Regular Article

British Journal of Cancer (1999) 79, 95–100. doi:10.1038/sj.bjc.6690017 www.bjcancer.com
Published online 11 December 1998

Bcl-2 overexpression blocks caspase activation and downstream apoptotic events instigated by photodynamic therapy

D J Granville1,2, H Jiang1, M T An1, J G Levy1,3, B M McManus2 and D W C Hunt1,2

  1. 1QLT PhotoTherapeutics, 520 West 6th Avenue, Vancouver, BC V5Z 4H5, Canada
  2. 2Department of Pathology and Laboratory Medicine, University of British Columbia, 2211 Westbrook Mall, Vancouver, BC V6T 2B5, Canada
  3. 3Department of Microbiology and Immunology, Faculty of Science, University of British Columbia, 300-6174 University Boulevard, Vancouver, BC V6T 1W5, Canada

Correspondence: D Granville, QLT PhotoTherapeutics 520 West 6th Avenue, Vancouver, BC V5Z 4H5, Canada

Received 23 January 1998; Revised 1 June 1998; Accepted 6 June 1998.

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Abstract

Treatment with the photosensitizer benzoporphyrin derivative monoacid ring A (BPD-MA, verteporfin) followed by irradiation with visible light induces apoptosis in human acute myelogenous leukaemia HL-60 cells. Photoactivation of BPD-MA induces procaspase 3 (CPP32/Yama/apopain) and procaspase 6 (Mch2) cleavage into their proteolytically active subunits in these cells. The Bcl-2 proto-oncogene product has been shown to protect cells from a number of proapoptotic stimuli. In the present study, the influence of Bcl-2 overexpression on cellular resistance to photoactivation of BPD-MA was studied. Overexpression of Bcl-2 in HL-60 cells prevented apoptosis-related events including caspase 3 and 6 activation, poly(ADP-ribose) polymerase cleavage and the formation of hypodiploid DNA produced by BPD-MA (0–200 ng ml–1) and light. However, Bcl-2 overexpression was less effective at preventing cell death that occurred after photoactivation at high levels (50–100 ng ml–1) compared with lower doses (10–25 ng ml–1) of BPD-MA. These results indicate that caspase 3 and 6 activation and their regulation by Bcl-2 may play important roles in photodynamic therapy (PDT)-induced cell killing.

Keywords:

apoptosis, photodynamic therapy, Bcl-2, caspase, resistance, leukaemic cells

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