Endothelial Massive Calcium Accumulation Death (MCAD): Mechanism, Target, and Predictive Biomarker for Anti-Angiogenic Therapy
Presented at the 13th international symposium on anti-angiogenic therapy: recent advances and future directions in basic and clinical cancer research. LaJolla, CA. Sponsor: MD Anderson Cancer Center; planning committee Robert S. Kerbel, Lee M Ellis, et al., 03 February 2011
Weisenthal Cancer Group
Abstract
We cultured human umbilical vein endothelial cells with bevacizumab, with tyrosine kinase inhibitors known to be AA, and with traditional cytotoxic drugs. The images below show that, in the presence of physiological saline and non-favorable culture conditions, the vast majority of the endothelial cells undergo a “non-specific” type of cell death (NSCD), not associated with calcium accumulation, but with loss of cell membrane integrity, allowing uptake of the Fast Green dye, staining these dead dells a pale blue green. In the presence of known AA agents (e.g. bevacizumab, some TK inhibitors) a large percentage of the endothelial cells undergo death associated with massive calcium accumulation (MCAD), with these cells staining hyperchromatic, refractile, blue-black, precisely as reported in
http://www.ncbi.nlm.nih.gov/pubmed/18793333
and
http://meeting.ascopubs.org/cgi/cont...5_suppl/e13617
and
http://tinyurl.com/weisenthal-breast-lapatinib
MCAD is strikingly demonstrated by Fast Green/Alizarin staining as reported in
http://precedings.nature.com/documents/4499/version/1
Traditional cytotoxic drugs (e.g. cisplatin) produce only NSCD and inhibit MCAD. We propose that MCAD is a cell death mechanism unique to endothelial cells and provides a practical biomarker to predict for AA activity in clinical oncology and drug development, as well as a potential drug target.
http://precedings.nature.com/documen...20116647-1.pdf
Nature Precedings doi:10.1038/npre.2011.6647.1