Cytoprotective effects of acidosis via heat shock protein HSP27 against the anticancer drug doxorubicin.
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.
Singh
Anurag Kumar
AK
Department of Gastroenterolgy, Hepatology and Endocrinology, Hannover Medical School, Germany.
Manns
Michael P
MP
Seidler
Ursula
U
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003592:Cytophotometry; D019610:Cytoprotection / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D004317:Doxorubicin / Q000378:metabolism* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles; D018613:Microscopy, Confocal; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D017931:DNA Primers; D055551:HSP27 Heat-Shock Proteins; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D034741:RNA, Small Interfering; D004317:Doxorubicin; C093642:SB 203580