Abstract 5611: A synthetic lethality combination with chloroquine and rapamycin on chemosensitization

Abstract

Abstract Chemoresistance is the main obstacle of successful cancer therapy. Autophagy may either enhance cancer cell death or activate chemoresistance. Simultaneous pushing and blocking of autophagy may be a valid strategy for overcoming drug resistance and improving responses. We hypothesized that simultaneous forcing hepatoma cells synchronized in a pro-autophagic status by rapamycin while blocking the final autophagic pathway by chloroquine is an example of synthetic lethality in synergism. Co-administration of the chemotherapeutic agents with rapamycin and chloroquine in 3 hepatoma cell lines have all demonstrated synergistic effects including 5-fluorouracil, navelbine, taxotere or cisplatin. Increasing doses of rapamycin and chloroquine resulted in a significant decrease of ED50 of different chemodrugs. Althrough hepatoma cell lines expressed difference status of autophage during various chemodrug treatments, co-administration of rapamycin and chloroquine could synchronize them on the pro-autophagic status while preveting them ensuring to the final autophagic status in all cell line tested. The combination of rapamycin and chloroquine and chemotherapeutic agents resulted in increased apoptotic cell death compared to chemotherapeutic agents alone. All of the observed synergistic chemosensitization effect from combination of chloroquine and rapamycin is more obvious than either agent alone. In vivo experiments are underway. If these synergistic effects can be reproduced in vivo, the combination of rapamycin and chloroquine may provide a valid reversing resistance strategy in treatment refractory cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5611. doi:1538-7445.AM2012-5611