Triple-negative breast cancer (TNBC) is a subtype of breast cancer, insensitive to endocrine therapy.Chemotherapy is the main form of treatment, but isaccompanied by a high rate of recidivism. Thesesquiterpene lactone Parthenolide (PN) exerts a cytotoxic effect on MDA-MB231 cells, a TNBC cell line(1),but was ineffective at low doses (2-5μM). This represents an obstacle for a therapeutic utilization ofPN. Wesupposed, in line with other authors (2), that PN causes a protective response, which at low doses prevailson the cytotoxic effect. With the aim of inhibitingthis protective effect we have shown that pre-treatment ofMDA-MB231 cells with SAHA (2-5μM), an histone deacetylates inhibitor, synergistically sensitizes the cells tothe cytotoxic effect of PN, also at low doses of this compound.SAHA/PN combination induced hyperacetylation of histones H3 and H4 and hypomethylation of DNA. Thesechanges cause epigenetic effects, which can be responsible for the increased expression of tumoursuppressors p21 and p27 and decreased levels of Bcl2 and p65, a component of NFkB.Moreover SAHA alone induced ROS generation as wellas autophagy, which favours cell survival, andapoptosis. The addition of PN (8μM) to SAHA reduced production of ROS and autophagy,while increased theapoptotic process.Interestingly PN activates Akt, mTOR, phospho-p70S6kinase and ULK1/2, a factor that inhibits autophagy. Inaddition PN caused nuclear accumulation of Nrf2 with stimulates antioxidant genes. SAHA prevented theseeffects.In conclusion SAHA/PN stimulated cytotoxicity through many mechanisms: (i) induces epigenetic events withchanges in gene expression, (ii) PN prevents SAHA effect on autophagy and (iii) SAHA suppresses theprotective response exerted by PN through inactivation of m-TOR. Taken together our results suggest thatcombination SAHA/PN can be a candidate for TNBC therapy.
|Numero di pagine||64|
|Stato di pubblicazione||Published - 2014|