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Induction of differential apoptotic pathways in multiple myeloma cells by class-selective histone deacetylase inhibitors

Leukemia volume 28, pages 457–460 (2014)Cite this article

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Histone deacetylase (HDAC) 6, a class-IIb HDAC, is the only HDAC with two functional deacetylase domains and a zinc-finger motif. HDAC6 was initially described as tubulin deacetylase; however, it also deacetylates other non-histone proteins, including heat-shock protein (Hsp90). Importantly, HDAC6 has an essential role in the aggresomal protein degradation pathway, an alternative system to the proteasome for degradation of polyubiquitinated misfolded/unfolded proteins. Specifically, HDAC6 binds to both polyubiquitinated proteins and dynein motors, thereby acting to recruit protein cargo to dynein motors for transport to aggresomes for lysosomal degradation.1 We have previously shown that inhibition of both proteasomal and aggresomal protein degradation using bortezomib (BTZ) to inhibit the proteasome and tubacin to inhibit HDAC6, respectively, induces accumulation of polyubiquitinated proteins and significant multiple myeloma (MM) cell stress, followed by apoptosis.2 More recently, a hydroxamic acid HDAC6-selective inhibitor ACY-1215 combined with BTZ shows significant anti-MM activities in preclinical studies,3 which have been rapidly translated to phase I/II clinical studies to treat relapsed/refractory MM.4 Previous studies have also shown that the non-selective HDAC inhibitor vorinostat in combination with BTZ also triggers synergistic cytotoxicity in MM,5 which has provided the framework for combination clinical trials.6

Carfilzomib (CFZ) is an epoxyketone proteasome inhibitor, which recently received accelerated Food and Drug Administration approval to treat relapsed refractory MM.7, 8 In this study, we asked whether HDAC6 inhibitors enhance anti-MM toxicity induced by CFZ. We also delineated differential molecular mechanisms that trigger synergistic MM toxicity triggered by CFZ in combination with either HDAC6-selective or class-I HDAC-selective inhibitors ACY-1215 and MS275 (entinostat), respectively.9

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Acknowledgements

This study was supported by the National Institute of Health Grants (SPORE-P50100707, P01 CA78378, R01 CA50947 (KCA) and P50 CA086355 (RM). KCA is an American Cancer Society Clinical Research Professor.

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Authors and Affiliations

  1. Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA, USA

    T Hideshima, N Mimura, G Gorgun, P G Richardson & K C Anderson

  2. Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA

    R Mazitschek

  3. MGH Cancer Center, Massachusetts General Hospital, Boston, MA, USA

    L Santo & N Raje

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  1. T Hideshima
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  2. R Mazitschek
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  3. L Santo
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  5. G Gorgun
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  6. P G Richardson
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  7. N Raje
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  8. K C Anderson
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Correspondence to K C Anderson.

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Competing interests

TH and NR are consultants for Acetylon Pharmaceuticals. KCA is a member of the advisory committees for Onyx, Celgene, Gilead and Sanofi-Aventis and is a scientific founder of Acetylon and Oncopep. RM has financial interests in SHAPE Pharmaceuticals and Acetylon Pharmaceuticals. He is also the inventor on IP licensed to these two entities. RM’s interests were reviewed and are managed by the Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies. PGR is a member of advisory board for Celgene, Millennium, Johnson & Johnson, Novartis and Keryx. Other authors declare no competing financial interests.

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The authors declare no conflict of interest.

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Hideshima, T., Mazitschek, R., Santo, L. et al. Induction of differential apoptotic pathways in multiple myeloma cells by class-selective histone deacetylase inhibitors. Leukemia 28, 457–460 (2014). https://doi.org/10.1038/leu.2013.301

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