Development of inhibitors of ATP-binding cassette drug transporters: present status and challenges.
BACKGROUND
Multi-drug resistance (MDR) of cancer cells is an obstacle to effective chemotherapy of cancer. The ATP-binding cassette (ABC) transporters, including P-glycoprotein (ABCB1), MRP1 (ABCC1) and ABCG2, play an important role in the development of this resistance. An attractive approach to overcoming MDR is the inhibition of the pumping action of these transporters. Several inhibitors/modulators of ABC transporters have been developed, but cytotoxic effects and adverse pharmacokinetics have prohibited their use. The ongoing search for such inhibitors/modulators that can be applied in the clinic has led to three generations of compounds. The most recent inhibitors are more potent and less toxic than first-generation compounds, yet some are still prone to adverse effects, poor solubility and unfavorable changes in the pharmacokinetics of the anticancer drugs.


OBJECTIVE
This review provides an update of the published work on the development of potent modulators to overcome MDR in cancer cells, their present status in clinical studies and suggestions for further improvement to obtain better inhibitors.


METHODS
This review summarizes recent advances in the development of less toxic modulators, including small molecules and natural products. In addition, a brief overview of other novel approaches that can be used to inhibit ABC drug transporters mediating MDR has also been provided.


CONCLUSIONS
The multifactorial nature of MDR indicates that it may be important to develop modulators that can simultaneously inhibit both the function of the drug transporters and key signaling pathways, which are responsible for development of this phenomenon.
Shukla
Suneet
S
National Cancer Institute, Laboratory of Cell Biology, Center for Cancer Research, NIH, Bethesda, MD 20892, USA.
Wu
Chung-Pu
CP
Ambudkar
Suresh V
SV
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015195:Drug Design; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D009363:Neoplasm Proteins / Q000187:drug effects / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000503:physiopathology
D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins