Ricolinostat suppresses proliferation, promotes apoptosis, and enhances the antiproliferative activity of topoisomerase inhibitors in cervical cancer cells.

Ricolinostat has been found to exhibit anticancer effects alone and in combination with various chemotherapeutic drugs in several cancer types. However, to the best of our knowledge, the efficacy of ricolinostat in cervical cancer is still not investigated. Therefore, in this study, we evaluated the effect of ricolinostat in cervical cancer alone and in combination with topoisomerase inhibitors. The effect of ricolinostat on cervical cancer cells was assessed using MTT, cell-cycle arrest, Annexin V/PI staining assay, reactive oxygen species (ROS) measurement, and western blot analysis. The antiproliferative effect of ricolinostat in combination with topoisomerase inhibitors was assessed using the MTT assay and synergism was computed using "CompuSyn" software. We found that ricolinostat inhibited proliferation, and induced G2/M phase arrest and apoptosis in cervical cancer cells. We further found that ricolinostat treatment resulted in increased ROS production, decreased Bcl-xL expression, and induced p21 expression. We also investigated the effect of ricolinostat in combination with topotecan and etoposide in cervical cancer cells. Ricolinostat was found to significantly enhance the antiproliferative activity of both, topotecan and etoposide, in cervical cancer cells in a concentration-dependent manner. In conclusion, our study showed that ricolinostat suppressed proliferation by inducing G2/M phase arrest and promoted apoptosis in cervical cancer cells, indicating that ricolinostat may be a promising antitumor agent in cervical cancer. Also, ricolinostat and topotecan/etoposide combination are synergistic in cervical cancer cells.

HDAC6: A unique HDAC family member as a cancer target.

BACKGROUND: HDAC6, a structurally and functionally distinct member of the HDAC family, is an integral part of multiple cellular functions such as cell proliferation, apoptosis, senescence, DNA damage and genomic stability, all of which when deregulated contribute to carcinogenesis. Among several HDAC family members known so far, HDAC6 holds a unique position. It differs from the other HDAC family members not only in terms of its subcellular localization, but also in terms of its substrate repertoire and hence cellular functions. Recent findings have considerably expanded the research related to the substrate pool, biological functions and regulation of HDAC6. Studies in HDAC6 knockout mice highlighted the importance of HDAC6 as a cell survival player in stressful situations, making it an important anticancer target. There is ample evidence stressing the importance of HDAC6 as an anti-cancer synergistic partner of many chemotherapeutic drugs. HDAC6 inhibitors have been found to enhance the effectiveness of conventional chemotherapeutic drugs such as DNA damaging agents, proteasome inhibitors and microtubule inhibitors, thereby highlighting the importance of combination therapies involving HDAC6 inhibitors and other anti-cancer agents. CONCLUSIONS: Here, we present a review on HDAC6 with emphasis on its role as a critical regulator of specific physiological cellular pathways which when deregulated contribute to tumorigenesis, thereby highlighting the importance of HDAC6 inhibitors as important anticancer agents alone and in combination with other chemotherapeutic drugs. We also discuss the synergistic anticancer effect of combination therapies of HDAC6 inhibitors with conventional chemotherapeutic drugs.