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Multidrug resistance proteins and folate supplementation: therapeutic implications for antifolates and other classes of drugs in cancer treatment

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Abstract

Over the past decades, numerous reports have covered the crucial role of multidrug resistance (MDR) transporters in the efficacy of various chemotherapeutic drugs. Specific cell membrane-associated transporters mediate drug resistance by effluxing a wide spectrum of toxic agents. Although several excellent reviews have addressed general aspects of drug resistance, this current review aims to highlight implications for the efficacy of folate-based and other types of chemotherapeutic drugs. Folates are vitamins that are daily required for many biosynthetic processes. Folate supplementation in our diet may convey protective effects against several diseases, including cancers, but folate supplementation also makes up an essential part of several current cancer chemotherapeutic regimens. Traditionally, the folate leucovorin, for instance, is used to reduce antifolate toxicity in leukemia or to enhance the effect of the fluoropyrimidine 5-fluorouracil in some solid tumors. More recently, it has also been noted that folic acid has the ability to increase antitumor activity of several structurally unrelated regimens, such as alimta/pemetrexed and cisplatin. Moreover, studies from our laboratory demonstrated that folates could modulate the expression and activity of at least two members of the MDR transporters: MRP1/ABCC1, and the breast cancer resistance protein BCRP/ABCG2. Thus, folate supplementation may have differential effects on chemotherapy: (1) reduction of toxicity, (2) increase of antitumor activity, and (3) induction of MRP1 and BCRP associated cellular drug resistance. In this review the role of MDR proteins is discussed in further detail for each of these three items from the perspective to optimally exploit folate supplementation for enhanced chemotherapeutic efficacy of both antifolate-based chemotherapy and other classes of chemotherapeutic drugs.

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Abbreviations

BCRP:

Breast cancer resistance protein

DHFR:

Dihydrofolate reductase

FPGS:

Folylpolyglutamate synthetase

GSH:

Glutathione

MDR:

Multiple drug resistance

MRPs:

Multidrug resistance proteins

MTX:

Methotrexate

TS:

Thymidylate synthase

ABC:

ATP binding cassette transporters

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Acknowledgment

We thank Dr. R. Honeywell for critically reading the paper. This study was supported by the Dutch Cancer Society (grant NKB-VU 2000-2237)

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Hooijberg, J.H., de Vries, N.A., Kaspers, G.J.L. et al. Multidrug resistance proteins and folate supplementation: therapeutic implications for antifolates and other classes of drugs in cancer treatment. Cancer Chemother Pharmacol 58, 1–12 (2006). https://doi.org/10.1007/s00280-005-0141-1

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