c-IAP1 is Overexpressed in HL-60 Cells Selected for Doxorubicin Resistance: Effects on Etoposide-induced Apoptosis

Susan A.J. Vaziri, Dale R. Grabowski, Masahiro Tabata, Katherine A. Holmes, Joseph Sterk, Nagio Takigawa, Ronald M. Bukowski, Mahrukh K. Ganapathi, Ram Ganapathi

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13 Citations (Scopus)

Abstract

Background: We previously demonstrated that KN-62, an inhibitor of calcium calmodulin-dependent enzymes, sensitizes human leukemia HL-60 cells resistant to topoisomerase II-targeting drugs. The objective of this study was to determine pathways of apoptosis downstream of DNA damage induced by KN-62 co-treatment with VP-16. Materials and Methods: HL-60/Y/DOX0. 05 cells were treated with VP-16, KN-62, or VP-16 +KN-62. Following treatment, cells were assayed for c-IAP1, c-IAP2 and XIAP protein expression, as well as caspase activation, cytochrome c release and PARP cleavage. Results: Baseline c-IAP1 protein levels were 2-fold higher in HL60 cells selected for resistance to doxorubicin compared to the parent sensitive line. VP-16 and KN-62 co-treatment was associated with caspase activation via the mitochondrial pathway and significant reductions (p=0.002) in c-IAP1 protein expression but not with c-IAP2 or XIAP. Conclusion: These data suggest that KN-62 co-treatment sensitizes doxorubicin-resistant cells to VP-16-induced apoptosis by enhancing caspase activity and reducing c-IAP1 expression.

Original languageEnglish
Pages (from-to)3657-3661
Number of pages5
JournalAnticancer research
Volume23
Issue number5 A
Publication statusPublished - Sep 2003

Keywords

  • Apoptosis
  • Etoposide
  • Inhibitor of calcium calmodulin-dependent enzymes
  • KN-62
  • Topoisomerase II-targeting drug resistance
  • c-IAP1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Vaziri, S. A. J., Grabowski, D. R., Tabata, M., Holmes, K. A., Sterk, J., Takigawa, N., Bukowski, R. M., Ganapathi, M. K., & Ganapathi, R. (2003). c-IAP1 is Overexpressed in HL-60 Cells Selected for Doxorubicin Resistance: Effects on Etoposide-induced Apoptosis. Anticancer research, 23(5 A), 3657-3661.