Abstract
Traditional Chinese Medicine (TCM) preparations are often extracts of single or multiple herbs containing hundreds of compounds, and hence it has been difficult to study their mechanisms of action. Compound Kushen Injection (CKI) is a complex mixture of compounds extracted from two medicinal plants and has been used in Chinese hospitals to treat cancer for over twenty years. To demonstrate that a systematic analysis of molecular changes resulting from complex mixtures of bioactives from TCM can identify a core set of differentially expressed (DE) genes and a reproducible set of candidate pathways. We used in vitro cancer models to measure the effect of CKI on cell cycle phases and apoptosis, and correlated those phenotypes with CKI induced changes in gene expression. We treated two cancer cell lines with or without CKI and assessed the resulting phenotypes by employing cell viability and proliferation assays. Based on these results, we carried out high-throughput transcriptome data analysis to identify genes and candidate pathways perturbed by CKI. We integrated these differential gene expression results with previously reported results and carried out validation of selected differentially expressed genes. CKI induced cell-cycle arrest and apoptosis in the cancer cell lines tested. In these cells CKI also altered the expression of 363 core candidate genes associated with cell cycle, apoptosis, DNA replication/repair, and various cancer pathways. Of these, 7 are clinically relevant to cancer diagnosis or therapy, 14 are cell cycle regulators, and most of these 21 candidates are downregulated by CKI. Comparison of our core candidate genes to a database of plant medicinal compounds and their effects on gene expression identified one-to-one, one-to-many and many-to-many regulatory relationships between compounds in CKI and DE genes. By identifying genes and promising candidate pathways associated with CKI treatment based on our transcriptome-based analysis, we have shown that this approach is useful for the systematic analysis of molecular changes resulting from complex mixtures of bioactives.
Highlights
The treatments of choice for cancer are often radiotherapy and/or chemotherapy, and while these can be effective, they can cause quite serious side-effects, including death
We had previously determined that low concentrations of Compound Kushen Injection (CKI) in our short-term cell assay showed no/little phenotypic effect within 48 hours, and very high doses resulted in excessive cell death at 48 hours precluding the isolation of sufficient RNA for transcriptome analysis [24]
Hep G2 and MDA-MB-231 are different cancer types, they shared a large number of CKI differentially expressed (DE) genes with similar expression profiles, presumably, these shared genes include CKI response genes that are essential to the apoptotic response triggered by CKI
Summary
The treatments of choice for cancer are often radiotherapy and/or chemotherapy, and while these can be effective, they can cause quite serious side-effects, including death. CKI is an herbal extract from two TCM plants, Kushen (Sophora flavescens) and Baituling (Smilax Glabra) and contains more than 200 different chemical compounds including alkaloids and flavonoids such as matrine, oxymatrine, and kurarinol that have been reported to have anti-cancer activities [2,3,4,5]. Some of these activities have been shown to influence the expression of TP53, BAX, BCL2, and other key genes which are known to be important in cancer cell growth and survival [6,7,8,9]. Z14021231) and it has been clinically used to treat a variety of cancers including lung cancer, liver cancer, breast cancer, ovarian cancer and colorectal cancer [10]
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