Biology subjects

Aung, T. N.

Publications and source records attributed to Aung, T. N..

4 recordsLinked to original sources

bioRxiv2018

The Effect of Compound Kushen Injection on Cancer Cells: Integrated Identification of Candidate Molecular Mechanisms.

BackgroundBecause Traditional Chinese Medicine (TCM) preparations are often combinations of multiple herbs containing hundreds of compounds, they have been difficult to study. Compound Kushen Injection (CKI) is a complex mixture cancer treatment used in Chinese hospitals for over twenty years.\n\nPurposeTo 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.\n\nStudy DesignWe used a cancer cell culture model to measure the effect of CKI on cell cycle phases, apoptosis and correlate those phenotypes with CKI induced changes in gene expression.\n\nMethodsWe treated cancer cells with CKI in order to generate and analyse high-throughput transcriptome data from two cancer cell lines. We integrated these differential gene expression results with previously reported results.\n\nResultsCKI induced cell-cycle arrest and apoptosis and 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 and 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.\n\nConclusionsBy identifying promising candidate pathways and genes associated with CKI based on our transcriptome-based analysis, we have shown this approach is useful for the systematic analysis of molecular changes resulting from complex mixtures of bioactives.

pharmacology and toxicology↗

bioRxiv2018

Effect of Compound Kushen Injection, a natural compound mixture, and its identified chemical components on migration and invasion of colon, brain and breast cancer cell lines

Cancer metastasis is a major cause of death. Traditional Chinese medicines (TCM) are promising sources of new anti-metastatic agents. Compound Kushen Injection (CKI), extracted from medicinal plants, Kushen (Sophora flavescens) and Baituling (Heterosmilax chinensis), contains a mixture of alkaloids and flavonoids known to disrupt cell cycle and induce apoptosis in breast cancer (MCF7). However, effects on cancer cell migration and invasion have remained unknown. CKI, fractionated mixtures, and single identified components were tested in migration assays with colon (HT-29, SW-480, DLD-1), brain (U-87 MG, U-251 MG), and breast (MDA-MB-231) cancer cell lines. Human embryonic kidney (HEK-293) and human foreskin fibroblast (HFF) served as non-cancerous controls. Wound closure, transwell invasion, and live cell imaging assays showed that CKI reduced motility in all eight cell lines. The greatest inhibition of migration occurred in HT-29 and MDA-MB-231, and the least in HEK-293. Fractionation and reconstitution of CKI showed that combinations of compounds were required for activity. Live cell imaging confirmed CKI strongly reduced migration of HT-29 and MDA-MB-231 cells, moderately slowed brain cancer cells, and had no effect on HEK-293. CKI uniformly blocked invasiveness through extracellular matrix. Apoptosis was increased by CKI in MDA-MB-231 cells but not in non-cancerous cells. Cell viability in CKI was unaffected in all cell lines. Transcriptomic analyses of MDA-MB-231 with and without CKI indicated down-regulated expression of actin cytoskeletal and focal adhesion genes, consistent with the observed impairment of cell migration. The pharmacological complexity of CKI is important for its effective block of cancer cell migration and invasion.

cancer biology↗

bioRxiv2018

FRACTIONAL DELETION OF COMPOUND KUSHEN INJECTION, A NATURAL COMPOUND MIXTURE, INDICATES CYTOKINE SIGNALING PATHWAYS ARE CRITICAL FOR ITS PERTURBATION OF THE CELL CYCLE.

We have used computational and experimental biology approaches to identify candidate mechanisms of action of a traditional Chinese medicine. Compound Kushen Injection (CKI), in a breast cancer cell line in which CKI causes apoptosis. Because CKI is a complex mixture of plant secondary metabolites, we used a high-performance liquid chromatography (HPLC) fractionation and reconstitution approach to define chemical fractions required for CKI to induce apoptosis in MDA-MB-231 cells. Our initial fractionation separated major from minor compounds, and showed that the major compounds accounted for little of the activity of CKI. By systematically perturbing the major compounds in CKI we found that removal of no single major compound could alter the effect of CKI on cell viability and apoptosis. However, simultaneous removal of two major compounds identified oxymatrine and oxysophocarpine as critical compounds with respect to CKI activity. We then used RNA sequencing and transcriptome analysis to correlate compound removal with gene expression and phenotype data. We determined that many compounds in CKI are required for its effectiveness in triggering apoptosis but that significant modulation of its activity is conferred by a small number of compounds. In conclusion, CKI may be typical of many plant based extracts that contain many compounds in that no single compound is responsible for all of the bioactivity of the mixture and that many compounds interact in a complex fashion to influence a network containing many targets.

pharmacology and toxicology↗

bioRxiv2018

Cell Cycle, Energy Metabolism and DNA Repair Pathways in Cancer Cells are Suppressed by Compound Kushen Injection.

In this report we examine candidate pathways perturbed by Compound Kushen Injection (CKI) a Traditional Chinese Medicine (TCM) that we have previously shown to alter the gene expression patterns of multiple pathways and induce apoptosis in cancer cells. We have measured protein levels in HEPG2 and MDA-MB-231 cells for genes in the cell cycle pathway, DNA repair pathway and DNA double strand breaks (DSBs) previously shown to have altered expression by CKI. We have also examined energy metabolism by measuring [ADT]/[ATP] ratio (cell energy charge), lactate production and glucose consumption. Our results demonstrate that CKI can suppress protein levels for cell cycle regulatory proteins and DNA repair while increasing the level of DSBs. We also show that energy metabolism is reduced based on reduced glucose consumption and reduced cellular energy charge. Our results validate these pathways as important targets for CKI. We also examined the effect of the major alkaloid component of CKI, oxymatrine and determined that it had no effect on DSBs, a small effect on the cell cycle and increased the cell energy charge. Our results indicate that CKI likely acts through the effect of multiple compounds on multiple targets where the observed phenotype is the integration of these effects and synergistic interactions.

cancer biology↗