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Nonsteroidal Anti-inflammatory Drugs Sensitize CD44-Overexpressing Cancer Cells to Hsp90 Inhibitor Through Autophagy Activation.
Moon, Hyun-Jung; Park, So-Young; Lee, Su-Hoon; Kang, Chi-Dug; Kim, Sun-Hee.
Afiliación
  • Moon HJ; Department of Biochemistry, Pusan National University School of Medicine, Yangsan, South Korea.
  • Park SY; Department of Biochemistry, Pusan National University School of Medicine, Yangsan, South Korea.
  • Lee SH; Department of Biochemistry, Pusan National University School of Medicine, Yangsan, South Korea.
  • Kang CD; Department of Biochemistry, Pusan National University School of Medicine, Yangsan, South Korea.
  • Kim SH; Department of Biochemistry, Pusan National University School of Medicine, Yangsan, South Korea.
Oncol Res ; 27(7): 835-847, 2019 Jul 12.
Article en En | MEDLINE | ID: mdl-30982499
Recently, novel therapeutic strategies have been designed with the aim of killing cancer stem-like cells (CSCs), and considerable interest has been generated in the development of specific therapies that target stemness-related marker of CSCs. In this study, nonsteroidal anti-inflammatory drugs (NSAIDs) significantly potentiated Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG)-mediated cytotoxicity through apoptotic and autophagic cell death induction, but COX-2-inhibitory function was not required for NSAID-induced autophagy in CD44-overexpressing human chronic myeloid leukemia K562 (CD44highK562) cells. Importantly, we found that treatment with NSAIDs resulted in a dose-dependent increase in LC3-II level and decrease in p62 level and simultaneous reduction in multiple stemness-related markers including CD44, Oct4, c-Myc, and mutant p53 (mutp53) in CD44highK562 cells, suggesting that NSAIDs could induce autophagy, which might mediate degradation of stemness-related marker proteins. Activation of AMPK and inhibition of Akt/mTOR/p70S6K/4EBP1 participated in NSAID-induced autophagy in CD44highK562 cells. In addition, treatment of CD44highK562 cells with NSAIDs inhibited expression of HSF1/Hsps, which resulted in suppression of 17-AAG-induced activation of Hsp70, leading to reversal of 17-AAG resistance and sensitization of CD44highK562 cells to 17-AAG by NSAIDs. In conclusion, combining NSAIDs with Hsp90 inhibitor may offer one of the most promising strategies for eradication of CD44-overexpressing CSCs.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Madre Neoplásicas / Leucemia Mielógena Crónica BCR-ABL Positiva / Antiinflamatorios no Esteroideos / Benzoquinonas / Proteínas HSP90 de Choque Térmico / Receptores de Hialuranos / Lactamas Macrocíclicas Límite: Humans Idioma: En Revista: Oncol Res Asunto de la revista: NEOPLASIAS Año: 2019 Tipo del documento: Article País de afiliación: Corea del Sur Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Madre Neoplásicas / Leucemia Mielógena Crónica BCR-ABL Positiva / Antiinflamatorios no Esteroideos / Benzoquinonas / Proteínas HSP90 de Choque Térmico / Receptores de Hialuranos / Lactamas Macrocíclicas Límite: Humans Idioma: En Revista: Oncol Res Asunto de la revista: NEOPLASIAS Año: 2019 Tipo del documento: Article País de afiliación: Corea del Sur Pais de publicación: Estados Unidos