Assessment of Interactions between Cisplatin and Two Histone Deacetylase Inhibitors in MCF7, T47D and MDA-MB-231 Human Breast Cancer Cell Lines – An Isobolographic Analysis

Abstract

Histone deacetylase inhibitors (HDIs) are promising anticancer drugs, which inhibit proliferation of a wide variety of cancer cells including breast carcinoma cells. In the present study, we investigated the influence of valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA, vorinostat), alone or in combination with cisplatin (CDDP) on proliferation, induction of apoptosis and cell cycle progression in MCF7, T47D and MDA-MB-231 human breast carcinoma cell lines. The type of interaction between HDIs and CDDP was determined by an isobolographic analysis. The isobolographic analysis is a very precise and rigorous pharmacodynamic method, to determine the presence of synergism, addition or antagonism between different drugs with using variety of fixed dose ratios. Our experiments show that the combinations of CDDP with SAHA or VPA at a fixed-ratio of 1:1 exerted additive interaction in the viability of MCF7 cells, while in T47D cells there was a tendency to synergy. In contrast, sub-additive (antagonistic) interaction was observed for the combination of CDDP with VPA in MDA-MB-231 “triple-negative” (i.e. estrogen receptor negative, progesterone receptor negative, and HER-2 negative) human breast cancer cells, whereas combination of CDDP with SAHA in the same MDA-MB-231 cell line yielded additive interaction. Additionally, combined HDIs/CDDP treatment resulted in increase in apoptosis and cell cycle arrest in all tested breast cancer cell lines in comparison with a single therapy. In conclusion, the additive interaction of CDDP with SAHA or VPA suggests that HDIs could be combined with CDDP in order to optimize treatment regimen in some human breast cancers.

Histone Deacetylases as New Therapeutic Targets in Triple-negative Breast Cancer: Progress and Promises

“…This combination achieved to reduce the doses of the compounds and to be therapeutically beneficial for head and neck squamous cell carcinomas (26,73) and BC in vitro (74,75). This study also showed that in MDA-MB231 cells, the combination of the CDDP and VPA at the ratio of 1:1 induced antagonistic interactions, while CDDP and SAHA co-treatment induced synergistic interactions (71). According to the investigators, this could be explained by the fact that SAHA is a potent inhibitor of the HDAC6 activity compared to VPA (26).…”

“…Nevertheless, the majority of studies in the field of TNBC therapy tend to combine HDAC inhibitors with kinase inhibitors, autophagy inhibitors, antibiotics, chemotherapy, IR, or even two HDAC inhibitors treatment in order to enhance their efficacy against TNBC (47,69,71,84,115,123,153). In the majority of the studies, co-treatment of an HDAC inhibitor with another compound induced the inhibition of tumor growth and showed anti-proliferative effects (46,47,77,84,115,123,138,154).…”

“…In the majority of the studies, co-treatment of an HDAC inhibitor with another compound induced the inhibition of tumor growth and showed anti-proliferative effects (46,47,77,84,115,123,138,154). Also, several HDAC inhibitors are assosiated not only with autophagic cell death, but also apoptosis (44,55,70,71,84,97,153). Interestingly, many studies have found that HDAC inhibitors have the ability to convert ER-negative tumors to ER-positive tumors (111,160,161).…”

“…The effects of HDAC inhibitors (VPA and SAHA) and cisplatin (CDDP), a chemotherapeutic agent, co-treatment against several types of BC cells have been explored using an isobolographic method (71,72). This combination achieved to reduce the doses of the compounds and to be therapeutically beneficial for head and neck squamous cell carcinomas (26,73) and BC in vitro (74,75).…”

“…Moreover, it has been reported that CDDP/HDAC inhibitor co-treatment induces apoptosis and cell-cycle arrest of TNBC cells (71). Further research in vivo is necessary in order to use this promising combination therapy in TNBC clinical trials.…”