Dichloroacetate induces apoptosis in endometrial cancer cells.
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/