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  • Title: Synergistic anticancer potential of dichloroacetate and estradiol analogue exerting their effect via ROS-JNK-Bcl-2-mediated signalling pathways.
    Author: Stander XX, Stander BA, Joubert AM.
    Journal: Cell Physiol Biochem; 2015; 35(4):1499-526. PubMed ID: 25791820.
    Abstract:
    BACKGROUND: C9, a newly in silico-designed inhibitor of microtubule dynamics induces G2/M arrest culminating in apoptosis. Dichloroacetate (DCA) inhibits pyruvate dehydrogenase kinase, an enzyme that promotes pyruvate entry into mitochondria. The use of antitumor drugs targeting different cancer features can be a more effective way to overcome drug resistance. METHODS: The influence of C9 (130 nM) + DCA (7.5 mM) on MCF-7 and MCF-12 cells was assessed via microscopy spectrophotometry global gene expression and flow cytometry assays. RESULTS: An LDH assay showed that C9+DCA treatment decreased cell viability to 83.5% in MCF-7 cells when compared to the non-tumorigenic MCF-12A cells 92.4% (P < 0.05). C9- and C9+DCA treatment induced mitochondrial membrane potential depolarization in MCF-7 cells but not in MCF-12A cells (P < 0.05). The occurrence of apoptosis was associated with increased hypo- and hyper-phosphorylation of Bcl-2 Ser(70) and caspase 7 activation. Kinase inhibition revealed sustained activation of the JNK pathway caused increased Bcl-2 protein Ser(70) hypo-and hyper-phosphorylation. Elevated levels of DCF fluorescence was observed in DCA-, C9- and C9+DCA-exposed MCF-7 cells, but not in MCF-12A cells, indicating cytosolic H₂O₂/Fe(2+) formation in treated tumorigenic cells. LC3-II expression was elevated in C9+DCA-treated cells in both cell lines, indicating that autophagy was also induced. CONCLUSIONS: Synergistic effects of C9+DCA were demonstrated on breast carcinoma and non-tumorigenic cells with selectivity towards the MCF-7 cells. Antimitotic compound C9 in combination with a glycolytic inhibitor dichloroacetate eradicates breast cancer cells through ROS-JNK-Bcl-2-mediated signalling pathways in vitro and it is argued that autophagy acts as protective mechanism in the treated cells before apoptosis occurs.
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