Induction of apoptosis in E渭-myc lymphoma cells in聽vitro and in聽vivo through calpain inhibition

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• 作者：Hongbing Li^a ; ^b ; Rajeev M. Nepal^b ; Alberto Martin^b ; Stuart A. Berger^a ; ^b ; ^{stuart.berger@utoronto.ca}
• 刊名：Experimental Hematology
• 出版年：2012
• 期刊代码：100_0301472x
• 类别：med
• 出版时间：July, 2012
• 卷：40
• 期：7
• 页码：548-563.e2
• 文件大小：2525 K

摘要

Calpains are cysteine proteases that have been implicated as both effectors and suppressors of apoptosis. Previously, we showed that c-myc transformation regulated calpain activity and sensitized cells to apoptosis induced by calpain inhibition. The objective of this study was to investigate the role of calpain in the E渭-myc transgenic model of B-cell lymphoma. Calpain activity assays, apoptosis, cell cycle assays, and expression measurements were used to determine the activity and role of calpain in聽vitro and in聽vivo. We found that E渭-myc transgenic cells have highly elevated calpain activity. Calpastatin, the negative calpain regulator, was expressed at much lower levels in E渭-myc lymphoma cells compared to normal splenic B cells. The primary isoform in E渭-myc lymphoma is calpain 1. Treatment of E渭-myc lymphoma cells with the calpain inhibitors PD150606 or calpain inhibitor III induced caspase-3鈭抎ependent apoptosis in聽vitro. General caspase inhibitors or caspase-3/7 inhibitor protected cells from death induced by calpain inhibitor, whereas caspase-9 inhibitors failed to rescue cells. Human Burkitt鈥檚 lymphoma (BL2) cells display a pattern of sensitivity and caspase-3 dependence similar to calpain inhibition. Treatment of E渭-myc lymphoma-bearing mice with PD150606 inhibited calpain activity in聽vivo and induced cell death in these cells as determined by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling staining. Multiple daily treatments resulted in reduced tumor load, particularly in combination with etoposide. In conclusion, calpain is highly elevated in the E渭-myc lymphoma and calpain inhibition has therapeutic potential.