ORCID Profile
0000-0002-4916-3965
Current Organisations
Geneva University
,
University of Toronto
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Publisher: Springer Science and Business Media LLC
Date: 04-04-2017
DOI: 10.1007/S00280-017-3298-5
Abstract: 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. 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. 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. 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.
Publisher: BRILL
Date: 2016
Publisher: Springer Science and Business Media LLC
Date: 08-10-2013
DOI: 10.1007/S00213-013-3301-8
Abstract: A subset of cancer survivors demonstrates impairments in cognition long after chemotherapy completion. At present, it is unclear whether these changes are due to direct neurotoxic effects of chemotherapy. This study examined the impact of variable docetaxel (DTX) chemotherapy dosing on brain DTX exposure via analyses of neural morphology and changes in cognition. Male CD-1 mice were treated with DTX either intermittently (8 mg/kg i.p. weekly) or via a sustained delivery system (DTX-PoLigel), which continuously releases DTX. Both groups received total DTX doses of 32 mg/kg. Mice were assessed on the novel object recognition (NOR) task and the Morris water maze (MWM) shortly after treatment. Post-treatment behavioral testing demonstrated impaired NOR in mice treated with either dosing schedule relative to controls. No differences were observed between groups in MWM training and initial testing, though control mice performed better than chance while DTX-treated mice did not. Appreciable amounts of DTX were found in the brain after both treatment regimens. DTX treatment did not significantly increase levels of apoptosis within the CNS. However, some elevation in neural autophagy was observed following DTX treatment. Analysis of astrocytic activation demonstrated that intermittent DTX treatment resulted in an elevation of GFAP-positive astrocytes for 48 h after administration. Sustained chemotherapy demonstrated prolonged but lower levels of astrocyte activation over 9 days following implantation. DTX treatment induced cognitive impairment shortly after treatment. Further, these findings suggest an association between DTX dosing, neurotoxicity, and cognitive effects.
Publisher: BRILL
Date: 2016
No related grants have been discovered for Christine Allen.