Dichloroacetate induces apoptosis in endometrial cancer cells.
1: Gynecol Oncol. 2008 Apr 16 [Epub ahead of print]
Wong JY, Huggins GS, Debidda M, Munshi NC, De Vivo I.
Channing Laboratory, Department of Medicine, Brigham and
Women's Hospital and Harvard Medical School, Boston Massachusetts, USA.
PURPOSE: A recent landmark study demonstrated that
Dichloroacetate (DCA) treatment promoted apoptosis in lung, breast, and
glioblastoma cancer cell lines by shifting metabolism from aerobic
glycolysis to glucose oxidation coupled with NFAT-Kv1.5 axis remodeling.
The objective of this study was to determine whether DCA induces
apoptosis in endometrial cancer cells and to assess apoptotic mechanism.
METHODS: A panel of endometrial cancer cell lines with varying degrees
of differentiation was treated with DCA and analyzed for apoptosis via
flow cytometry. Biological correlates such as gene expression,
intracellular Ca(2+), and mitochondrial membrane potential were examined
to assess apoptotic mechanism. RESULTS: Initiation of apoptosis was
observed in five low to moderately invasive cancer cell lines including
Ishikawa, RL95-2, KLE, AN3CA, and SKUT1B while treatment had no effect
on non-cancerous 293T cells. Two highly invasive endometrial
adenocarcinoma cell lines, HEC1A and HEC1B, were found to be resistant
to DCA-induced apoptosis. Apoptotic responding cell lines had a
significant increase in early and late apoptotis, a decrease in
mitochondrial membrane potential, and decreased Survivin transcript
abundance, which are consistent with a mitochondrial-regulated
mechanism. DCA treatment decreased intracellular calcium levels in most
apoptotic responding cell lines which suggests a contribution from the
NFAT-Kv1.5-mediated pathway. DCA treatment increased p53 upregulated
modulator of apoptosis (PUMA) transcripts in cell lines with an
apoptotic response, suggesting involvement of a p53-PUMA-mediated
mechanism. CONCLUSIONS: Dichloroacetate effectively sensitizes most
endometrial cancer cell lines to apoptosis via mitochondrial,
NFAT-Kv1.5, and PUMA-mediated mechanisms. Further investigation of the
cancer therapeutic potential of DCA is warranted.
PMID: 18423823 [PubMed - as supplied by publisher]
link to PubMed summary.
Their website: http://devivo.bwh.harvard.edu/
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