Parthenolide and DMAPT exert cytotoxic effects on breast cancer stem-like cells by inducing oxidative stress, mitochondrial dysfunction and necrosis

Abstract

Triple-negative breast cancers (TNBCs) are aggressive forms of breast carcinoma associated with a high rate of recidivism. In this paper, we report the production of mammospheres from three lines of TNBC cells and demonstrate that both parthenolide (PN) and its soluble analog dimethylaminoparthenolide (DMAPT) suppressed this production and induced cytotoxic effects in breast cancer stem-like cells, derived from dissociation of mammospheres. In particular, the drugs exerted a remarkable inhibitory effect on viability of stem-like cells. Such an effect was suppressed by N-acetylcysteine, suggesting a role of reactive oxygen species (ROS) generation in the cytotoxic effect. Instead z-VAD, a general inhibitor of caspase activity, was ineffective. Analysis of ROS generation, performed using fluorescent probes, showed that both the drugs stimulated in the first hours of treatment a very high production of hydrogen peroxide. This event was, at least in part, a consequence of activation of NADPH oxidases (NOXs), as it was reduced by apocynin and diphenylene iodinium, two inhibitors of NOXs. Moreover, both the drugs caused downregulation of Nrf2 (nuclear factor erythroid 2-related factor 2), which is a critical regulator of the intracellular antioxidant response. Prolonging the treatment with PN or DMAPT we observed between 12 and 24 h that the levels of both superoxide anion and hROS increased in concomitance with the downregulation of manganese superoxide dismutase and catalase. In addition, during this phase dissipation of mitochondrial membrane potential occurred together with necrosis of stem-like cells. Finally, our results suggested that the effect on ROS generation found in the first hours of treatment was, in part, responsible for the cytotoxic events observed in the successive phase. 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.

Mechanisms of Chromosome Congression during Mitosis

“…This is partially circumvented by the synthesis of a more water-soluble analog dimethylamino-parthenolide (DMAPT), which possesses an increased oral bioavailability [524]. DMAPT has already proved effective in selective eradication of human acute myeloid leukemia primary cultured stem cells [538] and breast cancer stem-like cultured cells [539], and has been shown to inhibit tumor growth and metastasis of prostate, lung and bladder cancer xenografts in mice [531,540]. However, although parthenolide and DMAPT demonstrated high potential in prevention of metastasis and treatment of cancer stem cells, they were not able to reduce tumor volumes.…”

Anti-inflammatory and Anti-tumor Activities of Parthenolide: An Update

“…The shrinkage in sphere growth is due to the inhibition of NFκB activity [17]. PTL and its derivatives may be effective anticancer agents against cholangiocarcinoma as it effectively induces apoptosis in these cells [18]. It has also been observed that pre-incubated HCT116 cells with parthenolide resulted in the absence of activation of NFκB after TNFα-treatment in both p53-proficient and p53-deficient cells [21].…”

“…References Cell Proliferation/ Apoptosis associated Molecules References NFκB [14], [30], [31], [35], [43], [48], [90] NFκB [17], [18], [21], [52], [54], [64], [78][79], [90] IKK-β [30][31][32], [48] [ERK/MEK/MAPK/ELK1] [14], [37], [48], [51] iNOS [39] β1-arrestin, Csk, FAK, FGFR2, PKC [51] STAT1/STAT3 [36], [51], [83][84][85][86][87][88] STAT1/STAT3 [36], [51], [55][56], [83][84][85][86][87][88] Cyclooxygenase (COX) [27][28][29], [37] JNK [42], [43], …”

“…The decrease of sphere growth was due to the inhibition of NFκB activity [17]. PTL and its derivatives may be effective anticancer agents against cholangiocarcinoma for the reason that they can effectively induce apoptosis in cholangiocarcinoma cells [18,19]. PTL-induced apoptosis was enhanced by the PKC-α inhibitor Ro317549 (Ro) through inhibition of Nrf2 expression and its nuclear translocation, resulting in suppression of HO-1 expression.…”

“…Recently, the anti-tumor property of parthenolide has attracted great interest among researchers. Parthenolide has been shown to inhibit growth or induce apoptosis in a number of tumor cell lines [16][17][18]40,41]. Many mechanisms have been proposed as being involved in the anti-tumorogenic effect of parthenolide, including inhibition of NFκB activation [17,41], suppression of STAT3 [36], inhibition of MAPK activity [37], sustained activation of JNK [42,43], activation of p53 [15,17], inhibition of nucleic acid synthesis [44,45], depletion of thiols, induction of oxidative stress [16,17], induction of mitochondrial dysfunction [16], disruption of intracellular calcium equilibrium, induction of cell cycle G2/M phase arrest [16,40], depletion of HDAC1 [43], and inhibition of tubulin carboxypeptidase activity [46,47].…”