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Antisense Bcl-xl Down-Regulation Switches the Response to Topoisomerase I Inhibition from Senescence to Apoptosis in Colorectal Cancer Cells, Enhancing Global Cytotoxicity
Purpose: To identify determinants of the effect of antisense-mediated Bcl-xl down-regulation (Bcl-xl knockdown) on the response of colorectal cancer cells to SN38, the active metabolite of irinotecan, a topoisomerase I inhibitor licensed for colorectal cancer chemotherapy. Experimental Design: Using...
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Published in: | Clinical cancer research 2003-07, Vol.9 (7), p.2856-2865 |
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Main Authors: | , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Online Access: | Get full text |
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Summary: | Purpose: To identify determinants of the effect of antisense-mediated Bcl-xl down-regulation (Bcl-xl knockdown) on the response of
colorectal cancer cells to SN38, the active metabolite of irinotecan, a topoisomerase I inhibitor licensed for colorectal
cancer chemotherapy.
Experimental Design: Using wild-type HCT116, p53 null, Bax null, or p21/WAF1 null isogenic derivatives, we measured expression of regulators of
cellular response, and associated growth arrests or apoptosis, after SN38 treatment, with or without antisense-mediated Bcl-xl
knockdown.
Results: A modified phosphorothioate antisense oligonucleotide (ISIS15999) reduced Bcl-xl protein expression by ∼90%. SN38 induced
p53, Bax, Bcl-xl, and p53-dependent p21/WAF1 protein accumulation. The Bax:Bcl-xl ratio changed little. In wild-type HCT116,
but not in Bax null cells, Bcl-xl knockdown induced a shift in response from drug-induced senescence to apoptosis, and enhanced
the global cytotoxicity of SN38. In p53 null or p21/WAF1 null cells marked apoptosis occurred after SN38 alone, and was additionally
enhanced by Bcl-xl knockdown in p21/WAF1 null cells but not in p53 null cells.
Conclusions: Drug-induced senescence is associated with late relapse after therapy in transgenic models of cancer in vivo . We have shown that abolition of p21/WAF1-mediated drug-induced senescence or antisense-mediated Bcl-xl knockdown can both,
independently, enhance the apoptotic response of colorectal cancer cells to SN38 in vitro . The growth arrest suppresses a p53-independent apoptotic pathway, whereas Bcl-xl induction suppresses a p53 and Bax-dependent
apoptotic pathway. The combination of irinotecan and Bcl-xL antisense merits testing in models of colorectal cancer in vivo . |
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ISSN: | 1078-0432 1557-3265 |