Characterization of a Small Molecule Compound Selectively Kills Drug-Selected P-Glycoprotein (Abcb1)-Overexpressing Mdr Cancer Cells by Preferential Induction of Apoptosis and Autophagy

A major problem in cancer involves the recurrence of disease followed by metastasis. Metastatic disease has been shown to be resistant to a variety of structurally unrelated anti-cancer drugs, also known as multidrug resistance (MDR). Despite decades of research on the phenomenon of MDR, it continues to be the major obstacle to successful chemotherapeutic treatment of cancer patients. Overexpression of the ATP-binding cassette (ABC) transporters ABCB1 (P-glycoprotein, Pgp) and/or ABCG2 is known to play a major role in the development of MDR. Previous attempts to improve the efficacy of anticancer drugs using single selective, drug-transporter inhibitors have met with limited success. Therefore, developing alternative multifunctional modulators targeting these drug transporters has great clinical significance. An unique small molecule NSC659321 was identified from our previous drug discovery program to be specifically cytotoxic to human epidermoid cancer cells that express high levels of Pgp and to murine fibroblast cells transfected with human ABCB1; as well as inhibits the function and restore drug sensitivity to cancer cells overexpressing Pgp or ABCG2. NSC659321 can affect the pharmacokinetics of compounds which cannot cross the blood-brain-barrier and significantly improve drug penetration to the brain. In turn, this can achieve higher efficacy of substrate anticancer drug to treat early stage brain tumors or malignant gliomas. Our preliminary results indicate that NSC659321 can eliminate drug-induced Pgp-overexpressing MDR cancer cells by preferentially inducing apoptosis and autophagy in these cells, without causing significant toxicity to cells that intrinsically express Pgp. A lead compound with this remarkable feature can be exploited to treat drug transporter-mediated MDR in cancer patients. However, many aspects of this candidate drug should be explored prior to preclinical assessment, in particular the overall effect of NSC659321 has on the expression and localization of ABC drug transporters; the potential use of NSC659321 in MDR cancer prevention and its overall impact on cancer cell survival. More specifically, we intended to gain some insight into the molecular mechanism and molecular target of NSC659321 in drug-induced Pgp-overexpressing MDR cancer cells. This study will investigate these issues and provide valuable clues into the molecular mechanisms regulating the survival of MDR cancer cells.

Project ID:PC10003-0001
External Project ID:NSC100-2320-B182-002