Colon cancer metastasis remains the leading cause of death due to this disease. It is important to identify the cause of events, maneuvering it to a more advanced stage and metastasis. In the proposed study we have hypothesized that high level of AKT expression is CRC is responsible for developing an aggressive and metastatic disease by influencing epithelial-mesenchymal transitions (EMT) endowing cells with migratory and invasive phenotype, hence targeting AKT activation can prevent metastasis in CRC. To prove the hypothesis we have checked the status of AKT in CRC cell lines and patient samples revealing high expression of AKT. In our cell culture and colon cancer xenograft models we have shown that overexpression of AKT leads to aggressive cell and tumor growth, angiogenesis in tumors and EMT phenotype in tumor cells. The goal of the current project is to characterize and generate preclinical data on withaferin-A (WA) or ita potent analog as an oral agent for the prevention of colon cancer metastasis. To inhibit AKT signaling we have employed Withaferin-A (WA) an herbal molecule that overcomes AKT-mediated EMT in preclinical models of CRC. Based on these finding we hypothesize that CRC cells have adapted for the high-level of AKT expression to develop an aggressive phenotypes, hence targeting AKT activation can prevent the development of aggressive CRC growth by inhibiting epithelial mesenchymal transition (EMT). We have proposed to identify and synthesize more potent molecules derived from WA, which bind more strongly to AKT. These derivatives will be further characterized in cell culture and animal (metastatic xenograft and an APC, mimicking advanced and metastatic human CRC) models. Preventing colon cancer using potent biomolecules targeting AKT specifically is a novel approach and may have significant impact on high-risk patients. In addition for the first time we have shown that AKT accumulation is a critical step towards EMT and we have proposed to develop biotin-labeled compounds to target AKT specifically. Chemoprevention of CRC by using these novel potent compounds may have a significant impact in high-risk patients or clinically relapsing patients by inhibiting AKT- induced EMT signaling and hence metastasis.

Public Health Relevance

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. The goal of the current project is to characterize and generate preclinical data on withaferin-A (WA) as an oral agent for the prevention of colon cancer metastasis, which is the third leading cause of cancer-related death for both men and women. The proposed study of the dietary supplement Withaferin-A (WA), the major bioactive compound from Withania somnifera) and its potent analog will provide molecular level insight into the mechanism of action of this agents against metastatic colon cancer, and clarify the clinical potential of WA or its potent analog with respect to the chemoprevention and/ or chemotherapy of colon cancer.

National Institute of Health (NIH)
Research Project (R01)
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Chemo/Dietary Prevention Study Section (CDP)
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Forry, Suzanne L
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University of Louisville
Schools of Medicine
United States
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Suman, Suman; Das, Trinath P; Ankem, Murali K et al. (2014) Targeting Notch Signaling in Colorectal Cancer. Curr Colorectal Cancer Rep 10:411-416