Histone Deacetylase Inhibitors

Histone deacetylase inhibitors (HDAC inhibitors) are a group of chemotherapy agents used to treat hematological cancers. The US Food and Drug Administration has approved the use of four different HDAC inhibitors to treat T-cell lymphoma and myeloma.

HDAC inhibitors have shown promising results as targeted cancer therapies because of their limited side effects and their ability to selectively kill cancer cells [1]. Interest in these drugs has been so high that there have been at least 80 clinical trials testing more than 11 new HDAC inhibitory drugs [2].  Only four are marketed in the US at this time.

How do histone deacetylase inhibitors work?

Histone deacetylase inhibitors are thought to act by inhibiting DNA repair, altering gene expression and making post-translational modifications to proteins [3]. In addition, HDAC inhibitors have been shown to stop the proliferation of cancer cells, stimulate apoptosis (cell death) and arrest the cell cycle [3]. These actions collectively result in the disruption of vital cell functions and stop the ability of cancerous cells to grow and multiply. Yet unlike other anti-cancer drugs, research shows that HDAC inhibitors may at times act selectively.

For example, Vorinostat (approved by the FDA for treatment of multiple myeloma) causes DNA strands to break in both normal and cancerous cells [4]. However, normal cells can recover from this destruction and will repair themselves while the cancerous cells cannot.

These multiple mechanisms of action make HDAC inhibitors an attractive area for medicinal chemists to pursue when looking for new anti-cancer drugs.

Specific Histone deacetylase inhibitors

The US FDA has approved the use of four HDACs inhibitors: Vorinostat (Zolinza) and Romidepsin (Istodax) for the treatment of cutaneous T-cell lymphoma [7] and Belinostat (Beleodaq) and Panobinstat (Farydak) for the treatment of peripheral T-cell lymphoma and multiple myeloma respectively.

Broadly speaking, Vorinostat and Romidepsin are used in cases where the cancer is still present in the body, if the cancer gets worse or if it comes back during or after treatment with other medications [5].

Belinostat is approved for use in relapsed or refractory peripheral T-cell lymphoma. This is cancer that has returned or has been resistant to other treatments.

Panobinstat has been marketed as the first HDAC inhibitor approved to treat multiple myeloma. It is intended for patients who have received at least two prior standard therapies and only in combination with bortezomib (another anti-cancer drug), chemotherapy and dexamethasone, an anti-inflammatory medication [9].

HDAC inhibitors are used as either monotherapy or in combination with other cancer treatments.

Tumors treated by Histone deacetylase inhibitors

To date histone deacetylase inhibitors have been used in the treatment of cancers like lymphoma and myeloma. For reasons still not fully understood by scientists these inhibitors don’t appear to work as well against solid tumors.

However some of the major clinical trials currently taking place are testing these medicines against more common solid tumors like lung, breast and prostate cancer [6].

Vorinostat is the most advanced HDAC inhibitor and is given orally in the treatment of peripheral T-cell lymphoma. Like other HDAC inhibitors, Vorinostat is fairly well tolerated with minimal side effects. The most common side effects experienced are fatigue, diarrhea and nausea [8].

Romidepsin and Belinostat have similar side effect profiles and are administered intravenously (into a vein). They are usually given on tightly scheduled days over a 28-day cycle.

Panobinstat is given orally to treat myeloma.

Although much is known about the actions of HDAC inhibitors and their future as cancer-fighting drugs appears promising, scientists still do not have a perfect understanding of how these drugs work. Observers hope research in this area will bring about further developments of more HDAC drugs that can be used in the fight against cancer.

 

References

1) Lee, J. H., Choy, M. L., Ngo, L., Foster, S. S., & Marks, P. A. (2010). Histone deacetylase inhibitor induces DNA damage, which normal but not transformed cells can repair. Proceedings of the National Academy of Sciences, 107(33), 14639-14644.
http://www.pnas.org/content/107/33/14639.full

2) Tan, J., Cang, S., Ma, Y., Petrillo, R. L., & Liu, D. (2010). Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents. Journal of hematology & oncology, 3(1), 5.
https://jhoonline.biomedcentral.com/articles/10.1186/1756-8722-3-5

3) Katoch O, Dwarakanath B and Agrawala P K: HDAC inhibitors: applications in oncology and beyond. HOAJ Biology 2013, 2:2 http://dx.doi.org/10.7243/2050-0874-2-2
http://www.hoajonline.com/hoajbiology/2050-0874/2/2

4) Lee, J. H., Choy, M. L., Ngo, L., Foster, S. S., & Marks, P. A. (2010). Histone deacetylase inhibitor induces DNA damage, which normal but not transformed cells can repair. Proceedings of the National Academy of Sciences, 107(33), 14639-14644.
http://www.pnas.org/content/107/33/14639.full

5) Bubna, A. K. (2015). Vorinostat—An Overview. Indian Journal of Dermatology, 60(4), 419. http://doi.org/10.4103/0019-5154.160511
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4533557/

6) Halsall, J. A. and Turner, B. M. (2016), Histone deacetylase inhibitors for cancer therapy: An evolutionarily ancient resistance response may explain their limited success. BioEssays, 38: 1102–1110. doi:10.1002/bies.201600070
http://onlinelibrary.wiley.com/doi/10.1002/bies.201600070/full

7) Science Direct. Histone deacetylase inhibitor
https://www.sciencedirect.com/topics/neuroscience/histone-deacetylase-inhibitor

8) Chemocare. Vorinostat
http://chemocare.com/chemotherapy/drug-info/Vorinostat.aspx

9) FDA News release. FDA approves Farydak for treatment of multiple myeloma. February 23, 2015
https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm435296.htm

Belinostat

Brand/Trade Names: Beleodaq

Formula: C15H14N2O4S

Mechanism: HDAC inhibitor

Class:

Administration: Intravenous

Notes:

Panobinostat

Brand/Trade Names: Farydak

Formula: C21H23N3O2

Mechanism: HDAC inhibitor

Class:

Administration: Intravenous and oral

Notes:

Romidepsin

Brand/Trade Names: Istodax, Chromadax

Formula: C24H36N4O6S2

Mechanism: HDAC inhibitor

Class:

Administration: Intravenous

Notes: Romidepsin for the treatment of relapsed/refractory peripheral T-cell lymphoma

Vorinostat

Brand/Trade Names: Zolinza

Formula: C14H20N2O3

Mechanism: HDAC inhibitor

Class:

Administration: Oral

Notes: HIV-1 Expression Within Resting CD4+ T Cells After Multiple Doses of Vorinostat