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Defining targets of modulation of human tumor cell response to cisplatin.

Abstract
We previously observed that in yeast cisplatin activates different pathways accounting for stress response. Here, we investigated whether genes involved in yeast drug response were modulated by cisplatin in human tumor cell lines (A2780, IGROV-1, A431, U2-OS) including cisplatin-resistant sublines (A2780/BBR, IGROV-1/Pt1, A431/Pt and U2-OS/Pt). Factors and pathways involved in stress response (glutathione-S-transferase, proteasome, checkpoint control and recombinational repair) were increased by cisplatin in human tumor sensitive and resistant cells. Moreover, sensitization to cisplatin by pharmacologically targeting glutathione or proteasome was observed in sensitive and resistant cells. Interestingly, only in IGROV-1/Pt1 cells, in which cisplatin up-regulated HSP70 and HSP90, targeting of HSP90 resulted in sensitization of resistant cells, suggesting a protective role of stress response. In conclusion, the present findings support the potential relevance of interfering with heat shock protein response to increase cisplatin cytotoxicity in resistant cells. Overall, pathways activated by cisplatin in human tumor cells appear cell-type specific, at least in part reflecting the stress response observed in yeast.
AuthorsGiovanni Luca Beretta, Laura Gatti, Elisabetta Corna, Nives Carenini, Franco Zunino, Paola Perego
JournalJournal of inorganic biochemistry (J Inorg Biochem) Vol. 102 Issue 7 Pg. 1406-15 (Jul 2008) ISSN: 1873-3344 [Electronic] United States
PMID18279962 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Heat-Shock Proteins
  • Proteasome Inhibitors
  • Glutathione
  • Cisplatin
Topics
  • Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
  • Cell Line, Tumor
  • Cisplatin (pharmacology)
  • Drug Delivery Systems (methods)
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Glutathione (antagonists & inhibitors)
  • Heat-Shock Proteins (antagonists & inhibitors)
  • Humans
  • Proteasome Inhibitors

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