Synthesis and biological evaluation of pentacyclic strychnos alkaloids as selective modulators of the ABCC10 (MRP7) efflux pump.

The selective modulation of ATP-binding cassette (ABC) efflux pumps overexpressed in multidrug resistant cancers (MDR) and attendant resensitization to chemotherapeutic agents represent a promising strategy for treating cancer. We have synthesized four novel pentacyclic Strychnos alkaloids alstolucines B (2), F (3), and A (5) and N-demethylalstogucine (4), in addition to known Strychnos alkaloid echitamidine (16), and we evaluated compounds 1-5 in biochemical assays with ABCC10 and P-glycoprotein (P-gp). Alstolucines B (2) and F (3) inhibited ABCC10 ATPase activity at 12.

Modulation of the ATPase and transport activities of broad-acting multidrug resistance factor ABCC10 (MRP7).

The cell surface molecule ABCC10 is a broad-acting transporter of xenobiotics, including cancer drugs, such as taxanes, epothilone B, and modulators of the estrogen pathway. Abcc10(-/-) mice exhibit increased tissue sensitivity and lethality resulting from paclitaxel exposure compared with wild-type counterparts, arguing ABCC10 functions as a major determinant of taxane sensitivity in mice. To better understand the mechanistic basis of ABCC10 action, we characterized the biochemical and vectorial transport properties of this protein.