Ibuprofen enhances the anticancer activity of cisplatin in lung cancer cells by inhibiting the heat shock protein 70.
Hsp70 is often overexpressed in cancer cells, and the selective cellular survival advantage that it confers may contribute to the process of tumour formation. Thus, the pharmacological manipulation of Hsp70 levels in cancer cells may be an effective means of preventing the progression of tumours. We found that the downregulation of Hsp70 by ibuprofen in vitro enhances the antitumoural activity of cisplatin in lung cancer. Ibuprofen prominently suppressed the expression of Hsp70 in A549 cells derived from lung adenocarcinoma and sensitized them to cisplatin in association with an increase in the mitochondrial apoptotic cascade, whereas ibuprofen alone did not induce cell death. The cisplatin-dependent events occurring up- and downstream of mitochondrial disruption were accelerated by treatment with ibuprofen. The increase in cisplatin-induced apoptosis caused by the depletion of Hsp70 by RNA interference is evidence that the increased apoptosis by ibuprofen is mediated by its effect on Hsp70. Our observations indicate that the suppression of Hsp70 by ibuprofen mediates the sensitivity to cisplatin by enhancing apoptosis at several stages of the mitochondrial cascade. Ibuprofen, therefore, is a potential therapeutic agent that might allow lowering the doses of cisplatin and limiting the many challenge associated with its toxicity and development of drug resistance.
1] Division of Enzyme Chemistry, Institute for Enzyme Research, The University of Tokushima, Tokushima, Japan [2] Department of Nutrition, School of Human Cultures, The University of Shiga Prefecture, Shiga, Japan.
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Endo
1] Division of Enzyme Chemistry, Institute for Enzyme Research, The University of Tokushima, Tokushima, Japan [2] Department of Nutrition, School of Human Cultures, The University of Shiga Prefecture, Shiga, Japan.
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Yano
Division of Enzyme Chemistry, Institute for Enzyme Research, The University of Tokushima, Tokushima, Japan.
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Okumura
Division of Enzyme Chemistry, Institute for Enzyme Research, The University of Tokushima, Tokushima, Japan.
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Kido
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D000077192:Adenocarcinoma of Lung; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects*; D004347:Drug Interactions; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology
D000970:Antineoplastic Agents; D018840:HSP70 Heat-Shock Proteins; D002945:Cisplatin; D007052:Ibuprofen