Autophagy as a Survival Mechanism for Tumor Cells Exposed to Chemotherapy or Hypoxia, and its Inhibition by Pantoprazole to Improve Outcome of Treatment

Chemotherapy is widely used as treatment for patients with metastatic cancer, and is also used to prevent disease recurrence and metastatic spread after local treatment. Autophagy allows recycling of cellular components and may facilitate cell survival after chemotherapy. The clinically used proton pump inhibitor (PPI) pantoprazole inhibits proton pumps, and is reported to inhibit autophagy. This thesis aims to gain insight as to whether pantoprazole inhibits autophagy to improve penetration and activity of anticancer drugs in solid tumors, thereby enhancing chemotherapy effectiveness. The first objective was to evaluate effects of pantoprazole to modify cytotoxicity of the anticancer drug docetaxel and underlying mechanisms. I found that autophagy is a mechanism of resistance to docetaxel that modified by pantoprazole to improve therapeutic index. The second objective addressed whether induction of autophagy is a general mechanism of resistance to chemotherapy, whether autophagy hence drug resistance can be inhibited by pantoprazole. It was found that seven clinically-used anti-cancer drugs induced autophagy in vitro and in vivo. Induction of autophagy was inhibited by pre-treatment with pantoprazole. The third objective determined whether autophagy is a survival mechanism for hypoxic cells. I found that hypoxia induced autophagy in vitro and inhibited by pantoprazole. Hypoxia-induced cell death was more rapid for autophagy deficient cells. Xenografts generated from autophagy-deficient cells grew more slowly than wild type tumors and the proportion of hypoxia cells was markedly decreased in xenografts generated from knockdown tumors. The work presented here highlights the importance of the tumor- microenvironment in determining response to chemotherapy and suggests that induction of autophagy is a common mechanism of drug resistance. Effects of anti-cancer drugs might be improved by using PPIs to inhibit autophagy. Based on these data, a phase I trial of pantoprazole +doxorubicin has been undertaken in patients with advanced solid tumors and a phase II study of pantoprazole + docetaxel is underway in men with castrate-resistant prostate cancer.Ph.D