Involvement of BH3-only proteins in hematologic malignancies.
The interaction between anti-apoptotic and pro-apoptotic members of the Bcl-2 family proteins determines life or death for cancer cells. In this context, BH3-only proteins (such as Bim), members of the pro-apoptotic Bcl-2 family proteins, act as key initiators of apoptosis by activating Bax and Bak through liberating them from anti-apoptotic Bcl-2 members. This then leads to the disruption of mitochondrial outer membrane, and eventually promotes proteolytic cascades for cellular dismantling. We here review the growing evidence of how BH3-only proteins are involved in tumorigenesis and in apoptosis induced by anti-cancer agents in hematologic malignancies. A deeper understanding of the roles of BH3-only proteins in cell death regulation may yield crucial insights for the further development of more effective and rational cell killing strategies. Recent developments in the direct therapeutic manipulation of Bcl-2 proteins using BH3-mimicking agents, such as ABT-737 or GX15-070, for hematologic malignancies are also summarized.
Kuroda
Junya
J
Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan. junkuro@koto.kpu-m.ac.jp
Taniwaki
Masafumi
M
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects / Q000502:physiology; D000072224:Bcl-2-Like Protein 11; D015195:Drug Design; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000503:physiopathology*; D006801:Humans; D008565:Membrane Proteins / Q000187:drug effects / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000502:physiology; D051025:bcl-Associated Death Protein / Q000187:drug effects / Q000502:physiology
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C494819:BAD protein, human; C494772:BAK1 protein, human; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein