Potential New Treatment for Pancreatic Cancer with Atherosclerosis Medication
Treatment with avasimibe causes pancreatic cancer cells to become more sensitive to ACAT-1 inhibition.
In a recent study, researchers found that controlling cholesterol metabolism reduces metastasis in pancreatic cancer, which leads them to believe atherosclerosis drugs could be a new treatment option for patients.
"We show for the first time that if you control the cholesterol metabolism you could reduce pancreatic cancer spread to other organs," said researcher Ji-Xin Cheng, PhD. "We chose pancreatic cancer to test this approach because it is the most aggressive disease of all the cancers."
In a previous study, the research team discovered a link between the aggressiveness of prostate cancer and the accumulation of a compound produced when cholesterol is metabolized. Researchers said their recent findings, published in Oncogene, suggest that a class of drugs developed to treat atherosclerosis could be used to treat pancreatic cancer.
In the current study, researchers found accumulations of cholesteryl ester in human pancreatic cancer cells and cell lines that prove a link between cholesterol esterification and metastasis. Excess cholesterol results in cholesteryl ester being stored in lipid droplets in the cancer cells.
"The results of this study demonstrate a new strategy for treating metastatic pancreatic cancer by inhibiting cholesterol esterification," said researcher Jingwu Xie, PhD.
Purdue researchers created an analytical tool called Raman spectromicroscopy, which conducts a compositional analysis of single lipid droplets in cells.
"We identified an aberrant accumulation of cholesteryl ester in human pancreatic cancer specimens and cell lines," said the study’s lead author Junjie Li, PhD. "Depletion of cholesterol esterification significantly reduced pancreatic tumor growth and metastasis in mice."
Researchers state that atherosclerosis drugs like avasimibe reduce the amount of cholesteryl ester. Accumulation of cholesteryl ester is controlled by the enzyme ACAT-1.
Higher levels of ACAT-1 correlate with poor survival rates. In the study, researchers gathered tissue samples from patients with pancreatic cancer and then tested the drug in orthotopic mouse models.
Researchers found that there was a decrease is the amount of lipid droplets. Raman spectral analysis confirmed that there was a reduction in cholesteryl ester in the lipid droplets, which suggests the drug blocks cholesterol esterification, according to the study.
There was no observed organ toxicity either. By blocking the storage of cholesteryl ester, cancer cells die due to damage of the endoplasmic reticulum, the authors wrote.
"By using avasimibe, a potent inhibitor of ACAT-1, we found that pancreatic cancer cells were much more sensitive to ACAT-1 inhibition than normal cells,” Dr Li said.
Additional research was able to confirm that avasimibe has an anti-cancer effect due to ACAT-1 inhibition. Biochemical assays and genetic ablation was used to confirm these findings, according to the study.
"The results showed that avasimibe treatment for four weeks remarkably suppressed tumor size and largely reduced tumor growth rate," concluded study co-author Timothy Ratliff, PhD. "Metastatic lesions in lymph nodes and distant organs also were assessed at the end of the study. A much higher number of metastatic lesions in lymph nodes were detected in the control group than the avasimibe-treated group."