Synergistic Anticancer Potential of Dichloroacetate and Estradiol Analogue Exerting their Effect via ROS-JNK-Bcl-2-Mediated Signalling Pathways

• Main Authors: Xiao Xing Stander, Barend André Stander, Annie Margaretha Joubert
• Format: Article
• Language: English
• Published: Cell Physiol Biochem Press GmbH & Co KG 2015-03-01
• Series: Cellular Physiology and Biochemistry
• Subjects: Combination treatment; Antimitotic; DCA; MCF-7; MCF-12A; Apoptosis; Autophagy; JNK; Bcl-2 and ROS
• Online Access: http://www.karger.com/Article/FullText/369710
• ISSN: 1015-8987; 1421-9778

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 P 70 and caspase 7 activation. Kinase inhibition revealed sustained activation of the JNK pathway caused increased Bcl-2 protein Ser70 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/Fe2+ 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.