Cytoprotective effects of acidosis via heat shock protein HSP27 against the anticancer drug doxorubicin |
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Authors: | Anurag Kumar Singh Michael P Manns Ursula Seidler |
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Institution: | (1) Department of Gastroenterolgy, Hepatology and Endocrinology, Hannover Medical School, Carl Neuberg Str. 1, Hannover, 30625, Germany; |
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Abstract: | Drug resistance continues to be a stumbling block in achieving better cure rates in several cancers. Doxorubicin is commonly
used in treatment of a wide range of cancers. The aim of this study was to look into the mechanisms of how low ambient pH
may contribute to down-regulation of apoptotic pathways in a gastric tumour cell line. Low pH culture conditions were found
to dramatically prolong cell survival after doxorubicin treatment, an effect that was in part reversed by co-incubation with
the specific p38 mitoge-activated protein kinase (MAP kinase) inhibitor SB203580, only mildly inhibited by blockade of the
multi-drug resistance 1 (MDR1) transporter, but completely abolished by siRNA-mediated knockdown of the heat shock protein
27 (HSP27). In conclusion, acidic pH causes less accumulation of cytotoxic drug in the nucleus of adeno gastric carcinoma
(AGS) cells and HSP27-dependent decrease in FasR-mediated gastric epithelial tumour cell apoptosis. |
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