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题名:Small-molecule Bcl-2 inhibitors sensitise tumour cells to immune-mediated destruction.
作者:Lickliter JD, Cox J, McCarron J, Martinez NR, Schmidt CW, Lin H, Nieda M, Nicol AJ. Related Articles, Links
来源:Br J Cancer[IF=4.115]. 2007 Feb 26;96(4):600-8.
URL :http://dx.doi.org/10.1038/sj.bjc.6603599
日期:070415
摘要: J D Lickliter1,2, J Cox1, J McCarron1, N R Martinez1, C W Schmidt1, H Lin1, M Nieda3 and A J Nicol4

1Clive Berghofer Cancer Research Centre, Queensland Institute of Medical Research, Herston, Queensland 4029, Australia
2Department of Medical Oncology, Royal Brisbane and Women s Hospital, Herston, Queensland 4029, Australia
3School of Medicine, Yokohama City University, Yokohama, Japan
4University of Queensland Centre for Immune and Targeted Therapy, Greenslopes Private Hospital, Greenslopes, Queensland 4120, Australia

Correspondence to: Dr JD Lickliter, Department of Medical Oncology, Royal Brisbane and Women s Hospital, Butterfield Street, Herston, Queensland 4029, Australia. E-mail: Jason_Lickliter@health.qld.gov.au

Revised 14 December 2006; accepted 19 December 2006

Abstract

The cytotoxic effects of anticancer immune cells are mediated by perforin/granzyme-B, Fas ligand and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), and therefore depend on intact apoptotic responses in target tumour cells. As killing by all three of these mechanisms is blocked by the frequently overexpressed antiapoptotic oncoprotein Bcl-2, we hypothesised that coexposure to a Bcl-2 inhibitor might enhance anticancer immune responses. We evaluated this in U937 lymphoma cells, and A02 melanoma cells, which both show strong Bcl-2 expression. V24+ V11+ natural killer T (NKT) cells expanded from peripheral blood of normal donors (n=3) were coincubated with PKH26-labelled U937 cells, and cytotoxicity was determined by flow cytometry after annexin-V-FITC and 7-AAD staining. In all cases, addition of the HA14-1 small-molecule Bcl-2 inhibitor to the cocultures significantly increased apoptosis in the target U937 cells. Using a similar assay, killing of A02 cells by the cytotoxic T-lymphocyte clone 1H3 was shown to be amplified by coexposure to the potent small-molecule Bcl-2 inhibitor ABT-737. Experiments with immune effectors preincubated with concanamycin-A suggested that sensitisation to perforin/granzyme-B may underlie enhanced target-cell killing observed in the presence of Bcl-2 inhibitors. We conclude that immune destruction of malignant cells can be amplified by molecular interventions that overcome Bcl-2-mediated resistance to apoptosis.

Keywords: Bcl-2 inhibitor; cancer immunotherapy; ABT-737; HA14-1; NKT cells 13:

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