The HDAC inhibitor SAHA synergistically stimulates the cytotoxic effect induced by Parthenolide in MDA-MB231 cells

Abstract

We showed that the sesquiterpene lactone Parthenolide (PN) exerts strong cytotoxic effects on triple negative breast cancer MDA-MB231 cells. Our recent results suggest that PN exerts in these cells a cytoprotective effect, which is due to the activation of mTOR pathway. To inhibit this protective response we employ the HDAC inhibitor SAHA, which is known to prevent AKT/mTOR pathway. We show that PN activates Akt, mTOR, p70S6kinase and NRF2 while SAHA abolishes these effects. Further cell pretreatment with SAHA synergistically sensitizes the cells to the cytotoxic effect of PN. Moreover SAHA alone activates the autophagic process. The addition of PN to SAHA reduces this effect and induces apoptosis. SAHA/PN combination also inhibits DNMT1 and produces hyperacetylation of histones. Epigenetic changes caused by these effects are responsible for the increased expression of oncosuppressor gene products, such as p21 and p27 and for the decrease of Bcl2 and p65 levels. In conclusion SAHA suppresses protective response exerted by PN; PN inhibits SAHA effect on autophagy and finally SAHA/PN combination induces epigenetic modifications with changes in gene expression.