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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Identification of Caspase-Independent Apoptosis in Epithelial and Cancer Cells

Brian S. Cummings, Gilbert R. Kinsey, Laura J. C. Bolchoz and Rick G. Schnellmann
Journal of Pharmacology and Experimental Therapeutics July 2004, 310 (1) 126-134; DOI: https://doi.org/10.1124/jpet.104.065862
Brian S. Cummings
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Gilbert R. Kinsey
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Laura J. C. Bolchoz
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Rick G. Schnellmann
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Abstract

We reported that 50% of cisplatin-induced apoptosis in primary cultures of rabbit renal proximal tubule cells (RPTC) proceeded via caspase-independent mechanisms. This study determined whether caspase-independent apoptosis, using multiple and diverse endpoints, could be produced by toxicants other than cisplatin and in cell models other than RPTC. Cisplatin, staurosporine, vincristine, and A23187 induced RPTC apoptosis after 24 h as indicated by 2- to 2.5-fold increases in annexin V and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) staining, and 2- to 10-fold increases in cell shrinkage. All toxicants induced 8- to 50-fold increases in caspase-3 activities, which were completely inhibited by the pan caspase inhibitor ZVAD-fmk. However, ZVAD-fmk only decreased cisplatin- and staurosporine-induced annexin V staining and cell shrinkage 30 to 50%, staurosporine-induced TUNEL staining 30%, and did not affect vincristine- or A23187-induced RPTC apoptosis. All toxicants tested induced apoptotic RPTC nuclear morphology. However, similar to its effect on annexin V and TUNEL staining, ZVAD-fmk only partially inhibited toxicant-induced apoptotic nuclear morphology. Cisplatin and staurosporine also induced annexin V staining in the human epithelial cancer cell lines Caki-1 (kidney carcinoma), A549 (lung carcinoma), A172 (glioblastoma), and murine lymphocytic leukemia L1210 cells. Pretreatment with ZVAD-fmk inhibited cisplatin-induced annexin V staining in Caki-1, A172, and A549 cells but had no affect in L1210 cells. Pretreatment with ZVAD-fmk did not decrease staurosporine-induced annexin V staining in Caki-1, A549, L1210, and A172 cells. These results suggest that a significant fraction of apoptosis induced by diverse toxicants in renal epithelial cells and in four different cancer cell lines is caspase-independent.

Footnotes

  • This work was supported by a Department of Defense Institutional grant (to R.G.S.), National Institutes of Health National Research Service Award DK-10079 (to B.S.C.), National Institutes of Health Training Grant T32DK07752 (to L.J.C.B.), and a Gateway Research Scholarship from the American Foundation for Pharmaceutical Education and a Medical University of South Carolina Summer Health Professionals Research grant (to G.R.K).

  • DOI: 10.1124/jpet.104.065862.

  • ABBREVIATIONS; RPTC, renal proximal tubule cell(s); DAPI, 4′,6-diamidino-2-phenylindole-dihydrochloride; PI, propidium iodide; PBS, phosphate-buffered saline; TdT, terminal deoxynucleotidyl transferase; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling.

  • ↵1 Present address: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602.

    • Received January 21, 2004.
    • Accepted March 11, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 310 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 310, Issue 1
1 Jul 2004
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Identification of Caspase-Independent Apoptosis in Epithelial and Cancer Cells

Brian S. Cummings, Gilbert R. Kinsey, Laura J. C. Bolchoz and Rick G. Schnellmann
Journal of Pharmacology and Experimental Therapeutics July 1, 2004, 310 (1) 126-134; DOI: https://doi.org/10.1124/jpet.104.065862

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Identification of Caspase-Independent Apoptosis in Epithelial and Cancer Cells

Brian S. Cummings, Gilbert R. Kinsey, Laura J. C. Bolchoz and Rick G. Schnellmann
Journal of Pharmacology and Experimental Therapeutics July 1, 2004, 310 (1) 126-134; DOI: https://doi.org/10.1124/jpet.104.065862
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