The cytotoxic effect exerted by parthenolide and DMAPT on breast cancer stem-like cells

Abstract

Triple-negative breast cancers (TNBCs) are aggressive forms of breast carcinoma associated with a high rate of recidivism. It is known that a small proportion of tumour cells, termed cancer stem cells (CSCs), is responsible for tumour formation, progression and recurrence. The sesquiterpene lactone parthenolide (PN) was identified as the first small molecule capable of killing CSCs.1 Previously we have shown2 that PN and its soluble analogue DMAPT induce a strong cytotoxic effect in MDA-MB231 cells, the most studied line of TNBCs. In the present research we investigated about the effects exerted by both PN and DMAPT on breast cancer stem-like cells derived from three lines of TNBCs (MDA-MB231, BT20 and MDA-MB436). The two compounds inhibited both the production of mammospheres from the three lines of cells and the viability of breast cancer stem-like cells derived from dissociation of mammospheres. This effect was suppressed by NAC, while z-VAD, a general inhibitor of caspase activity, was ineffective. PN and DMAPT induced in stem-like cells, in the first hours of treatment, a strong production of hydrogen peroxide. Prolonging the time of treatment (12-24h) the levels of both superoxide anion and hROS (hydroxyl radicals and peroxynitrite) increased in concomitance with down-regulation of MnSOD and catalase, dissipation of mitochondrial membrane potential and cell necrosis. It is noteworthy that treatment with PN and DMAPT also caused a rapid and remarkable decrement of the level of Nrf-2, which is a critical regulator of the intracellular antioxidant response. In conclusion PN and DMAPT markedly inhibited viability of stem-like cells derived from three lines of TNBCs by inducing ROS generation, mitochondrial dysfunction and cell necrosis.