Plant-Based Chemoprevention Investigated for Lung Cancer
Division of Cancer Prevention
Despite extensive anti-smoking campaigns and a substantial drop in the number of adult smokers in the United States, lung cancer continues to be a disease that affects smokers, non-smokers, and even former smokers, years after quitting. These substantial, lingering risk factors for lung cancer in the population make developing effective chemoprevention agents – that prevent cancer from developing or progressing into detectible disease – a priority.
Fekadu Kassie, D.V.M, Ph.D., a toxicologist and assistant professor of oncology at the University of Minnesota Masonic Cancer Center, has chosen to focus his career on identifying promising compounds for testing in human lung cancer chemoprevention trials. Since 2007, his research team has been exploring the anticancer effects of a compound called indole-3-carbinol (I3C), found in cruciferous vegetables such as broccoli and cabbage.
Population-based studies have suggested that people who eat more cruciferous vegetables have a lower risk of lung cancer, and laboratory experiments with cells and animals show promising anticancer activity of I3C. These findings led Dr. Kassie, with funding from NCI*, to investigate the molecular mechanisms behind the observed effects of I3C, and to determine the dose of I3C for use in early-phase human chemoprevention trials.
The safety of I3C has been well established, explained Dr. Kassie: “No toxic or undesirable effects of these vegetables are reported in Asian countries where they’re consumed at high levels. The dietary intake of I3C among populations in these countries is close to the dose found to be safe in clinical trials.”
In their earlier mouse studies, administration of I3C, or a dimer of I3C that develops in the gastrointestinal tract called 3,3’-diindolylmethane (DIM), reduced the number of tobacco smoke carcinogen-induced mouse lung tumors by 60%-80%. This experimental model mimics the condition of current smokers since administration of I3C was begun during carcinogen treatment.
In addition, experiments revealed that exposure to the carcinogen resulted in changes in the expression of several proteins associated with tumor formation, including cell division and avoidance of normal, programmed cell death. According to Dr. Kassie, administering I3C along with the carcinogen blocked some of these changes.
Further mouse studies designed to mimic chemoprevention in former smokers showed that I3C also reduced the number of small lung tumors formed after carcinogen exposure by about 75% at a high dose**, Dr. Kassie noted. Additional protein expression studies suggested that I3C inhibits cell survival and division in precancerous and cancerous lung cells, he said.
Although additional tests suggested that I3C administration after precancerous cells and small tumors had already been formed could not decrease the number of these smaller tumors, it could decrease the number of these early tumors progressing to lung adenocarcinoma (a type of lung cancer)***, Dr. Kassie explained.
Dr. Kassie and his colleagues believe that their results warrant moving I3C into human studies. They are currently writing a grant to obtain funding for an early phase chemoprevention trial, which will likely use both I3C and DIM, which have similar mechanisms of action in the body.
Marjorie Perloff, M.D., program director with the NCI Division of Cancer Prevention, commented: “The studies in this grant complement the goals of the Chemopreventive Agent Development Research Group to develop new agents for cancer prevention. This trial studies a compound derived from a group of natural compounds found in cruciferous vegetables which purports to be the ‘active’ agent in terms of cancer prevention, and is also the source of another agent, 3,3’-diindolylmethane (DIM), which has been extensively studied for possible cancer preventive activity.”
* Grant number: 5R01CA128801-04
** Kassie F., Matise I., Negia M., Upadhyaya P., & Hecht S.S. (2008). Dose-dependent inhibition of tobacco smoke carcinogen-induced lung tumorigenesis in A/J mice by indole-3-carbinol. Cancer Prevention Research, 1(7), 568-76.
*** Qian X., Melkamu T., Upadhyaya P., & Kassie F. (2011). Indole-3-carbinol inhibited tobacco smoke carcinogen-induced lung adenocarcinoma in A/J mice when administered during the post-initiation or progression phase of lung tumorigenesis. Cancer Letters, 311(1), 57-65. annual report on complementary and alternative medicine f y 2011