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 language | English |
|---|---|
| Pages (from-to) | 3657-3661 |
| Number of pages | 5 |
| Journal | Anticancer Research |
| Volume | 23 |
| Issue number | 5 A |
| Publication status | Published - Sep 2003 |
| Externally published | Yes |
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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
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 journal › Article
}
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 -