Colorectal cancer is the second most prevalent cancer and the second leading cause of cancer related death in the United States. Botanicals could potentially have anti-cancer compounds that may be used alone or as adjuncts to existing chemotherapy to improve efficacy and reduce the drug-induced toxicity. Identifying herbal sources to develop ideal chemoprevention remains an essential step in advancing the treatment of this cancer and will be addressed in the proposed project. The current proposal postulates based on convincing preliminary results and literature reports that two specific herbs from the ginseng family, steamed or unsteamed roots of American ginseng and notoginseng, may have significant anti-cancer activities. The aim of this project is to thoroughly characterize the anti-proliferative actions of test herbs and the underlying mechanisms of action in their direct and adjuvant anti-cancer effects. We hypothesize that American ginseng and notoginseng, particularly after steaming preparation, are effective tumoricidal and chemo-adjuvant compounds against human colorectal cancer. In the proposed project, we will test the tumoricidal effects of these two ginseng herbs on distinct human colorectal cancer cell lines and a mouse xenograft model, and determine the involved mechanisms. We will further test whether the extracts potentiate the tumoricidal effects of colon cancer chemotherapeutic agents, 5-fluorouracil and irinotecan, using the cell lines and mouse model. If synergistic interactions between test herbs and chemotherapeutic drugs exist, then it will enable lowering of the drug dose thus reducing the dose-related toxicity. In addition, whether the newly identified active constituents from steamed herbs increase chemotherapeutic agents' activity will be determined. Finally, pharmacokinetic interaction between the chemotherapeutic drugs and the test herbs, if any, will be characterized. A novelty of this project is the use of knockout herbal extracts which will allow a more conclusive association of the effect of the herbal extract to the responsible active constituent(s). Data from the proposed study have a potential to improve treatment regimens and the quality of life for patients suffering from colorectal cancer.