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

Research output: Contribution to journalArticle

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
Externally publishedYes

Fingerprint

KN 62
HL-60 Cells
Etoposide
Doxorubicin
Apoptosis
Inhibitor of Apoptosis Proteins
Caspases
X-Linked Inhibitor of Apoptosis Protein
Type II DNA Topoisomerase
Calmodulin
Therapeutics
Drug Delivery Systems
Cytochromes c
DNA Damage
Leukemia

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Vaziri, S. A. J., Grabowski, D. R., Tabata, M., Holmes, K. A., Sterk, J., Takigawa, N., ... 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.

c-IAP1 is Overexpressed in HL-60 Cells Selected for Doxorubicin Resistance : Effects on Etoposide-induced Apoptosis. / Vaziri, Susan A J; Grabowski, Dale R.; Tabata, Masahiro; Holmes, Katherine A.; Sterk, Joseph; Takigawa, Nagio; Bukowski, Ronald M.; Ganapathi, Mahrukh K.; Ganapathi, Ram.

In: Anticancer Research, Vol. 23, No. 5 A, 09.2003, p. 3657-3661.

Research output: Contribution to journalArticle

Vaziri, SAJ, Grabowski, DR, Tabata, M, Holmes, KA, Sterk, J, Takigawa, N, Bukowski, RM, Ganapathi, MK & Ganapathi, R 2003, 'c-IAP1 is Overexpressed in HL-60 Cells Selected for Doxorubicin Resistance: Effects on Etoposide-induced Apoptosis', Anticancer Research, vol. 23, no. 5 A, pp. 3657-3661.
Vaziri, Susan A J ; Grabowski, Dale R. ; Tabata, Masahiro ; Holmes, Katherine A. ; Sterk, Joseph ; Takigawa, Nagio ; Bukowski, Ronald M. ; Ganapathi, Mahrukh K. ; Ganapathi, Ram. / c-IAP1 is Overexpressed in HL-60 Cells Selected for Doxorubicin Resistance : Effects on Etoposide-induced Apoptosis. In: Anticancer Research. 2003 ; Vol. 23, No. 5 A. pp. 3657-3661.
@article{4676b342770f4fd7b984e47012eb66f1,
title = "c-IAP1 is Overexpressed in HL-60 Cells Selected for Doxorubicin Resistance: Effects on Etoposide-induced Apoptosis",
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.",
keywords = "Apoptosis, c-IAP1, Etoposide, Inhibitor of calcium calmodulin-dependent enzymes, KN-62, Topoisomerase II-targeting drug resistance",
author = "Vaziri, {Susan A J} and Grabowski, {Dale R.} and Masahiro Tabata and Holmes, {Katherine A.} and Joseph Sterk and Nagio Takigawa and Bukowski, {Ronald M.} and Ganapathi, {Mahrukh K.} and Ram Ganapathi",
year = "2003",
month = "9",
language = "English",
volume = "23",
pages = "3657--3661",
journal = "Anticancer Research",
issn = "0250-7005",
publisher = "International Institute of Anticancer Research",
number = "5 A",

}

TY - JOUR

T1 - c-IAP1 is Overexpressed in HL-60 Cells Selected for Doxorubicin Resistance

T2 - Effects on Etoposide-induced Apoptosis

AU - Vaziri, Susan A J

AU - Grabowski, Dale R.

AU - Tabata, Masahiro

AU - Holmes, Katherine A.

AU - Sterk, Joseph

AU - Takigawa, Nagio

AU - Bukowski, Ronald M.

AU - Ganapathi, Mahrukh K.

AU - Ganapathi, Ram

PY - 2003/9

Y1 - 2003/9

N2 - 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.

AB - 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.

KW - Apoptosis

KW - c-IAP1

KW - Etoposide

KW - Inhibitor of calcium calmodulin-dependent enzymes

KW - KN-62

KW - Topoisomerase II-targeting drug resistance

UR - http://www.scopus.com/inward/record.url?scp=0344442296&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0344442296&partnerID=8YFLogxK

M3 - Article

C2 - 14666661

AN - SCOPUS:0344442296

VL - 23

SP - 3657

EP - 3661

JO - Anticancer Research

JF - Anticancer Research

SN - 0250-7005

IS - 5 A

ER -