., Fogh L., Belling K.C., Wang J., Yang H., Gupta R., Ditzel H.J., Mo­reira J., Brünner N., Stenvang J., Schrohl A.S.: Acquisition of doceta­xel resistance in breast cancer cells reveals upregulation of ABCB1 expression as a key mediator of resistance accompanied by discrete upregulation of other specific genes and pathways. Tumour Biol., 2015; 36: 4327–4338
  Google Scholar
• 17. Hari M., Loganzo F., Annable T., Tan X., Musto S., Morilla D.B., Nettles J.H., Snyder J.P., Greenberger L.M.: Paclitaxel resistant cells have a mutation in the paclitaxel-binding region of β-tubulin (Asp­26Glu) and less stable microtubules. Mol. Cancer Ther., 2006; 5: 270–278
  Google Scholar
• 18. Harris J.W., Rahman A., Kim B.R., Guengerich F.P., Collins J.M.: Metabolism of taxol by human hepatic microsomes and liver slices: participation of cytochrome P450 3A4 and an unknown P450 enzy­me. Cancer Res., 1994; 54: 4026–4035
  Google Scholar
• 19. Kapse-Mistry S., Govender T., Srivastava R., Yergeri M.: Na­nodrug delivery in reversing multidrug resistance in cancer cells. Front. Pharmacol., 2014; 5: 159
  Google Scholar
• 20. Kastl L., Brown I., Schofield A.C.: Altered DNA methylation is associated with docetaxel resistance in human breast cancer cells. Int. J. Oncol., 2010; 36: 1235–1241
  Google Scholar
• 21. Kathawala R.J., Gupta P., Ashby C.R. Jr., Chen Z.S.: The modula­tion of ABC transporter-mediated multidrug resistance in cancer: a review of the past decade. Drug Resist. Updat., 2015; 18: 1–17
  Google Scholar
• 22. Kavallaris M.: Microtubules and resistance to tubulin-binding agents. Nat. Rev. Cancer, 2010; 10: 194–204
  Google Scholar
• 23. Kelly R.J., Draper D., Chen C.C., Robey R.W., Figg W.D., Piekarz R.L., Chen X., Gardner E.R., Balis F.M., Venkatesan A.M., Steinberg S.M., Fojo T., Bates S.E.: A pharmacodynamic study of docetaxel in combination with the P-glycoprotein antagonist tariquidar (XR9576) in patients with lung, ovarian, and cervical cancer. Clin. Cancer Res., 2011; 17: 569–580
  Google Scholar
• 24. Kelly R.J., Robey R.W., Chen C.C., Draper D., Luchenko V., Barnett D., Oldham R.K., Caluag Z., Frye A.R., Steinberg S.M., Fojo T., Bates S.E.: A pharmacodynamic study of the P-glycoprotein antagonist CBT-1® in combination with paclitaxel in solid tumors. Oncologist, 2012; 17: 512
  Google Scholar
• 25. Kim M.S., Haney M.J., Zhao Y., Mahajan V., Deygen I., Klyach­ko N.L., Inskoe E., Piroyan A., Sokolsky M., Okolie O., Hingtgen S.D., Kabanov A.V., Batrakova E.V.: Development of exosome-encapsu­lated paclitaxel to overcome MDR in cancer cells. Nanomedicine, 2016; 12: 655–664
  Google Scholar
• 26. Kuang Y.H., Shen T., Chen X., Sodani K., Hopper-Borge E., Tiwari A.K., Lee J.W., Fu L.W., Chen Z.S.: Lapatinib and erlotinib are potent reversal agents for MRP7 (ABCC10)-mediated multidrug resistance. Biochem. Pharmacol., 2010; 79: 154–161
  Google Scholar
• 27. Lhommé C., Joly F., Walker J.L., Lissoni A.A., Nicoletto M.O., Ma­nikhas G.M., Baekelandt M.M., Gordon A.N., Fracasso P.M., Mietlowski W.L., Jones G.J., Dugan M.H.: Phase III study of valspodar (PSC 833) combined with paclitaxel and carboplatin compared with paclita­xel and carboplatin alone in patients with stage IV or suboptimally debulked stage III epithelial ovarian cancer or primary peritoneal cancer. J. Clin. Oncol., 2008; 26: 2674–2682
  Google Scholar
• 28. Li W., Zhai B., Zhi H., Li Y., Jia L., Ding C., Zhang B., You W.: As­sociation of ABCB1, β tubulin I, and III with multidrug resistance of MCF7/DOC subline from breast cancer cell line MCF7. Tumour Biol., 2014; 35: 8883–8891
  Google Scholar
• 29. Li W.J., Zhong S.L., Wu Y.J., Xu W.D., Xu J.J., Tang J.H., Zhao J.H.: Systematic expression analysis of genes related to multidrug-resi­stance in isogenic docetaxel and adriamycin-resistant breast cancer cell lines. Mol. Biol. Rep., 2013; 40: 6143–6150
  Google Scholar
• 30. Litviakov N.V., Cherdyntseva N.V., Tsyganov M.M., Denisov E.V., Garbukov E.Y., Merzliakova M.K., Volkomorov V.V., Vtorushin S.V., Zavyalova M.V., Slonimskaya E.M., Perelmuter V.M.: Changing the expression vector of multidrug resistance genes is related to neo­adjuvant chemotherapy response. Cancer Chemother. Pharmacol., 2013; 71: 153–163
  Google Scholar
• 31. Löwe J., Li H., Downing K.H., Nogales E.: Refined structure of αβ-tubulin at 3.5 A resolution. J. Mol. Biol., 2001; 313: 1045–1057
  Google Scholar
• 32. Luo Y., Wang X., Wang H., Xu Y., Wen Q., Fan S., Zhao R., Jiang S., Yang J., Liu Y., Li X., Xiong W., Ma J., Peng S., Zeng Z., Li X., Phillips J.B., Li G., Tan M., Zhou M.: High Bak expression is associated with a favorable prognosis in breast cancer and sensitizes breast cancer cells to paclitaxel. PLoS One, 2015; 10: e0138955
  Google Scholar
• 33. Malaguti P., Vari S., Cognetti F., Fabi A.: The mammalian target of rapamycin inhibitors in breast cancer: current evidence and fu­ture directions. Anticancer Res., 2013; 33: 21–28
  Google Scholar
• 34. Miki Y., Suzuki T., Kitada K., Yabuki N., Shibuya R., Moriya T., Ishida T., Ohuchi N., Blumberg B., Sasano H.: Expression of the steroid and xenobiotic receptor and its possible target gene, organic anion transporting polypeptide-A, in human breast carcinoma. Cancer Res., 2006; 66: 535–542
  Google Scholar
• 35. Murray S., Briasoulis E., Linardou H., Bafaloukos D., Papadimi­triou C.: Taxane resistance in breast cancer: mechanisms, predic­tive biomarkers and circumvention strategies. Cancer Treat. Rev., 2012; 38: 890–903
  Google Scholar
• 36. Němcová-Fürstová V., Kopperová D., Balušíková K., Ehrlicho­vá M., Brynychová V., Václavíková R., Daniel P., Souček P., Kovář J.: Characterization of acquired paclitaxel resistance of breast cancer cells and involvement of ABC transporters. Toxicol. Appl. Pharma­col., 2016; 310: 215–228
  Google Scholar
• 37. Peereboom D.M., Murphy C., Ahluwalia M.S., Conlin A., Eichler A., Van Poznak C., Baar J., Elson P., Seidman A.D.: Phase II trial of patupilone in patients with brain metastases from breast cancer. Neuro Oncol., 2014; 16: 579–583
  Google Scholar
• 38. Perez EA.: Paclitaxel in breast cancer. Oncologist, 1998; 3: 373–389
  Google Scholar
• 39. Pusztai L., Wagner P., Ibrahim N., Rivera E., Theriault R., Booser D., Symmans F.W., Wong F., Blumenschein G., Fleming D.R., Rouzier R., Boniface G., Hortobagyi G.N.: Phase II study of tariquidar, a se­lective P-glycoprotein inhibitor, in patients with chemotherapy­-resistant, advanced breast carcinoma. Cancer, 2005; 104: 682–691
  Google Scholar
• 40. Qiao E.Q., Yang H.J.: Effect of pregnane X receptor expression on drug resistance in breast cancer. Oncol. Lett., 2014; 7: 1191–1196
  Google Scholar
• 41. Rahman A., Korzekwa K.R., Grogan J., Gonzalez F.J., Harris J.W.: Selective biotransformation of taxol to 6α-hydroxytaxol by human cytochrome P450 2C8. Cancer Res., 1994; 54: 5543–5546
  Google Scholar
• 42. Reed K., Hembruff S.L., Sprowl J.A., Parissenti A.M.: The tempo­ral relationship between ABCB1 promoter hypomethylation, ABCB1 expression and acquisition of drug resistance. Pharmacogenomics J., 2010; 10: 489–504
  Google Scholar
• 43. Roque D.M., Bellone S., English D.P., Buza N., Cocco E., Gaspar­rini S., Bortolomai I., Ratner E., Silasi D.A., Azodi M., Rutherford T.J., Schwartz P.E., Santin A.D.: Tubulin-β-III overexpression by uterine serous carcinomas is a marker for poor overall survival after plati­num/taxane chemotherapy and sensitivity to epothilones. Cancer, 2013; 119: 2582–2592
  Google Scholar
• 44. Seiden M.V., Swenerton K.D., Matulonis U., Campos S., Rose P., Batist G., Ette E., Garg V., Fuller A., Harding M.W., Charpentier D.: A phase II study of the MDR inhibitor biricodar (INCEL, VX-710) and paclitaxel in women with advanced ovarian cancer refractory to paclitaxel therapy. Gynecol. Oncol., 2002; 86: 302–310
  Google Scholar
• 45. Sève P., Dumontet C.: Is class III β-tubulin a predictive factor in patients receiving tubulin-binding agents? Lancet Oncol., 2008; 9: 168–175
  Google Scholar
• 46. Sharifi S., Barar J., Hejazi M.S., Samadi N.: Roles of the Bcl-2/Bax ratio, caspase-8 and 9 in resistance of breast cancer cells to paclita­xel. Asian Pac. J. Cancer Prev., 2014; 15: 8617–8622
  Google Scholar
• 47. Shen T., Kuang Y.H., Ashby C.R., Lei Y., Chen A., Zhou Y., Chen X., Tiwari A.K., Hopper-Borge E., Ouyang J., Chen Z.S.: Imatinib and nilotinib reverse multidrug resistance in cancer cells by inhibiting the efflux activity of the MRP7 (ABCC10). PLoS One, 2009; 4: e7520
  Google Scholar
• 48. Shi X., Sun X.: Regulation of paclitaxel activity by microtubu­le-associated proteins in cancer chemotherapy. Cancer Chemother. Pharmacol., 2017; 80: 909–917
  Google Scholar
• 49. Sparano J.A., Vrdoljak E., Rixe O., Xu B., Manikhas A., Medina C., Da Costa S.C., Ro J., Rubio G., Rondinon M., Perez Manga G., Peck R., Poulart V., Conte P.: Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J. Clin. Oncol., 2010; 28: 3256–3263
  Google Scholar
• 50. Stavrovskaya A.A.: Cellular mechanisms of multidrug resistance of tumor cells. Biochemistry, 2000; 65: 95–106
  Google Scholar
• 51. Sudo T., Nitta M., Saya H., Ueno N.T.: Dependence of paclitaxel sensitivity on a functional spindle assembly checkpoint. Cancer Res., 2004; 64: 2502–2508
  Google Scholar
• 52. Sun Y.L., Kumar P., Sodani K., Patel A., Pan Y., Baer M.R., Chen Z.S., Jiang W.Q.: Ponatinib enhances anticancer drug sensitivity in MRP7-overexpressing cells. Oncol. Rep., 2014; 31: 1605–1612
  Google Scholar
• 53. Tamaki A., Ierano C., Szakacs G., Robey R.W., Bates S.E.: The controversial role of ABC transporters in clinical oncology. Essays Biochem., 2011; 50: 209–232
  Google Scholar
• 54. Tanaka S., Nohara T., Iwamoto M., Sumiyoshi K., Kimura K., Ta­kahashi Y., Tanigawa N.: Tau expression and efficacy of paclitaxel treatment in metastatic breast cancer. Cancer Chemother. Pharma­col., 2009; 64: 341–346
  Google Scholar
• 55. Tanei T., Morimoto K., Shimazu K., Kim S.J., Tanji Y., Taguchi T., Tamaki Y., Noguchi S.: Association of breast cancer stem cells iden­tified by aldehyde dehydrogenase 1 expression with resistance to sequential paclitaxel and epirubicin- based chemotherapy for breast cancers. Clin. Cancer Res., 2009; 15: 4234–4241
  Google Scholar
• 56. Tian W., Liu J., Guo Y., Shen Y., Zhou D., Guo S.: Self-assembled micelles of amphiphilic PEGylated rapamycin for loading paclita­xel and resisting multidrug resistant cancer cells. J. Mater. Chem. B, 2015; 3: 1204–1207
  Google Scholar
• 57. Tiwari A.K., Sodani K., Dai C.L., Abuznait A.H., Singh S., Xiao Z.J., Patel A., Talele T.T., Fu L., Kaddoumi A., Gallo J.M., Chen Z.S.: Nilotinib potentiates anticancer drug sensitivity in murine ABCB1-, ABCG2-, and ABCC10-multidrug resistance xenograft models. Cancer Lett., 2013; 328: 307–317
  Google Scholar
• 58. Toppmeyer D., Seidman A.D., Pollak M., Russell C., Tkaczuk K., Verma S., Overmoyer B., Garg V., Ette E., Harding M.W., Demetri G.D.: Safety and efficacy of the multidrug resistance inhibitor Incel (biri­codar; VX-710) in combination with paclitaxel for advanced breast cancer refractory to paclitaxel. Clin. Cancer Res., 2002; 8: 670–678
  Google Scholar
• 59. Wang M.Y., Chen P.S., Prakash E., Hsu H.C., Huang H.Y., Lin M.T., Chang K.J., Kuo M.L.: Connective tissue growth factor confers drug resistance in breast cancer through concomitant up-regulation of Bcl-xL and cIAP1. Cancer Res., 2009; 69: 3482–3491
  Google Scholar
• 60. Wang W., Zhang H., Wang X., Patterson J., Winter P., Graham K., Ghosh S., Lee J.C., Katsetos C.D., Mackey J.R., Tuszynski J.A., Wong G.K., Ludueña R.F.: Novel mutations involving βI-, βIIA-, or βIVB-tubulin isotypes with functional resemblance to βIII-tubulin in bre­ast cancer. Protoplasma, 2017; 254: 1163–1173
  Google Scholar
• 61. Wang X., Yi L., Zhu Y., Zou J., Hong Y., Zheng W.: AKT signaling pathway in invasive ductal carcinoma of the breast: correlation with ERa, ERβ and HER-2 expression. Tumori, 2011; 97: 185–190
  Google Scholar
• 62. Wang Y., Yin S., Blade K., Cooper G., Menick D.R., Cabral F.: Mu­tations at leucine 215 of β-tubulin affect paclitaxel sensitivity by two distinct mechanisms. Biochemistry, 2006; 45: 185–194
  Google Scholar
• 63. Xu F., Wang F., Yang T., Sheng Y., Zhong T., Chen Y.: Differential drug resistance acquisition to doxorubicin and paclitaxel in breast cancer cells. Cancer Cell Int., 2014; 14: 538
  Google Scholar
• 64. Yang X., Shen J., Gao Y., Feng Y., Guan Y., Zhang Z., Mankin H., Hornicek F.J., Duan Z.: Nsc23925 prevents the development of pacli­taxel resistance by inhibiting the introduction of P-glycoprotein and enhancing apoptosis. Int. J. Cancer., 2015; 137: 2029–2039
  Google Scholar
• 65. Yen W.C., Lamph W.W.: The selective retinoid X receptor ago­nist bexarotene (LGD1069, Targretin) prevents and overcomes mul­tidrug resistance in advanced breast carcinoma. Mol. Cancer Ther., 2005; 4: 824–834
  Google Scholar
• 66. Yin S., Bhattacharya R., Cabral F.: Human mutations that confer paclitaxel resistance. Mol. Cancer Ther., 2010; 9: 327–335
  Google Scholar
• 67. Yin S., Cabral F., Veeraraghavan S.: Amino acid substitutions at proline 220 of β-tubulin confer resistance to paclitaxel and colcemid. Mol. Cancer Ther., 2007; 6: 2798–2806
  Google Scholar
• 68. Zhang H., Zhang X., Wu X., Li W., Su P., Cheng H., Xiang L., Gao P., Zhou G.: Interference of Frizzled 1 (FZD1) reverses multidrug re­sistance in breast cancer cells through the Wnt/β-catenin pathway. Cancer Lett., 2012; 323: 106–113
  Google Scholar
• 69. Zhang K., Song H., Yang P., Dai X., Li Y., Wang L., Du J., Pan K., Zhang T.: Silencing dishevelled-1 sensitizes paclitaxel-resistant hu­man ovarian cancer cells via AKT/GSK-3β/β-catenin signalling. Cell Prolif., 2015; 48: 249–258
  Google Scholar
• 70. Zhao W., Song Y., Xu B., Zhan Q.: Overexpression of centroso­mal protein Nlp confers breast carcinoma resistance to paclitaxel. Cancer Biol. Ther., 2012; 13:156–163
  Google Scholar
• 71. Zhuo W., Hu L., Lv J., Wang H., Zhou H., Fan L.: Role of pregna­ne X receptor in chemotherapeutic treatment. Cancer Chemother. Pharmacol., 2014; 74: 217–227
  Google Scholar

Full text