Apoptosis induced by novel aldehyde calpain inhibitors in human tumor cell lines

  • Authors:
    • Na Guan
    • Rajani Korukonda
    • Eunju Hurh
    • Thomas D. Schmittgen
    • Isaac O. Donkor
    • James T. Dalton
  • View Affiliations

  • Published online on: September 1, 2006     https://doi.org/10.3892/ijo.29.3.655
  • Pages: 655-663
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Abstract

Calpain is a class of Ca2+-dependent cysteine proteases and has been suggested to be involved in several important signaling cascades. A series of novel aldehyde calpain inhibitors identified in our laboratory were more potent and specific than commercially available calpain inhibitors, and were used to assess the involvement of calpain in cancer. Our inhibitors demonstrated potent anti-proliferative activity in four cancer cell lines (PC-3, HeLa, Jurkat and Daudi) with IC50's ranging from 2 to >30 µM. A non-cancer cell line (CV-1) was 4-7-fold less sensitive than the cancer cell lines. Apoptotic activity was determined and appeared to be inversely correlated to calpain expression levels in the different cell types. Leukemia cell lines (i.e., Daudi and Jurkat) with undetectable m-calpain were more susceptible to the apoptotic effects in response to calpain inhibition, while apoptosis was not detected in PC-3 prostate cancer cells, which highly express m-calpain. The extent of apoptosis in HeLa cells was moderate under identical conditions. Apoptosis induced by calpain inhibition was accompanied by caspase-3 activation. Furthermore, cell cycle analysis showed that aldehyde calpain inhibitors arrested cells at the G2/M boundary in a concentration-dependent manner. These results indicate that aldehyde calpain inhibitors exhibit their cytotoxic effects via induction of G2/M arrest and apoptosis. Importantly, the compounds failed to exert any inhibitory effects toward 20S proteasome. Collectively, our results suggest that calpain is a novel target for the treatment of a variety of cancer diseases and provide leads for further discovery and development of calpain inhibitors.

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September 2006
Volume 29 Issue 3

Print ISSN: 1019-6439
Online ISSN:1791-2423

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APA
Guan, N., Korukonda, R., Hurh, E., Schmittgen, T.D., Donkor, I.O., & Dalton, J.T. (2006). Apoptosis induced by novel aldehyde calpain inhibitors in human tumor cell lines. International Journal of Oncology, 29, 655-663. https://doi.org/10.3892/ijo.29.3.655
MLA
Guan, N., Korukonda, R., Hurh, E., Schmittgen, T. D., Donkor, I. O., Dalton, J. T."Apoptosis induced by novel aldehyde calpain inhibitors in human tumor cell lines". International Journal of Oncology 29.3 (2006): 655-663.
Chicago
Guan, N., Korukonda, R., Hurh, E., Schmittgen, T. D., Donkor, I. O., Dalton, J. T."Apoptosis induced by novel aldehyde calpain inhibitors in human tumor cell lines". International Journal of Oncology 29, no. 3 (2006): 655-663. https://doi.org/10.3892/ijo.29.3.655