Anti-cancer effects of tocotrienols and a carboxychromanol in an innovative colon cancer model

Colorectal cancer (CRC) is one of the leading causes of cancer death, but there is no effective treatment for the late-stage cancer. Early detection with colonoscopy appeared to lower CRC risk but not associated death. To reduce cancer mortality, it is important to develop effective agents for inhibiting high-risk CRC in people with cancer driver mutations and adenomas. Although inhibition of cyclooxygenases (COX-1/-2) by NSAIDs including aspirin have been recognized for preventing CRC, long-term use of NSAIDs is limited due to side effects and moderate anticancer efficacy. It is therefore necessary to search for alternative and improved preventive strategies and agents. Research has shown that pro-inflammatory 5-lipoxygenase (5-LOX) promotes colon cancer development and may be a target for inhibiting CRC. Further, nuclear factor (NF)-κB and JAK-STAT3 are known to contribute to inflammation and promotion of CRC. Importantly, we and others have shown that γand δ-tocotrienol (γTE, δTE), which are members in the vitamin E family, inhibit 5-LOX activity, NF-κB and STAT3 activation and the growth of cancer cells. δTE-13’-COOH, a metabolite of δTE, has been shown to be a unique inhibitor of COXs and 5-LOX. In agreement with these findings, a δTE/γTE (8/1) mixture and δTE-13’-COOH have been reported to inhibit chemically-induced colon cancer in mice. Based on these observations, we hypothesize that δTE/γTE and δTE-13’-COOH are novel and effective preventive agents against CRC. Despite existing evidence supporting our hypothesis, there are key knowledge gaps hindering translation of the use of these promising agents to the clinic. In particular, the anticancer effects of these compounds have not been examined in a “human-like” CRC model. The objective of this application is to delineate the anticancer effects and mechanisms of δTE/γTE and δTE-13’-COOH in an innovative CRC model (AKC), which like CRC patients, has mutant Apc and Kras and spontaneously develop adenoma tumors in the large intestine. Significance: The success of this study will develop new cancer-preventive agents, generate preliminary data for R01 application to further validate these compounds for CRC prevention, and offer key preclinical data for translation of basic research to the clinic.