Synergistic anticancer potential of dichloroacetate and estradiol analogue exerting their effect via ROS-JNK-Bcl-2-mediated signalling pathways

Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology
Xiao Xing StanderAnnie Margaretha Joubert

Abstract

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. 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. 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 ...Continue Reading

Citations

Oct 16, 2016·International Journal of Immunopathology and Pharmacology·Jurate StanevičiūtėDonatas Stakišaitis
Nov 28, 2018·Dose-response : a Publication of International Hormesis Society·Jūratė StanevičiūtėDonatas Stakišaitis
Jun 11, 2019·BioMed Research International·Jūratė StanevičiūtėDonatas Stakišaitis
Dec 12, 2018·Scientific Reports·Aistė SkeberdytėSonata Jarmalaitė
Sep 15, 2020·Therapeutic Advances in Medical Oncology·Lili DuanDaiming Fan

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