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10.18632/oncotarget.11503 http://scihub22266oqcxt.onion/10.18632/oncotarget.11503 C5325373!5325373 !27566564     free     free     free Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=27566564 &cmd=llinks): Failed to open stream: HTTP request failed! 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Altered pH gradient at the plasma membrane of osteosarcoma cells is a key mechanism of drug resistance |pdf=|usr=}}{{27566564 }} gab.com Text Altered pH gradient at the plasma membrane of osteosarcoma cells is a key mechanism of drug resistance JO: Oncotarget http://www.kidney.de/pget.php?&tw=1&pmid=27566564 #FOAvip Current therapy of osteosarcoma (OS), the most common primary bone malignancy, is based on a combination of surgery and chemotherapy. Multidrug resistance mediated by P-glycoprotein (P-gp) overexpression has been previously associated with treatment failure and progression of OS, although other mechanisms may also play a role. We considered the typical acidic extracellular pH (pHe) of sarcomas, and found that doxorubicin (DXR) cytotoxicity is reduced in P-gp negative OS cells cultured at pHe 6.5 compared to standard 7.4. Short-time (24-48 hours) exposure to low pHe significantly increased the number and acidity of lysosomes, and the combination of DXR with omeprazole, a proton pump inhibitor targeting lysosomal acidity, significantly enhanced DXR cytotoxicity. In OS xenografts, the combination treatment of DXR and omeprazole significantly reduced tumor volume and body weight loss. The impaired toxicity of DXR at low pHe was not associated with increased autophagy or lysosomal acidification, but rather, as shown by SNARF staining, with a reversal of the pH gradient at the plasma membrane (?pHcm), eventually leading to a reduced DXR intracellular accumulation. Finally, the reversal of ?pHcm in OS cells promoted resistance not only to DXR, but also to cisplatin and methotrexate, and, to a lesser extent, to vincristine. Altogether, our findings show that, in OS cells, short-term acidosis induces resistance to different chemotherapeutic drugs by a reversal of ?pHcm, suggesting that buffer therapies or regimens including proton pump inhibitors in combination to low concentrations of conventional anticancer agents may offer novel solutions to overcome drug resistance. Twit Text FOAVip Altered pH gradient at the plasma membrane of osteosarcoma cells is a key mechanism of drug resistance ????Oncotarget http://www.kidney.de/pget.php?&tw=1&pmid=27566564 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=27566564 #FOAvip English Wikipedia <ref>{{Cite pmid|27566564 }}</ref> Altered pH gradient at the plasma membrane of osteosarcoma cells is a key mechanism of drug resistance #MMPMID27566564 Avnet S ; Lemma S ; Cortini M ; Pellegrini P ; Perut F ; Zini N ; Kusuzaki K ; Chano T ; Grisendi G ; Dominici M ; De Milito A ; Baldini N Oncotarget 2016[Sep]; 7 (39 ): 63408-63423 PMID27566564 show ga Current therapy of osteosarcoma (OS), the most common primary bone malignancy, is based on a combination of surgery and chemotherapy. Multidrug resistance mediated by P-glycoprotein (P-gp) overexpression has been previously associated with treatment failure and progression of OS, although other mechanisms may also play a role. We considered the typical acidic extracellular pH (pHe) of sarcomas, and found that doxorubicin (DXR) cytotoxicity is reduced in P-gp negative OS cells cultured at pHe 6.5 compared to standard 7.4. Short-time (24-48 hours) exposure to low pHe significantly increased the number and acidity of lysosomes, and the combination of DXR with omeprazole, a proton pump inhibitor targeting lysosomal acidity, significantly enhanced DXR cytotoxicity. In OS xenografts, the combination treatment of DXR and omeprazole significantly reduced tumor volume and body weight loss. The impaired toxicity of DXR at low pHe was not associated with increased autophagy or lysosomal acidification, but rather, as shown by SNARF staining, with a reversal of the pH gradient at the plasma membrane (?pHcm), eventually leading to a reduced DXR intracellular accumulation. Finally, the reversal of ?pHcm in OS cells promoted resistance not only to DXR, but also to cisplatin and methotrexate, and, to a lesser extent, to vincristine. Altogether, our findings show that, in OS cells, short-term acidosis induces resistance to different chemotherapeutic drugs by a reversal of ?pHcm, suggesting that buffer therapies or regimens including proton pump inhibitors in combination to low concentrations of conventional anticancer agents may offer novel solutions to overcome drug resistance. |*Drug Resistance, Multiple [MESH] |*Drug Resistance, Neoplasm [MESH] |ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism [MESH] |Animals [MESH] |Antineoplastic Agents/pharmacology [MESH] |Apoptosis/drug effects [MESH] |Bone Neoplasms/drug therapy/metabolism/*pathology [MESH] |Cell Membrane/drug effects/metabolism/*pathology [MESH] |Cell Proliferation/drug effects [MESH] |Doxorubicin/pharmacology [MESH] |Humans [MESH] |Hydrogen-Ion Concentration [MESH] |Male [MESH] |Mice [MESH] |Mice, Inbred NOD [MESH] |Mice, SCID [MESH] |Muramidase/metabolism [MESH] |Osteosarcoma/drug therapy/metabolism/*pathology [MESH] |Tumor Cells, Cultured [MESH] |Tumor Microenvironment/*drug effects [MESH]Altered pH gradient at the plasma membrane of osteosarcoma cells is a (epmc).pdf DeepDyve Pubget Overpricing