Small-molecule Bcl-2 inhibitors sensitise tumour cells to immune-mediated destruction

Lickliter, J. D., Cox, J., McCarron, J., Martinez, N. R., Schmidt, C. W., Lin, H., Nieda, M. and Nicol, A. J. (2007) Small-molecule Bcl-2 inhibitors sensitise tumour cells to immune-mediated destruction. British Journal of Cancer, 96 4: 600-608. doi:10.1038/sj.bjc.6603599


Author Lickliter, J. D.
Cox, J.
McCarron, J.
Martinez, N. R.
Schmidt, C. W.
Lin, H.
Nieda, M.
Nicol, A. J.
Title Small-molecule Bcl-2 inhibitors sensitise tumour cells to immune-mediated destruction
Journal name British Journal of Cancer   Check publisher's open access policy
ISSN 0007-0920
1532-1827
Publication date 2007
Sub-type Article (original research)
DOI 10.1038/sj.bjc.6603599
Open Access Status DOI
Volume 96
Issue 4
Start page 600
End page 608
Total pages 9
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Collection year 2008
Language eng
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. V alpha 24(+) Vb11(+) 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 annexinV-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 IH3 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.
Keyword Oncology
Bcl-2 inhibitor
cancer immunotherapy
ABT-737
HAI4-I
NKT cells
Induced Apoptosis
In-vitro
Alpha-glycosylceramide
Protein Expression
Antitumor-activity
Human-melanoma
Lymphoma
Leukemia
Distinct
Death
Q-Index Code C1
Q-Index Status Confirmed Code

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
2008 Higher Education Research Data Collection
School of Medicine Publications
 
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Created: Mon, 18 Feb 2008, 16:29:52 EST