Like PB&J or Brangelina, some things are just better together. Now a new study suggests that combining derivatives of the histone deacetylase (HDAC) inhibitor valproic acid with the chemotherapy drug cisplatin may kill human lung cancer cells better than either drug alone.
HDAC inhibitors such as valproic acid show great promise as treatments for a variety of cancers. The drugs are thought to function by inhibiting the removal of acetyl groups from histone tails by HDACs, thereby de-repressing genes silenced in cancer, such as tumor suppressor genes. However, valproic acid as a cancer drug is pretty wimpy, necessitating large doses that cause unpleasant side effects in patients.
Previous studies have shown that derivatives of valproic acid that contain hydrogen sulfide-releasing groups show improved potency against experimental models of prostate cancer and non-small cell lung cancer (NSCLC). In the new study, researchers led by Anna Tesei at the Istituto Scientifico Romagnolo per lo Studio e la Cure dei Tumori, in Italy, evaluated the activity and mechanism of action of some organosulfur valproic acid derivatives, alone or in combination with the conventional chemotherapy drug cisplatin, in three human NSCLC cell lines. Their findings include the following:
- The valproic acid derivative known as ACS2 showed the greatest cytotoxic activity of the tested compounds, killing more than 50% of cells at concentrations of 64.5–72 µM.
- ACS2 triggered apoptosis by the mitochondrial pathway in 30–60% of cells in the NSCLC lines and reduced their metastatic potential.
- Treating cells with both ACS2 and cisplatin for 6 h, followed by a continuous 66-h exposure to ACS2, decreased cell survival, even at relatively low doses of both drugs.
- ACS2 may enhance the ability of cisplatin to form adducts on DNA by decondensing chromatin. In support of this hypothesis, ACS2 increased the levels of histone H3 and H4 acetylation and the proportion of single-stranded DNA regions in NSCLC cells.
This study confirms that organosulfur derivatives of valproic acid can have much higher cytotoxic activities than their parent compound. Moreover, low doses of one compound, ACS2, in combination with cisplatin kill NSCLC cells more effectively than either drug alone, suggesting new strategies for NSCLC therapy.
To learn more about the new and improved valproic acid derivatives, check out Journal of Cellular Physiology, December 2011.