Abstract #905: The small molecule Tetradrine (NSC77037), identified in a high-throughput cell-based screen, reverses multidrug resistance in cancer cells

Multidrug resistance (MDR) is one of the major factors which contributes to the failure of cancer chemotherapy treatment, and because of MDR, numerous efforts have been made to overcome it in the recent years. To identify novel MDR inhibitors, we developed a 96-well plate high-throughput cell-based screening assay. Using this assay on the National Cancer Institute Diversity Set Library, we identified tetradrine (NSC77037), a small molecular compound that, reverses MDR1 (Pgp) but not MRP or BCRP-mediated MDR in multidrug resistant cell lines derived from human tumors. The ability to reverse MDR is comparable to that of frequently used reversal agents such as verapamil and CsA. Cytotoxic activity of tetradrine was evaluated in vitro using human sarcoma and ovarian, breast, and colon cancer cell lines expressing various levels of Pgp, as well as using a lung cancer cell line expressing MRP and a breast cancer cell line expressing BCRP. From these results, we found that tetradrine itself at concentration >10µM moderately inhibits the proliferation of both sensitive and resistant cells with almost equal activity, but its inhibitory effect is not altered by co-incubation with verapamil, suggesting that tetradrine may not be a substrate of Pgp. Additionally, tetradrine increases the intracellular accumulation of Pgp substrates: Calcein AM, Rhodamine-123, paclitaxel, mitoxantrone, and doxorubicin, by enhancing the uptake and/or decreasing the efflux of these compounds in resistant cells. Finally, we are also able to show that tetradrine directly inhibiting the function of Pgp in a dose-dependent manner. In contrast, tetradrine does not inhibit the total expression level of Pgp. These results indicate that tetradrine is capable of reversing MDR in many cancer cells to chemotherapeutic agents by directly inhibiting the function of Pgp. The ability of tetradrine to restore sensitivity to drug therapy or to prevent resistance could potentially benefit a large number of cancer patients. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 905.