Poster Sessions

PHARM -12

Chung-Pu Wu

C.-P. Wu, S. Shukla, A. M. Calcagno, K. Garfield, S. V. Ambudkar

A novel therapy for MDR: NSC659321 selectively targets drug-induced ABCB1-overexpressing cancer cells and re-sensitizes cancer cells to ABCG2 substrates

Although many innovative therapies have been developed to combat cancer, the development of multidrug resistance (MDR) continues to be the major obstacle to chemotherapeutic success. Overexpression of the ATP-binding cassette drug transporter ABCB1 (P-glycoprotein, Pgp) and/or ABCG2 (breast cancer resistance protein, BCRP) is known to play a major role in the development of MDR in cancer patients. In an effort to find effective agents that modulate both ABCB1 and ABCG2, we screened compounds from the NCI’s Developmental Therapeutic Program. NSC659321 was identified to potently reverse resistance-mediated by ABCG2 and preferentially cytotoxic to cancer cells overexpressing Pgp. This hypersensitivity to NSC659321 was inversely correlated to the Pgp function. Furthermore, we demonstrated using biochemical techniques that a compound with collateral sensitivity properties interacts directly with both Pgp and ABCG2. In summary, exposing cancer cells to constant drug pressure essentially alters key features that are vital to cell survival, such as overexpression of Pgp (or ABCG2). Other modifications in cells during long term drug treatment can render these MDR cancer cells vulnerable to agents such as NSC659321. Therefore, the unique properties of NSC659321 with dual functionality could potentially be exploited to develop an ideal agent to combat drug transporter-mediated MDR in cancer patients.