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.
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.
Turner
Brian C
BC
Program in Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado 80206, USA.
Eves
Taylor
T
Refaeli
Yosef
Y
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D000072224:Bcl-2-Like Protein 11; D032701:Biomimetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D017434:Protein Structure, Tertiary / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D012074:Remission Induction; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects*; D025521:Tumor Suppressor Proteins / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; C488588:PUMA protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D025521:Tumor Suppressor Proteins