Suberoylanilide hydroxamic acid, or SAHA, is a synthetic compound belonging to a class of drugs known as histone deacetylase inhibitors. It is more commonly recognized by its brand name, Vorinostat. This compound is used as a therapeutic agent for specific types of cancer, focusing on epigenetic regulation within cells.
The Mechanism of Action
DNA is tightly coiled around proteins called histones, forming a structure known as chromatin. This packaging allows vast amounts of genetic information to fit inside the cell’s nucleus. The tightness of this coiling can determine whether the genes within that DNA segment are active or dormant.
Enzymes called histone deacetylases (HDACs) play a part in this process. HDACs remove acetyl groups from histones, which causes the chromatin to condense and tighten. This tightening can effectively “silence” genes, preventing them from being read and transcribed into proteins. In some cancers, the genes that are supposed to suppress tumor growth are silenced in this manner, allowing cancer cells to proliferate without restraint.
SAHA functions as an HDAC inhibitor. Its molecular structure allows it to bind to the active site of HDAC enzymes, specifically chelating the zinc ion that is necessary for their function. This action blocks the enzymes from removing acetyl groups, leading to an accumulation of acetylated histones. This accumulation results in a more relaxed, open chromatin structure.
This loosening of the DNA “thread” from the histone “spool” allows the cellular machinery to access and read the previously silenced genes. By re-expressing these tumor suppressor genes, SAHA can trigger several outcomes detrimental to cancer cells. These include inducing cell cycle arrest, which stops the cells from dividing, or initiating apoptosis, a form of programmed cell death.
Approved Medical Applications
The U.S. Food and Drug Administration (FDA) has approved Suberoylanilide hydroxamic acid (SAHA), under the name Vorinostat, for a specific medical purpose. Its primary and only FDA-approved use is for the treatment of cutaneous T-cell lymphoma (CTCL). This approval is specifically for patients whose disease shows cutaneous manifestations and is progressive, persistent, or has recurred after two other systemic therapies have been tried.
Cutaneous T-cell lymphoma is a type of non-Hodgkin lymphoma where the immune system’s T-cells become cancerous and primarily affect the skin. This can result in various skin problems, including rashes, patches, plaques, and tumors.
Studies showed an overall objective response rate of around 24% to 30% in patients with advanced, refractory CTCL. The treatment helps manage the skin-related symptoms of the disease. It is important to note that while it shows efficacy, complete responses are rare, and the focus is on managing the disease and its manifestations on the skin.
Administration and Side Effects
Vorinostat is administered orally in the form of a capsule, which offers a convenient alternative to intravenous treatments. The standard recommended dosage for treating CTCL is 400 mg taken once daily with food. This regimen is typically continued until there is evidence of disease progression or the patient experiences unacceptable toxicity.
Patients taking Vorinostat may experience a range of side effects. The most common adverse effects are generally mild to moderate and include fatigue, diarrhea, nausea, decreased appetite, and changes in taste.
More serious side effects can also occur and require prompt medical attention. A significant concern is the risk of developing blood clots, such as deep vein thrombosis in the legs or a pulmonary embolism in the lungs. Other serious potential adverse events include high blood sugar (hyperglycemia) and a reduction in blood cell counts, which can lead to thrombocytopenia (low platelets) and anemia. Because of these risks, regular monitoring, including blood tests, is a standard part of the treatment protocol.
Investigational Research Areas
Beyond its approved use for CTCL, Vorinostat is the subject of extensive investigational research for other conditions. Scientists are exploring its potential in treating a variety of other cancers, both solid tumors and hematologic malignancies. For instance, studies have examined its activity against recurrent glioblastoma, a type of aggressive brain tumor, and in patients with multiple myeloma.
The research extends into non-cancer applications as well. One notable area is in the field of HIV research, where Vorinostat is being investigated as a latency-reversing agent. The “shock and kill” strategy aims to reactivate latent HIV hidden in T-cells, making the virus visible to the immune system and antiretroviral drugs. Preclinical studies have shown that SAHA can reactivate these dormant viruses.
Furthermore, there is interest in Vorinostat’s potential for treating certain neurodegenerative diseases. Research has suggested it might have some activity against the pathological changes seen in Huntington’s disease. These investigational uses are still in experimental stages, and the compound’s efficacy and safety for these conditions have not been established.