The survival rate of metastatic colorectal carcinoma (CRC) is less than 5%. Use of 5-fluorouracil (5-FU), radiation, and surgery are the primary treatments; however, most metastatic cancers eventually cause death. Developing approaches to prevent progression to metastasis could therefore be part of an important therapeutic strategy, especially for high-risk patients, including those patients already diagnosed with high grade polyps or localized colon cancer. In our preclinical and clinical data, we hypothesized that accumulation of AKT (protein kinase-B) is a critical step in the aggressive phenotype of disease. The metastatic cascade of CRC involves the crucial process of the epithelial–mesenchymal transition (EMT), which endows cancer cells with migratory and invasive capabilities via acquisition of a mesenchymal phenotype. These characteristics also contribute to cellular resistance to chemotherapeutic drugs.

Withaferin-A (WA) is a potent herbal molecule from withania sominefera herbal plant, inhibited CRC growth by down regulating AKT signaling. Furthermore, over expression of AKT significantly increased cell proliferation, aggressiveness and angiogenesis of colon tumors in xenograft models. However, WA overcomes AKT mediated growth in both cell culture and animal models by transcriptionally down regulating Epithelial Mesenchymal Transition (EMT) related transcription factors and genes such as Snail, Slug and β-catenin. We also found AKT expression is steadily increased in CRC patients in a stage specific manner, suggesting accumulation of AKT could be a critical step for CRC metastasis. We found that WA binds to AKT with a predicted affinity of -10.6 kcal/mol and inhibited its activation. We have identified several novel WA–derived analogs which may be more potent than the parental compound with high AKT binding affinity. We have identified a potent analog which inhibited AKT kinase activity and induced growth arrest (~30 times potent) more significantly than WA. Currently, we are testing the invivo efficacy of the potent analog of WA, which could be a used as a novel agent for chemoprevention and/or chemotherapy of colon cancer.

Citation Format: Suman Suman, Trinath P. Das, Chendil Damodaran. Withaferin-A, a natural compound inhibits AKT-induced metastatic colorectal cancer. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr A10.