Suberoylanilide hydroxamic acid, known as SAHA or Vorinostat, is a medication classified as a histone deacetylase (HDAC) inhibitor. It is used in oncology and is available as oral capsules under the brand name Zolinza.
Understanding HDAC Inhibitors
Histone deacetylases (HDACs) are enzymes that regulate gene expression within cells. They remove acetyl groups from histone proteins, structural proteins around which DNA is wound. This removal causes DNA to become more tightly packed, making it less accessible for gene transcription and suppressing gene expression.
HDACs are categorized into four main classes based on their structure and function. Class I HDACs are primarily found in the nucleus and influence cell cycle regulation. Class II HDACs can move between the nucleus and cytoplasm and are involved in tissue-specific gene expression. Class III HDACs, known as sirtuins, are dependent on NAD+ and participate in cellular metabolism, while Class IV includes HDAC11, which shares characteristics with both Class I and Class II.
The balanced activity of HDACs and histone acetyltransferases (HATs), which add acetyl groups, is important for proper gene regulation. In many diseases, especially cancers, this balance is disrupted, leading to abnormal cell growth and proliferation. Overexpression or increased activity of certain HDACs can silence tumor suppressor genes, promoting uncontrolled cell division. Inhibiting HDACs can therefore be a therapeutic strategy to restore normal gene expression patterns and counteract abnormal cell growth.
How SAHA Works
Vorinostat functions by binding directly to the active site of HDAC enzymes. Its hydroxamic acid moiety allows it to bind to the zinc ion in the active site, blocking the enzyme’s ability to remove acetyl groups from histone proteins.
The inhibition of HDAC activity by Vorinostat leads to an accumulation of acetylated histones within the cell. This increased acetylation results in a more relaxed and open chromatin structure, which makes DNA more accessible to transcription factors. Consequently, the expression of certain genes that were previously suppressed, including tumor suppressor genes, can be reactivated.
Beyond histones, Vorinostat also influences the acetylation of various non-histone proteins. These changes can affect cellular pathways involved in cell growth, differentiation, and programmed cell death (apoptosis) in cancer cells. By restoring a more normal acetylation balance, Vorinostat helps induce cell cycle arrest and promote the death of malignant cells, generally showing less toxicity to healthy cells.
Medical Uses of SAHA
Vorinostat is approved for treating cutaneous T-cell lymphoma (CTCL), a type of non-Hodgkin lymphoma primarily affecting the skin. It is used for patients whose disease has progressed or returned after prior systemic therapies.
Its effectiveness in CTCL is linked to its HDAC inhibitor mechanism. In CTCL cells, Vorinostat promotes acetylated histone accumulation, changing gene expression to induce cell differentiation and programmed cell death in malignant T-cells. Vorinostat can cause apoptosis in CTCL cell lines and peripheral blood lymphocytes.
Vorinostat’s ability to induce apoptosis in CTCL cells involves the activation of both extrinsic and intrinsic apoptotic pathways, as evidenced by the processing of initiator caspases and the loss of mitochondrial membrane potential. While its primary approved use is for CTCL, Vorinostat has also been investigated in clinical trials for other cancers, including certain solid tumors and hematologic malignancies, and has shown some activity in conditions like recurrent glioblastoma multiforme.
Safety and Potential Side Effects
Vorinostat treatment can lead to various side effects, with gastrointestinal issues being common. Patients may experience nausea, vomiting, and diarrhea. Antiemetic and antidiarrheal medications might be necessary to manage these symptoms, and maintaining adequate fluid and electrolyte balance is important, especially if severe gastrointestinal distress occurs.
Fatigue is another reported side effect. Patients may also experience changes in blood counts, including thrombocytopenia (low platelet count) and anemia (low red blood cell count). Regular monitoring of blood counts and electrolytes is recommended, typically every two weeks during the initial two months of treatment and then monthly thereafter.
Other potential adverse events include loss of appetite, weight loss, and changes in taste perception. Less common but serious side effects can involve blood clots, such as deep vein thrombosis or pulmonary embolism, and prolongation of the QTc interval, an electrical activity measurement of the heart. Patients with pre-existing heart conditions or those taking medications known to prolong the QTc interval should be closely monitored.