探討 DYZ-2-90 和 MPT0G030 在人類大腸直腸癌細胞中之抗癌機轉

Abstract

Latest statistics reported by Taiwan’s Health Promotion Administration, malignancy has been the major causes of death in Taiwan for 30 years; among those, colorectal cancer is the first-leading cause of cancer deaths. Meanwhile, colorectal cancer is the 3rd most common cancer worldwide. In contrast to other cancers, development of colorectal cancer is an ordered event of genetic and epigenetic changes that called adenoma-carcinoma sequence. Our laboratory cooperates with Dr. Kuo-Hsiung Lee (Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC, USA) and Dr. Jing-Ping Liou (School of Pharmacy, College of Pharmacy, Taipei Medical University, Taiwan) to evaluate the anticancer effect and the underlying mechanisms of DYZ-2-90 and MPT0G030 in human colorectal cancer, respectively. In situations of aberrant hyperproliferation, DYZ-2-90 targets to the mitotic spindles, the critical structure of cell mitosis, and leads to microtubule depolymerization in HT-29 cells. DYZ-2-90 is a novel ring-opened compound modified from neo-tanshinlactone isolated from Chinese medicinal herb Tanshen. It binds directly to microtubules and rapidly suppresses microtubule polymerization in human colorectal cancer cells. Thus, the alteration of mitotic spindle organization changes the scaffolding properties of microtubules, which induces strong and sustained ERK activation and leads to mitotic arrest. Prolonged ERK activation and cyclin B degradation contributes to maintain the cell mitotic state and protect cells from apoptosis, but meanwhile provides more time to accumulate mitotic stress/cell death signals. Then, the cell apoptosis is triggered by anti-apoptotic protein Mcl-1 degradation and JNK activation, which breach the death threshold. The cell fate of mitotic arrest cells is dictated by two competing networks: one is the cytoprotective ERK pathway, and the other is stressed-related JNK pathway. Whereas, MPT0G030, a HDAC inhibitor, redirects colorectal cancer cells (HT-29 cells) to normal colonic life cycle to undergo cell differentiation and cell apoptosis. MPT0G030 is a potent HDAC inhibitor that showed broad-spectrum cytotoxicity against various human cancer cell lines. It not only effectively inhibits class I HDACs, which are overexpressed in many malignant neoplasms, but also redistributes E-cadherin and activates PKCδ, which is linked to cell apoptosis and differentiation. Further, activation of PKCδ is demonstrated to be modulated through HDAC1. Collectively, MPT0G030-induced PKCδ participates in cell apoptosis and concomitantly promotes differentiation of colon cancer cells through E-cadherin redistribution and changes in cell morphology. In this thesis, our results indicate that both DYZ-2-90, a novel microtubule-destabilizing agent, and MPT0G030, a class I HDAC inhibitor, have great potential as new drug candidates for colorectal cancer therapy.