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 cytoprotectiveeffect, which is due to the activation of mTOR pathway. To inhibit thisprotective response we employ the HDAC inhibitor SAHA, which isknown to prevent AKT/mTOR pathway. We show that PN activatesAkt, mTOR, p70S6kinase and NRF2 while SAHA abolishes theseeffects. Further cell pretreatment with SAHA synergistically sensitizesthe cells to the cytotoxic effect of PN. Moreover SAHA alone activatesthe autophagic process. The addition of PN to SAHA reduces thiseffect and induces apoptosis. SAHA/PN combination also inhibitsDNMT1 and produces hyperacetylation of histones. Epigenetic changescaused by these effects are responsible for the increased expression ofoncosuppressor gene products, such as p21 and p27 and for the decreaseof Bcl2 and p65 levels. In conclusion SAHA suppresses protectiveresponse exerted by PN; PN inhibits SAHA effect on autophagy andfinally SAHA/PN combination induces epigenetic modifications withchanges in gene expression.
|Numero di pagine||126|
|Stato di pubblicazione||Published - 2014|