Statins Reverse Doxorubicin Resistance in Mesothelioma Cells

NEW YORK JUL 12, 2006 (Reuters Health) - Statins reverse doxorubicin resistance in human malignant mesothelioma cells in culture, a finding that may lead to new clinical strategies to improve doxorubicin efficacy in this hard to treat cancer.

"The mechanism of statin-mediated inhibition of small G-protein function is the molecular basis of the drug-elicited reversion of doxorubicin resistance in human malignant mesothelioma cells," Dr. Amalia Bosia from University of Torino, Italy told Reuters Health.

Dr. Bosia and colleagues investigated the ability of statins to reverse resistance to doxorubicin in drug-resistant primary human malignant mesothelioma cells and the molecular mechanism behind the reversion, according to their report in the July 1st issue of the International Journal of Cancer.

Mevastatin and simvastatin significantly increased the intracellular accumulation of doxorubicin in the mesothelioma cells and increased the cytotoxicity of doxorubicin, the authors report.

These effects were completely abolished after the statins were incubated with mevalonic acid, the product of HMGCoA reductase, or with the nitric oxide synthase inhibitor L-NMMA.

The statins appeared to exert their effect by down-regulating active RhoA and RhoA-associated kinase activity and increasing phosphorylation and activation in mesothelioma cells, the researchers note.

Y27632 and toxin B also enhanced doxorubicin accumulation and cytotoxicity by way of increased nitric oxide synthesis in the mesothelioma cells, the results indicate.
 
Parthenolide, an inhibitor of IkB kinase-alpha activation, significantly reduced nitric oxide synthesis and doxorubicin accumulation in the presence of simvastatin, mevastatin, toxin B, and Y27632, the investigators say.
 
"To our knowledge, this is the first report showing a correlation between RhoA/Rho kinase inhibition, nitric oxide production and reversion of doxorubicin resistance," the authors conclude. "Our results could suggest new clinical strategies aimed to improve doxorubicin efficacy in the treatment of human malignant mesothelioma."
 
"We want to determine the therapeutic potential of statins in reverting the doxorubicin resistance of human malignant mesothelioma in a severe combined immunodeficiency mouse model of human malignant mesothelioma in vivo, in which malignant mesothelioma cells may be transplanted without rejection," Dr. Bosia said.
 
"A better knowledge of the whole molecular pathway involved in doxorubicin-resistance in malignant mesothelioma may allow the design of more specific and more potent drugs, with less side effects than statins," she concluded.
 
SOURCE:

• Int J Cancer 2006;119:17-27.