Synergistic effect of Chloroquine and Panobinostat in ovarian cancer through induction of DNA damage and inhibition of DNA repair
María Ovejero Sánchez
Centro de Investigación del Cáncer (CIC-IBMCC)
Ovarian cancer (OC) includes a collection of malignant tumors that affects the ovaries, the peritoneum and the fallopian tubes. These tumors can be originated from three different cellular types: epithelial, stromal or germ cells. Around 90% of ovarian cancers have an epithelial origin. Within this group it can be distinguished five types of tumors based on histopathological and molecular features: high grade serous carcinoma, low grade serous carcinoma, endometrioid carcinoma, clear cell carcinoma or mucinous carcinoma.
OC is one of the most common gynecologic malignancy and has the highest mortality rate among them. This high rate is mainly due to a late-stage diagnosis and chemotherapy resistance. Indeed, around 70% of the patients relapse during the first two years after diagnosis, even after an optimal cytoreductive surgery and a complete standard chemotherapeutic regimen. Therefore, there is a clear need to develop new and more effective therapeutic strategies against this type of cancer. One of these strategies should be efficient drug combinations that could overcome resistances and improve ovarian cancer survival.
Histone deacetylase inhibitors (HDACi) represents promising agents in cancer treatment. These molecules inhibit HDACs, critical regulators of gene expression that deacetylase different histones acting as transcriptional repressors, promoting transcriptional activation of several genes that are silenced in human tumors. HDACi have been shown to exert pleiotropic antineoplastic effects such as induction of apoptosis, cellular differentiation and cell cycle arrest, as well as impair DNA repair. In addition, HDACi promote autophagy, but this effect has been proposed as a potential resistance mechanism to these drugs. Therefore, the combination of HDACi and autophagy inhibitors, as Chloroquine, could improve HDACi antitumor effect.
The aim of this study was to analyze the effect of two drugs, Chloroquine and the histone deacetylase inhibitor Panobinostat, in the survival of ovarian cancer cells and the potential underlying mechanism of action.