Abstract
Abstract The eventual development of multidrug resistance (MDR) during the course of chemotherapy treatment is a fundamental obstacle associated with cancer care. Prior studies have identified NSC23925 ((2-(4-methoxyphenyl)-4-quinolinyl) (2-piperidinyl) methanol)) to be a small molecule agent that reverses MDR in cancer cells. Analysis of the structure of NSC23925 indicates that NSC23925 has two chiral centers which lead to 4 different stereo-isomers (erythro-7a, threo-7b, threo-9a and erythro-9b). Each isomer may or may not have distinct bio-activity from the others. In this study, we synthesized all four isomers of NSC23925 and analyzed by liquid chromatography-mass spectrometry (LCMS, HPLC-MS). Structure and activity relationships for reversing MDR in several MDR human cancer cell lines were evaluated by MTT assay. We observed that compound erythro-9b (NSC23925-9b) is the most potent isomer on reversing drug resistance, threo-7b and threo-9a also showed modest but lesser activity, and Erythro-7a showed the least potency. NSC23925-9b is able to reverse MDR in several drug resistant cell lines expressing Pgp in vitro, including ovarian, breast, colon, and sarcoma cancer cell lines. NSC23925-9b was able to re-sensitize these cell lines to paclitaxel, doxorubicin, vincristine and ET-743 with no effect on cell sensitivity to cisplatin, topotecan and methotrexate. NSC23925-9b was unable to reverse drug resistance in non-Pgp expressing drug resistant cell lines. Furthermore, NSC23925-9b significantly enhanced in vivo antitumor activity of paclitaxel in MDR ovarian cancer cell line SKOV-3TR xenograft models, without significant increasing the level of paclitaxel toxicity. In conclusion, these results demonstrated that NSC23925-9b and derivatives of this compound may hold therapeutic value in the treatment of MDR dependent cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1732. doi:10.1158/1538-7445.AM2011-1732
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