• Potential conflict of interest: Nothing to report.

We thank Dr. Vinciguerra for his interest in our article regarding synergistic inhibition of hepatocellular carcinoma (HCC) growth by cotargeting the enzymatic activities of histone deacetylases (HDACs) and poly(ADP-ribose) polymerases (PARPs) in HCC cell lines.1 The amplified in liver cancer 1 (ALC1, also known as CHD1L) oncogene, originally isolated in primary HCC, is frequently amplified and overexpressed in HCC, and plays an important role in HCC pathogenesis through promoting proliferation and inhibiting apoptosis.2 Subsequent studies demonstrate that ALC1 is specifically targeted to the sites of DNA damage through interaction with PARP1 and regulates chromatin remodeling during the process of DNA repair.3, 4 Consequently, knockdown of ALC1 results in increased cellular sensitivity to specific DNA damaging agents phleomycin and H2O2.3 Given that the HepG2 cells expressing high levels of ALC12 are sensitive to both PARP and HDAC inhibitors,1 there is increasing interest in seeing the expression status of ALC1 in SNU-398 and SNU-449 cell lines, with sensitive versus resistant phenotype to both enzymatic inhibitors, respectively. Interestingly, gene expression profiling analysis demonstrated no significant difference in ALC1 mRNA levels between both cell lines,1 suggesting that the observed distinct sensitivity of SNU-398 versus SNU-449 cells to PARP and HDAC inhibitors may be irrelevant to ALC1 expression levels, at least under the experimental conditions used in this study.

Although HDAC inhibitor research in cancer therapeutics is still in its infancy, it has been demonstrated that the safety profile of HDAC inhibitors in phase I and II trials has been favorable, especially in comparison to traditional cytotoxic chemotherapy.5 Thus, a rational combination of selective and potent HDAC and PARP inhibitors may represent a promising avenue for inhibiting HCC growth, especially in molecularly defined HCC patient populations. Additional preclinical studies and clinical trials are definitely needed to validate these findings.

Da-Qiang Li M.D.*, Rakesh Kumar Ph.D.*, * Department of Biochemistry and Molecular Biology, The George Washington University, Washington, DC.