Compound in Cruciferous Vegetables Studied Against Pancreatic Cancer

NCI CAM Annual Report-FY10

“Eat your broccoli – it’s good for you” is a common refrain of many parents. Subrata Haldar, Ph.D., a pharmacology researcher at Case Western Reserve Univer­sity, would agree. Dr. Haldar and his colleague Aruna Basu, Ph.D., are interested in the pos­sible anti-cancer effects of a compound that is produced when our digestive system breaks down certain substances found in abundance in broccoli and other cruciferous vegetables, including cabbage and cauliflower.

With support from NCI*, Drs. Basu and Hal­dar are exploring whether the compound benzyl isothiocyanate, or BITC, that is produced when consuming these vegetables could be used to help prevent or even treat pancreatic cancer. Pancreatic cancer is one of the most aggressive malignancies in the world,” and few effective treatments are available, noted Dr. Haldar. Several epidemiological studies have shown that frequent consumption of cruciferous vegetables is linked with a reduced risk of some types of cancer, including pancreatic cancer. Moreover, preliminary studies by Drs. Haldar and Basu showed that BITC impairs the ability of pan­creatic cancer cells grown in the laboratory to proliferate, or multiply.

BITC is produced when microbes that live in the human gut break down substances called glucosinolates, which are plentiful in crucifer­ous vegetables. “BITC readily accumulates in the cell at high concentrations, and it is a multi-target compound that can attack mul­tiple signaling pathways [in the cell] simulta­neously,” making it appealing as an anti-cancer agent, Dr. Haldar noted. One key goal of Drs. Basu and Haldar’s current study is to deter­mine the molecular mechanism by which BITC inhibits the growth of pancreatic cancer cells. In a series of recent experiments, they found that BITC alters the levels of microRNAs in pancreatic cancer cells.

MicroRNAs are small RNA molecules that regulate gene expression, the process by which a gene gets turned on in a cell to make proteins. These small RNA molecules help regulate gene expression by preventing the translation of target genes. In translation, the information in genes is converted, or “translated,” into pro­teins. There are many types of microRNAs and a single microRNA can block the translation of hundreds of genes.

Studies in patients with pancreatic cancer have revealed that levels of a select set of microRNAs are altered in pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, as compared to levels in normal pancreas or benign pancreatic tissue. Researchers discovered that the levels of one microRNA, miR-221, commonly go up in PDAC patients, whereas the levels of another microRNA, miR-375, go down in these patients. Drs. Haldar and Basu found that in laboratory-grown pancreatic cancer cells treated with BITC, miR-221 levels went down, while miR-375 levels went up – in other words, the effects of BITC on these microRNAs were the opposite of what was seen in people with pancreatic cancer.

These findings suggest that BITC may target the levels of certain microRNAs “to switch hyperproliferative (rapidly dividing) cancer cells to a hypoproliferative (slower dividing) state,” said Dr. Haldar – that is, to stop cancer cells from growing out of control. “These microRNAs have been shown to have important roles in other cancers too,” he added.

Drs. Haldar and Basu are now working to see whether BITC has similar effects on microRNA in a mouse model of pancreatic cancer and, if so, whether those effects can prevent the develop­ment of pancreatic cancer or even help treat the disease in mice. If the findings in mice are promising, the researchers hope that eventually BITC could be tested in humans.

“Our investigation is now focused on whether we can reprogram microRNA networks in pan­creatic cancer which would hold the potential of an important therapeutic and preventive target” if such findings can be extended to humans, Dr. Haldar added.