Small-molecule inhibitors of Bcl-2 family proteins are able to induce tumor regression in a mouse model of pre-B-cell acute lymphocytic lymphoma
- PMID:18163880
- DOI: 10.1089/dna.2007.0675
Small-molecule inhibitors of Bcl-2 family proteins are able to induce tumor regression in a mouse model of pre-B-cell acute lymphocytic lymphoma
Abstract
The overexpression of prosurvival members of the Bcl-2 family is commonly associated with the enhanced malignancy of hematological tumors. There has been great interest in a novel set of agents that are able to mimic the function of the BH3 domain by binding to the groove of Bcl-2-like proteins and initiating the cell death sequence. We sought to examine the efficacy of BH3 mimetics in a spontaneous mouse model of B-cell neoplasia. We evaluated the ability of the BH3 mimetics to preferentially target tumor cells while sparing normal cells. In addition, we examined the contributions of Bim and Puma to the sensitivity of tumor cells to the BH3 mimetics. We report here that two BH3 mimetics (HA-14-1 and BH3-I-2') were able to induce apoptosis of murine B-cell lymphoma cells in vitro and in vivo. Tumors that arose from transplantation of primary lymphoma cells regressed following 7 days of treatment with BH3-mimetic drugs. The long-term benefits of the transient treatment of tumor-bearing mice with the BH3 mimetics, however, could not be properly evaluated, due to the high levels of toxicity we observed in vivo with these drugs. Decreased expression of either Bim or Puma from B-cell tumor cells was able to protect these cells from the apoptosis induced by these BH3 mimetics, suggesting that they function through other means. We conclude that while the BH3-mimetic drugs are effective at inducing cell death of lymphoma cells in vitro and in vivo, their unclear molecular specificity and their ability to kill normal cells may limit their therapeutic uses in humans.
Similar articles
- Defining specificity and on-target activity of BH3-mimetics using engineered B-ALL cell lines.Koss B, Ryan J, Budhraja A, Szarama K, Yang X, Bathina M, Cardone MH, Nikolovska-Coleska Z, Letai A, Opferman JT.Koss B, et al.Oncotarget. 2016 Mar 8;7(10):11500-11. doi: 10.18632/oncotarget.7204.Oncotarget. 2016.PMID:26862853Free PMC article.
- Targeting ERK1/2-bim signaling cascades by BH3-mimetic ABT-737 as an alternative therapeutic strategy for oral cancer.Shin JA, Kim LH, Lee SJ, Jeong JH, Jung JY, Lee HN, Hong IS, Cho SD.Shin JA, et al.Oncotarget. 2015 Nov 3;6(34):35667-83. doi: 10.18632/oncotarget.5523.Oncotarget. 2015.PMID:26447615Free PMC article.
- Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia.Iacovelli S, Ricciardi MR, Allegretti M, Mirabilii S, Licchetta R, Bergamo P, Rinaldo C, Zeuner A, Foà R, Milella M, McCubrey JA, Martelli AM, Tafuri A.Iacovelli S, et al.Oncotarget. 2015 Oct 13;6(31):32089-103. doi: 10.18632/oncotarget.5156.Oncotarget. 2015.PMID:26392332Free PMC article.
- Design of novel BH3 mimetics for the treatment of chronic lymphocytic leukemia.Billard C.Billard C.Leukemia. 2012 Sep;26(9):2032-8. doi: 10.1038/leu.2012.88. Epub 2012 Mar 28.Leukemia. 2012.PMID:22453662Review.
- New dimension in therapeutic targeting of BCL-2 family proteins.Besbes S, Mirshahi M, Pocard M, Billard C.Besbes S, et al.Oncotarget. 2015 May 30;6(15):12862-71. doi: 10.18632/oncotarget.3868.Oncotarget. 2015.PMID:25970783Free PMC article.Review.
Cited by
- Chronic myelomonocytic leukemia and atypical chronic myeloid leukemia: novel pathogenetic lesions.Muramatsu H, Makishima H, Maciejewski JP.Muramatsu H, et al.Semin Oncol. 2012 Feb;39(1):67-73. doi: 10.1053/j.seminoncol.2011.11.004.Semin Oncol. 2012.PMID:22289493Free PMC article.Review.
- Expansion of human and murine hematopoietic stem and progenitor cells ex vivo without genetic modification using MYC and Bcl-2 fusion proteins.Bird GA, Polsky A, Estes P, Hanlon T, Hamilton H, Morton JJ, Gutman J, Jimeno A, Turner BC, Refaeli Y.Bird GA, et al.PLoS One. 2014 Aug 29;9(8):e105525. doi: 10.1371/journal.pone.0105525. eCollection 2014.PLoS One. 2014.PMID:25170611Free PMC article.
- Subcellular location of antitumor tripeptide-tyroserleutide in human hepatocellular carcinoma cells.Jian X, Fu Z, Zhang Y, Che X, Lu R, Yao Z.Jian X, et al.Exp Ther Med. 2012 Feb;3(2):195-199. doi: 10.3892/etm.2011.401. Epub 2011 Dec 1.Exp Ther Med. 2012.PMID:22969868Free PMC article.
Publication types
MeSH terms
Substances
Related information
Grants and funding
LinkOut - more resources
Full Text Sources