Evaluation of mechanisms underlying anticancer activity of Aciculatin and YXM110 in human cancer cells

• Main Authors: Chin-Yu Lai, 賴清裕
• Other Authors: Che-Ming Teng
• Format: Others
• Language: en_US
• Published: 2013
• Online Access: http://ndltd.ncl.edu.tw/handle/51575480992065056300

博士 === 國立臺灣大學 === 藥理學研究所 === 101 === Malignant tumor has been the major cause of death in Taiwan for the recent 30 years and the incidence of lung cancer and colorectal cancer are the first place, and the third place respectively. Until now, researchers are still seeking for better cancer therapy. Cancer cells obtain various immortal abilities such as sustaining proliferative signaling, evading growth suppressors, resisting cell death and activating invasion and metastasis. When tumors are unable to be removed surgically or already undergo metastasis, systemic chemotherapy and targeted therapy become crucial for patient’s survival. Natural products have always been a profuse database for developing new chemo agents, thus modification from natural compounds which exhibit potent antitumor activity could be an effective strategy. In this thesis, we aim to discover and study the promising anticancer agents from natural products. Aciculatin is a natural compound isolated from the medicinal herb, Elephantopus scaber Linn and Chrysopogon aciculatus by the team of Prof. Chien-Chih Chen from Department of Biotechnology, Hungkuang University. This study is the first to prove that aciculatin induces cell death in human cancer cells and HCT116 mouse xenografts due to G1 arrest and subsequent apoptosis. The primary reason for cell cycle arrest and cell death was p53 accumulation followed by increased p21 level, PUMA expression, and induction of apoptosis. Aciculatin is also proved to induce p53 accumulation via MDM2 mRNA depletion without apparent genomic toxicity. Compared to the current chemotherapy which induce p53 through DNA damage, aciculatin exhibits higher safety therefore this compound is worthy to be further modified and developed. Cryptopleurine is a phenanthroquinolizidine alkaloid purified from Cynanchum paniculatum which shows excellent antitumor activity. Prof. Kuo-Hsiung Lee from Natural Product Research Lab (NPRL) in UNC at Chapel Hill has synthesized a series of compounds named YXM based on cryptopleurine. The results showed that YXM110 exhibited greatest activity against human colorectal cancer cell line HCT116; it induced cell growth inhibition in early stage and apoptosis in late stage. The anticancer mechanisms of YXM110 could be protein synthesis inhibition and autophagy regulation. YXM110 also exhibited anticancer effects in drug-resistant cell lines, and decreased levels of 4E-BP1 which is correlated with hypoxia-induced resistance. Moreover, YXM110 was found to inhibit the kinase activity and protein levels of CK2α, which is proved to regulate apoptosis and autophagy pathways. YXM110 shows the in vivo potency in xenograft model and the pharmacokinetics and toxicity are also confirmed. The NPRL will keep optimizing the YXM110 structure. Hope this lead compound could be modified to a drug candidate with better anti-tumor activity and safety.