Research on Compound Kushen Injection (CKI): Anti-cancer Mechanism Pathway/Network structure

Abstract

Traditional Chinese medicine (TCM) is built on a foundation of more than 2,500 years of Chinese medical practice with most therapies relying on herbal formulae. In China and the surrounding countries, TCM has been the standard system of medicine. In the west medical system, it is gradually being accepted as alternative medicine, especially for some systems and chronic diseases. Although the efficacy of TCM is accepted by many, the lack of Western-style evidence-based medicine and scientific basis for diagnosis and treatment is a barrier to acceptance and wider adoption. Compound Kushen injection (CKI) is a TCM anticancer agent commoditized for more than 20 years in China. It is primarily used in combination with chemotherapeutic agents in clinics to relieve cancer pain, cancer metastasis and to enhance immunity. Growing evidence indicates that several compounds isolated from CKI demonstrate significant anticancer activity, although questions still remain concerning its underlying mechanisms. In this thesis, I used a systems-based approach to analyze transcriptomic data from different cancer cell lines in order to identify candidate molecular anticancer mechanisms of CKI. Previous research on this topic is incomplete because it was based on the collection and integration of data from the literature, and there was a lack of data from genome-scale experiments. I have addressed these limitations by generating transcriptome data from cancer cells treated with CKI, and have comprehensively analyzed data sets from different cancer cell types. I was able to identify a number of novel potential mechanisms of action and some previously overlooked anticancer effects of CKI. It was clear from the comparison of gene expression patterns of the cells treated with chemotherapy drugs that CKI acts through different mechanisms. By integrating the analysis across different cancer cell types, core features of CKI dependent gene regulation were identified. CKI is able to regulate the expression of many genes, with the majority of those down-regulated. Functions associated with downregulated genes include energy metabolism, cell cycle, cell migration, some cancerrelevant pathways and immune response. The genetic networks associated with these processes or pathways cover almost the entire physiological progression of cancer as well as the body’s response to the illness. CKI, therefore, appears to act on cancer cells in a comprehensive fashion. ii A preconceived notion of CKI mechanism only considers its effects to result from the additive combination of its components. My work has demonstrated this is not necessarily the case. I compared the effects of oxymatrine, the most abundant compound present in CKI to those of CKI. An equivalent amount of oxymatrine has some similar effects compared to CKI, but some of the effects are weaker, or even opposite to CKI. Altogether, this thesis presents a systems-based approach for identifying the mechanism of action of CKI. By characterizing and validating the transcriptome data from three cancer cell lines, we provide candidate pathways for CKI as an anticancer agent.