The major research focus of our Division is to discover anticancer agents from natural sources by targeting cancer cells’ characteristic performance (such as tolerance to nutrient starvation) in tumor microenvironment.
Bridging the traditional medical knowledge with modern science for the development of novel anticancer agents.
In general, tumor cells proliferate very fast in an unregulated manner and are often exposed to a nutrition and oxygen deficient environment due to poor and disorganized vasculature. However, tumor cells show an inherent ability to tolerate such extreme conditions of low nutrient and oxygen supply by modulating their energy metabolism. In particular, human pancreatic tumor cells such as PANC-1 are known to have severe tolerance that enables them to survive for a prolonged period of time in a critical environment characterized by low nutrition and oxygen. Therefore, the agent that can eliminate the cancer cells’ tolerance to nutrient starvation (called an anti-austerity agent) is regarded as a novel target in anticancer drug discovery.
Until now there has been no reliable drug for the treatment of pancreatic cancer, which shows intrinsic resistance to the conventional anticancer drugs such as 5-fluorouracil, taxol, doxorubicin, cisplatin, gemcitabine and camptothecin. Almost all patients of pancreatic cancer rapidly develop metastases and die within a short period of time after being diagnosed. Pancreatic cancer ranks the fourth place as a cause of common cancer-related death, which has a median survival time of less than 6 months and has the lowest 5-year survival rate (5.5%) as compared with other cancers. Therefore, the discovery of natural medicine-based and improved antitumor drug by targeting tumor cells resistance to nutrient starvation (called an anti-austerity strategy) is one of the important research goals of our Division. In order to achieve this goal, we are actively engaged in researching the followings:
1. Screening traditional medicinal plants from different origins (e.g. Japanese Kampo, Ayurveda, etc.) for anticancer activity by utilizing human pancreatic cancer cell lines.
2. Discovering novel anticancer drug candidates by using bioactivity as an index.
The active plants are subjected to bioactivity (the anticancer activity against PANC-1)-guided isolation and identification by utilizing state-of-the-art chromatographic techniques (e.g. Silica gel, ODS, HPTLC, MPLC, HPLC, etc.) and spectroscopic techniques (e.g. NMR, MS, UV, IR, CD, etc.). The structure-activity relationship of the lead compounds and their functional structures are investigated by studying their effects on a panel of other human pancreatic cancer cell lines (e.g. MIA Paca2, KLM-1, NOR-P1, Capan-1, PSN-1, etc.). Successful candidates will be evaluated for their in vivo anti-tumor activity by using the pancreatic cancer mouse model.
3. Elucidating the mechanism of action of the anticancer drugs by conducting quantitative metabolome analysis.
Although the expression and activity of numerous proteins in cancer cells are well studied, cancer cells’ metabolites such as organic acids, amino acids, sugars and lipids have not yet been well focused. The cancer cells with resistance to nutrient starvation are believed to have different energy metabolism. Hence, an exhaustive analysis of their metabolites, including the intracellular small molecules, would be helpful to elucidate the mechanism of action of the anticancer agents. Therefore, besides studying on the key proteins involved in the cancer cells’ survival, we are also conducting the metabolome analysis by using FT-NMR and FT-MS.
We believe that the traditional knowledge and the medicinal plants, in combination with the modern investigative techniques, will prove to be a valuable source for the development of new anticancer therapeutics, especially against the deadly pancreatic cancers for which there are no effective treatments at present.
||Natural Drugs, Drug Discovery and Development Research, Traditional Medicine, Kampo, Natural Products, Nuclear Magnetic Resonance (NMR), FT-MS, Structure Elucidation, Life Sciences, Cancer Research, Antiausterity Strategy, Mechanism of Action, Chemical Biology, Cancer Metabolomics, Biomarker Discovery