Qian Tan1,2, A M Joshua3,4, M Wang5, R G Bristow5,3, B G Wouters5, C J Allen6, Ian F Tannock7,8,9. 1. Department of Medical Biophysics, University Health Network, University of Toronto, Toronto, ON, Canada. susie.tan@uhnres.utoronto.ca. 2. Princess Margaret Cancer Center, 9 floor room 417, 610 University Ave, Toronto, ON, M5G2M9, Canada. susie.tan@uhnres.utoronto.ca. 3. Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre and University Health Network, University of Toronto, Toronto, ON, Canada. 4. Institute of Medical Science, University of Toronto, Toronto, Canada. 5. Department of Medical Biophysics, University Health Network, University of Toronto, Toronto, ON, Canada. 6. Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada. 7. Department of Medical Biophysics, University Health Network, University of Toronto, Toronto, ON, Canada. ian.tannock@uhn.ca. 8. Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre and University Health Network, University of Toronto, Toronto, ON, Canada. ian.tannock@uhn.ca. 9. Princess Margaret Cancer Center, 9 floor room 417, 610 University Ave, Toronto, ON, M5G2M9, Canada. ian.tannock@uhn.ca.
Abstract
BACKGROUND: Autophagy is a survival mechanism that allows recycling of cellular breakdown products, particularly in stressed cells. Here we evaluate the hypotheses that up-regulation of autophagy is a common mechanism of resistance to chemotherapy, and that drug resistance can be reversed by inhibiting autophagy with a proton pump inhibitor. METHODS: We exposed human PC3, LNCaP and MCF7 cells to seven clinically-used chemotherapy drugs ± pantoprazole, examined the up-regulation of autophagy and the effect on cellular proliferation by Western Blots, MTS assay and colony-forming assay. The distribution of drug effects and of autophagy was quantified in LNCaP tumor sections in relation to blood vessels and hypoxia by immunohistochemistry using γH2AX, cleaved caspase-3 and p62. RESULTS: All anticancer drugs led to up-regulation of autophagy in cultured tumor cells. Pantoprazole inhibited the induction of autophagy in a time- and dose-dependent manner, and sensitized cancer cells to the seven anti-cancer drugs. Treatment of LNCaP xenografts with paclitaxel induced both DNA damage and autophagy; autophagy was inhibited and markers of toxicity were increased by pantoprazole. CONCLUSIONS: Induction of autophagy is a general mechanism associated with resistance to anticancer drugs and that its inhibition is a promising therapeutic strategy to enhance the effects of chemotherapy and improve clinical outcomes.
BACKGROUND: Autophagy is a survival mechanism that allows recycling of cellular breakdown products, particularly in stressed cells. Here we evaluate the hypotheses that up-regulation of autophagy is a common mechanism of resistance to chemotherapy, and that drug resistance can be reversed by inhibiting autophagy with a proton pump inhibitor. METHODS: We exposed humanPC3, LNCaP and MCF7 cells to seven clinically-used chemotherapy drugs ± pantoprazole, examined the up-regulation of autophagy and the effect on cellular proliferation by Western Blots, MTS assay and colony-forming assay. The distribution of drug effects and of autophagy was quantified in LNCaP tumor sections in relation to blood vessels and hypoxia by immunohistochemistry using γH2AX, cleaved caspase-3 and p62. RESULTS: All anticancer drugs led to up-regulation of autophagy in cultured tumor cells. Pantoprazole inhibited the induction of autophagy in a time- and dose-dependent manner, and sensitized cancer cells to the seven anti-cancer drugs. Treatment of LNCaP xenografts with paclitaxel induced both DNA damage and autophagy; autophagy was inhibited and markers of toxicity were increased by pantoprazole. CONCLUSIONS: Induction of autophagy is a general mechanism associated with resistance to anticancer drugs and that its inhibition is a promising therapeutic strategy to enhance the effects of chemotherapy and improve clinical outcomes.
Authors: Aaron R Hansen; Ian F Tannock; Arnoud Templeton; Eric Chen; Andrew Evans; Jennifer Knox; Amy Prawira; Srikala S Sridhar; Susie Tan; Francisco Vera-Badillo; Lisa Wang; Bradly G Wouters; Anthony M Joshua Journal: Oncologist Date: 2019-04-05
Authors: Waleska K Martins; Renata Belotto; Maryana N Silva; Daniel Grasso; Maynne D Suriani; Tayná S Lavor; Rosangela Itri; Mauricio S Baptista; Tayana M Tsubone Journal: Front Oncol Date: 2021-01-20 Impact factor: 6.244