Taiwanese Journal of Obstetrics and Gynecology
Volume 48, Issue 3 , Pages 239-244, September 2009

Mechanisms of Chemotherapeutic Drug Resistance in Cancer Therapy—A Quick Review

  • Fu-Shing Liu

      Affiliations

    • Corresponding Author InformationCorrespondence to: Dr Fu-Shing Liu, Department of Obstetrics and Gynecology, Show Chwan Memorial Hospital, 542, Section 1, Chung-Shang Road, Changhua 500, Taiwan

Department of Obstetrics and Gynecology, Show Chwan Memorial Hospital, Changhua, Taiwan

Accepted 10 March 2009.

Article Outline

Summary 

Chemotherapy is one of the principal modes of treatment for cancer patients. Clinically, many tumors present a satisfactory response when they are first exposed to the chemotherapeutic drugs. However, drug resistance occurs sooner or later in these tumors, and the majority of the patients develop progressive disease. The mechanisms of treatment failure of chemotherapeutic drugs have been well studied. Via a unique protection system, i.e. multidrug resistance (MDR), the cancer cells can escape the toxic effect of most commonly used cancer drugs in spite of their different chemical structures and different mechanisms of intracellular activity. There are two classes of transporter proteins at the cellular surface which are responsible for MDR in tumors. One is the adenosine triphosphate-binding cassette transporter superfamily, which is an energy-requiring efflux pump with the function of extruding toxic chemotherapeutic drugs from the cancer cells. The other is the solute carrier transporter superfamily, which mediates the cellular uptake of anticancer drugs, and drug resistance may result from decreased activity of these transporters. Although transporters of MDR are responsible for the tumor resistance to many chemotherapeutic drugs currently used in cancer therapy, the mechanisms of resistance to platinum-based anti- tumor agents are through different pathways. In this article, the mechanisms of MDR transporters mediating resistance to the commonly used chemotherapeutic drugs and to platinum-based agents are reviewed. Finally, with the finding of cancer stem cells in more and more solid tumors, it is recognized that the cancer stem cell is spared along with its normal tissue stem cell counterparts with very subtle differences. One characteristic of the normal tissue stem cell is the self-protection ability through innate MDR transporters. Therefore, the essential self- protection property is also present in the cancer stem cells. The quiescent tumor stem cell with constitutive MDR is the main barrier to therapy. Successful cancer therapy will depend on the ability to discern the subtle differences between the tumor and normal stem cells so that approaches can be developed to eliminate the tumor stem cells without excessive toxicity to normal stem cells.

Key Words:  antineoplastic drug resistance , cancer , membrane transporters , multidrug resistance , stem cells

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References 

  1. Huang Y . Pharmacogenetics/genomics of membrane transporters in cancer chemotherapy . Cancer Metastasis Rev . 2007;26:183–201
  2. Stavrovskaya AA , Stromskaya TP . Transport proteins of the ABC family and multidrug resistance of tumor cells . Biochemistry . 2008;73:592–604
  3. Sarkadi B , Homolya L , Szakacs G , Varadi A . Human multidrug resistance ABCB and ABCG transporters: participation in chemoimmunity defense system . Physiol Rev . 2006;86:1179–1236
  4. Hrycyna CA, Ramachandra M, Ambudkar SV, Ko YH, Pedersen PL, Pastan I, et al. Mechanism of action of human P-glycoprotein ATPase activity: photochemical cleavage during a catalytic transition state using orthovanadate reveals cross-talk between the two ATP sites . J Biol Chem . 1998;273:16631–16634
  5. Ambudkar SV , Kimchi-Sarfaty C , Sauna ZE , Gottesman MM . P-glycoprotein: from genomics to mechanism . Oncogene . 2003;22:7468–7485
  6. Bourguignon LYW , Peyrollier K , Xia W , Gilad E . Hyaluronan-CD44 interaction activates stem cell marker, Nanog, Stat-3-mediated MDR1 gene expression, and ankyrin-regulated multidrug efflux in breast and ovarian tumor cells . J Biol Chem . 2008;283:17635–17651
  7. Chang XB . A molecular understanding of ATP-dependent solute transport by multidrug resistance-associated protein MRP1 . Cancer Metastasis Rev . 2007;26:15–37
  8. Chen YN , Mickley LA , Schwartz AM , Acton EM , Hwang J , Fojo AT . Characterization of adriamycin-resistant human breast cancer cells which display overexpression of a novel resistance-related membrane protein . J Biol Chem . 1990;265:10073–10080
  9. Robey RW , Polgar O , Deeken J , To KW , Bates SE . ABCG2: determining its relevance in clinical drug resistance . Cancer Metastasis Rev . 2007;26:39–57
  10. Kuo MT , Chen HHW , Song IS , Savaraj N , Ishikawa T . The roles of copper transporters in cisplatin resistance . Cancer Metastasis Rev . 2007;26:71–83
  11. Wang D , Lippard SJ . Cellular processing of platinum anticancer drugs . Nat Rev Drug Discov . 2005;4:307–320
  12. Siddik ZH . Cisplatin: mode of cytotoxic action and molecular basis of resistance . Oncogene . 2003;22:7265–7279
  13. Samimi G , Safaei R , Katano K , et al.   Increased expression of the copper efflux transporter ATP7A mediates resistance to cisplatin, carboplatin, and oxaliplatin in ovarian cancer cells . Clin Cancer Res . 2004;10:4661–4669
  14. Samimi G , Varki NM , Wilczynski S , Safaei R , Alberts DS , Howell SB . Increase in expression of the copper transporter ATP7A during platinum drug-based treatment is associated with poor survival in ovarian cancer patients . Clin Cancer Res . 2003;9:5853–5859
  15. Donnenberg VS , Donnenberg AD . Multiple drug resistance in cancer revisited: the cancer stem cell hypothesis . J Clin Pharmacol . 2005;45:872–877
  16. Lou H , Dean M . Targeted therapy for cancer stem cells: the patched pathway and ABC transporters . Oncogene . 2007;26:1357–1360

PII: S1028-4559(09)60296-5

doi:10.1016/S1028-4559(09)60296-5

Taiwanese Journal of Obstetrics and Gynecology
Volume 48, Issue 3 , Pages 239-244, September 2009

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