Vorinostat Explained

Vorinostat (rINN),[1] also known as suberoylanilide hydroxamic acid (suberoyl+anilide+hydroxamic acid abbreviated as SAHA), is a member of a larger class of compounds that inhibit histone deacetylases (HDAC). Histone deacetylase inhibitors (HDI) have a broad spectrum of epigenetic activities.

Vorinostat is marketed under the name Zolinza by Merck for the treatment of cutaneous manifestations in patients with cutaneous T cell lymphoma (CTCL) when the disease persists, gets worse, or comes back during or after two systemic therapies.[2] The compound was developed by Columbia University chemist Ronald Breslow and Memorial Sloan-Kettering researcher Paul Marks.[3] [4]

Medical uses

Vorinostat was the first histone deacetylase inhibitor[5] approved by the U.S. Food and Drug Administration (FDA) for the treatment of CTCL on October 6, 2006.[6]

Development

In 1966, Charlotte Friend published her observation that a suspension of murine erythroleukemia cells underwent cytodifferentiation to normal erythrocytes when treated with dimethylsulfoxide (DMSO, a common drug solvent and cryoprotectant frequently used for cell culture freezing) at 280 mmolar.[7] [8] Memorial Sloan-Kettering researcher Paul Marks approached Columbia University chemist Ronald Breslow about these findings and together they decided to develop more potent analogs of DMSO, in order to make use of this property for cancer treatment. Their optimization process lead to the discovery of suberoylanilide hydroxamic acid and its HDAC-inhibiting property.[9]

Mechanism of action

Vorinostat has been shown to bind to the active site of histone deacetylases and act as a chelator for zinc ions also found in the active site of histone deacetylases.[10] Vorinostat's inhibition of histone deacetylases results in the accumulation of acetylated histones and acetylated proteins, including transcription factors crucial for the expression of genes needed to induce cell differentiation. It acts on class I, II and IV of histone deacetylase.

Clinical trials

Vorinostat has also been used to treat Sézary syndrome, another type of lymphoma closely related to CTCL.[11]

A recent study suggested that vorinostat also possesses some activity against recurrent glioblastoma multiforme, resulting in a median overall survival of 5.7 months (compared to 4–4.4 months in earlier studies).[12] Further brain tumor trials are planned in which vorinostat will be combined with other drugs.

Including vorinostat in treatment of advanced non-small-cell lung carcinoma (NSCLC) showed improved response rates and increased median progression free survival and overall survival.[13]

It has given encouraging results in a phase II trial[14] for myelodysplastic syndromes in combination with idarubicin and cytarabine.[15] It failed to demonstrate efficacy in treating acute myeloid leukemia in an earlier phase II study.[16]

Preclinical investigations

Vorinostat is being investigated as a potential HIV latency reversing agent (LRA) as part of an investigational therapeutic strategy known as "shock and kill". Vorinostat was shown to reactivate HIV in latently HIV-infected T cells, both in vitro and in vivo.[17] [18]

Vorinostat also has shown some activity against the pathophysiological changes in α1-antitrypsin deficiency[19] and cystic fibrosis.[20] Recent evidence also suggests vorinostat can be a therapeutic tool for Niemann-Pick type C1 (NPC1), a rare lysosomal lipid storage disease.[21]

Preclinical experiments by University of Alabama at Birmingham researchers suggest the cancer drugs vorinostat, belinostat and panobinostat might be repurposed to treat infections caused by human papillomavirus, or HPV.[22]

See also

External links

Notes and References

  1. International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 56. WHO Drug Information. 2006. 20. 3. 232. https://web.archive.org/web/20110705092935/http://apps.who.int/medicinedocs/documents/s14181e/s14181e.pdf. dead. July 5, 2011. 1 September 2016.
  2. ZOLINZA, Merck's Investigational Medicine for Advanced Cutaneous T-Cell Lymphoma (CTCL), To Receive Priority Review from U.S. Food and Drug Administration . Merck & Co. . June 7, 2006 . 2006-10-06 . https://web.archive.org/web/20060914014021/http://www.merck.com/newsroom/press_releases/research_and_development/2006_0607.html . September 14, 2006 . dead . mdy-all .
  3. Lee JH, Mahendran A, Yao Y, Ngo L, Venta-Perez G, Choy ML, Kim N, Ham WS, Breslow R, Marks PA . 6 . Development of a histone deacetylase 6 inhibitor and its biological effects . Proceedings of the National Academy of Sciences of the United States of America . 110 . 39 . 15704–15709 . September 2013 . 24023063 . 3785767 . 10.1073/pnas.1313893110 . free . 2013PNAS..11015704L .
  4. Marks PA, Breslow R . Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug . Nature Biotechnology . 25 . 1 . 84–90 . January 2007 . 17211407 . 10.1038/nbt1272 . 12656582 .
  5. Web site: Vorinostat . HDAC Inhibitors Base .
  6. Web site: Zolinza (vorinostat) dosing, indications, interactions, adverse effects, and more. Medscape Reference. WebMD. 16 February 2014.
  7. Friend C, Patuleia MC, De Harven E . Erythrocytic maturation in vitro of murine (Friend) virus-induced leukemic cells . National Cancer Institute Monograph . 22 . 505–522 . September 1966 . 5923328 .
  8. Friend C, Scher W, Holland JG, Sato T . Hemoglobin synthesis in murine virus-induced leukemic cells in vitro: stimulation of erythroid differentiation by dimethyl sulfoxide . Proceedings of the National Academy of Sciences of the United States of America . 68 . 2 . 378–382 . February 1971 . 5277089 . 388942 . 10.1073/pnas.68.2.378 . free . 1971PNAS...68..378F .
  9. Book: Breslow R . From DMSO to the Anticancer Compound SAHA, an Unusual Intellectual Pathway for Drug Design . 2016-12-02 . https://onlinelibrary.wiley.com/doi/10.1002/9783527800315.ch1 . Successful Drug Discovery . 1–11 . Fischer J, Childers WE . Weinheim, Germany . Wiley-VCH Verlag GmbH & Co. KGaA . en . 10.1002/9783527800315.ch1 . 978-3-527-80031-5 . 2022-11-18 .
  10. Marks PA, Dokmanovic M . Histone deacetylase inhibitors: discovery and development as anticancer agents . Expert Opinion on Investigational Drugs . 14 . 12 . 1497–1511 . December 2005 . 16307490 . 2360770 . 10.1038/sj.bjc.6603463 .
  11. Web site: Castoldi G, Cuneo A . May 2005 . Mycosis fungoides/Sezary's syndrome . 2008-02-15 . Atlas of Genetics and Cytogenetics in Oncology and Haematology .
  12. Vorinostat shows anti-cancer activity in recurrent gliomas . Mayo Clinic . June 3, 2007 . 2007-06-03 .
  13. Ramalingam SS, Maitland ML, Frankel P, Argiris AE, Koczywas M, Gitlitz B, Thomas S, Espinoza-Delgado I, Vokes EE, Gandara DR, Belani CP . 6 . Carboplatin and Paclitaxel in combination with either vorinostat or placebo for first-line therapy of advanced non-small-cell lung cancer . Journal of Clinical Oncology . 28 . 1 . 56–62 . January 2010 . 19933908 . 2799233 . 10.1200/JCO.2009.24.9094 .
  14. Garcia-Manero G, Tambaro FP, Bekele NB, Yang H, Ravandi F, Jabbour E, Borthakur G, Kadia TM, Konopleva MY, Faderl S, Cortes JE, Brandt M, Hu Y, McCue D, Newsome WM, Pierce SR, de Lima M, Kantarjian HM . 6 . Phase II trial of vorinostat with idarubicin and cytarabine for patients with newly diagnosed acute myelogenous leukemia or myelodysplastic syndrome . Journal of Clinical Oncology . 30 . 18 . 2204–2210 . June 2012 . 22585696 . 4879705 . 10.1200/JCO.2011.38.3265 .
  15. Web site: Langholtz J, Haehle M . 11 January 2012 . The MDS Beacon . Zolinza, Idarubicin, Cytarabine Combination Yields High Response Rates In MDS Patients (ASH 2011) . 2012-01-17 . 2014-10-30 . https://web.archive.org/web/20141030050144/http://www.mdsbeacon.com/news/2012/01/11/zolinza-vorinostat-idarubicin-cytarabine-combination-yields-high-response-rates-for-mds-patients-ash-2011/ . dead .
  16. Schaefer EW, Loaiza-Bonilla A, Juckett M, DiPersio JF, Roy V, Slack J, Wu W, Laumann K, Espinoza-Delgado I, Gore SD . 6 . A phase 2 study of vorinostat in acute myeloid leukemia . Haematologica . 94 . 10 . 1375–1382 . October 2009 . 19794082 . 2754953 . 10.3324/haematol.2009.009217 .
  17. Archin NM, Espeseth A, Parker D, Cheema M, Hazuda D, Margolis DM . Expression of latent HIV induced by the potent HDAC inhibitor suberoylanilide hydroxamic acid . AIDS Research and Human Retroviruses . 25 . 2 . 207–212 . February 2009 . 19239360 . 2853863 . 10.1089/aid.2008.0191 .
  18. Contreras X, Schweneker M, Chen CS, McCune JM, Deeks SG, Martin J, Peterlin BM . Suberoylanilide hydroxamic acid reactivates HIV from latently infected cells . The Journal of Biological Chemistry . 284 . 11 . 6782–6789 . March 2009 . 19136668 . 2652322 . 10.1074/jbc.M807898200 . free .
  19. Bouchecareilh M, Hutt DM, Szajner P, Flotte TR, Balch WE . Histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA)-mediated correction of α1-antitrypsin deficiency . The Journal of Biological Chemistry . 287 . 45 . 38265–38278 . November 2012 . 22995909 . 3488095 . 10.1074/jbc.M112.404707 . free .
  20. Hutt DM, Herman D, Rodrigues AP, Noel S, Pilewski JM, Matteson J, Hoch B, Kellner W, Kelly JW, Schmidt A, Thomas PJ, Matsumura Y, Skach WR, Gentzsch M, Riordan JR, Sorscher EJ, Okiyoneda T, Yates JR, Lukacs GL, Frizzell RA, Manning G, Gottesfeld JM, Balch WE . 6 . Reduced histone deacetylase 7 activity restores function to misfolded CFTR in cystic fibrosis . Nature Chemical Biology . 6 . 1 . 25–33 . January 2010 . 19966789 . 2901172 . 10.1038/nchembio.275 .
  21. Alam MS, Getz M, Haldar K . Chronic administration of an HDAC inhibitor treats both neurological and systemic Niemann-Pick type C disease in a mouse model . Science Translational Medicine . 8 . 326 . 326ra23 . February 2016 . 26888431 . 10.1126/scitranslmed.aad9407 . 5762569 .
  22. Web site: Cancer drug may help treat human papillomavirus infections . ScienceDaily . 30 November 2018 . 2018-11-30 .

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