Although the genetic code held within DNA contributes largely to risk factors for developing non-small cell lung cancer (NSCLC), external manipulation of DNA, known as epigenetics, plays an equally important role. The mediators of epigenetic changes are known as histones, and these proteins regulate which genes in cells are active. Pharmacological agents that act on these proteins are becoming more mainstream in cancer research, and these include the class of molecules known as histone deacetylase (HDAC) inhibitors.
In the study “Epigenetic Modulation with HDAC Inhibitor CG200745 Induces Anti-Proliferation in Non-Small Cell Lung Cancer Cells,” a team from Asan Medical Center at The University of Ulsan College of Medicine in Korea investigated a specific HDAC inhibitor (CG200745) to battle NSCLC in vitro. “Our results suggest that the HDAC inhibitor CG200745 causes epigenetic reactivation of critical genes that are transcriptionally suppressed in cancers, and therefore can be a promising NSCLC cancer therapeutic,” stated Dr. Sung-Min Chun, lead author of the study.
The findings were made using three main experimental techniques: chromatin immunoprecipitation (ChIP)-on-chip assays, real-time PCR quantification, and western blotting. These techniques identify DNA-protein interactions, mRNA expression, and protein levels within cells, respectively.
Cells used in the study were human NSCLC cells derived from normal bronchial epithelial cells. They were exposed to increasing concentrations of CG200745 to find the dose at which 50% of HDACs are inhibited (IC50) to serve as an indicator of potency. The IC50 was in the micromolar range, which is on-par with vorinostat (SAHA), another HDAC inhibitor that has been used to fight cancer cells.
Moving forward with the studies, the researchers identified that CG200745 truly did increase histone acetylation and was capable of inhibiting NSCLC cell growth. “HDAC inhibitor molecules have been reported to induce a range of anticancer effects, including tumor cell apoptosis, cell cycle arrest, differentiation, senescence, modulation of immune responses, and altered angiogenesis,” stated Dr. Chun. In this study, “HDAC inhibitor treatment induced the inhibition of lung cancer cell growth, cell growth arrest, and apoptosis… at comparable IC50 concentrations to that of SAHA (also known as vorinostat), the only HDAC inhibitor currently approved for the clinical treatment of cutaneous T-cell lymphoma.”
Currently, CG200745 is in phase 1 clinical trials and has shown effects on tumor cells in prostate cancer, renal cell carcinoma, and colon carcinoma, both on its own and in combination with another anticancer drug. The present study suggests that CG200745 may be a suitable therapeutic for future clinical trials involving NSCLC patients.