Enhancing the apoptotic and therapeutic effects of HDAC inhibitors.
Histone deacetylase inhibitors (HDACi) are anti-cancer drugs that have moved rapidly through clinical development and in 2006 vorinostat (SAHA, Zolinza) was given FDA approval for the treatment of cutaneous T cell lymphoma. Class I, II and IV HDACs that are targets for these compounds deacetylate histone proteins, resulting in chromatin remodelling and altered gene transcription. In addition, numerous non-histone proteins are modified by acetylation and the inhibition of HDAC activity can therefore affect various molecular processes. This broad effect on protein function may account for the pleiotropic anti-tumor responses elicited by HDACi that include induction of tumor cell apoptosis, cell cycle arrest, differentiation and senescence, modulation of immune responses and altered angiogenesis. The ability of HDACi to selectively induce tumor cells to undergo apoptosis is important for the therapeutic efficacy observed in pre-clinical models. Moreover, HDACi can augment the apoptotic effects of other anti-cancer agents that have diverse molecular targets. While HDACi are promising anti-cancer drugs, particularly given the scope to combine HDACi with other agents, identifying the key molecular events that determine the biological response of cells to HDACi treatment remains a challenge. Herein we focus on HDACi-induced apoptosis and discuss the various proteins and pathways that are affected by HDACi to mediate this programmed cell death response. In addition, we highlight the ability of HDACi to synergise with other anti-cancer agents to potently kill tumor cells and discuss the possible molecular processes that underpin the combination effect.
Cancer Immunology Program, The Peter MacCallum Cancer Centre, Trescowthick Research Laboratories, East Melbourne, Victoria, Australia.
Ailsa J
AJ
Frew
Ricky W
RW
Johnstone
Jessica E
JE
Bolden
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D003131:Combined Modality Therapy; D004357:Drug Synergism; D019337:Hematologic Neoplasms / Q000188:drug therapy; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000502:physiology; D006801:Humans; D017382:Reactive Oxygen Species / Q000378:metabolism; D053218:Receptors, Death Domain / Q000819:agonists / Q000502:physiology
D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D017382:Reactive Oxygen Species; D053218:Receptors, Death Domain; D006655:Histone Deacetylases