Analysis of energy metabolism with BM038 and BM050 compounds in treatment of pancreatic cancer

• Main Authors: Jun-Hao Xu, 許峻豪
• Other Authors: Jian-Fu Huang
• Format: Others
• Language: zh-TW
• Published: 2019
• Online Access: http://ndltd.ncl.edu.tw/handle/5sn2sk

碩士 === 義守大學 === 生物科技學系 === 107 === Pancreatic ductal adenocarcinoma (PDAC), known as a highly-malignant cancer, has the lowest five-year survival rate among a variety of cancers. Clearly, development of effective anticancer drugs is urgently needed. Many lines of evidence strongly suggest that PDAC is a metabolic cancer type, and targeting its metabolic dependency may be a potential anticancer strategy. In our previous immunohistochemical study, expression of salt-inducible kinase (SIK3) was gradually downregulated during the disease progression of PDAC. To determine the affected energy status of PDAC cells with different metabolic subtypes caused by attenuated expression of SIK3, the metabolic statuses of the PDAC cells were determined by the Seahorse Energy system. They all indicated that attenuation of SIK3 expression would markedly reprogram the energy metabolism, show elevation of glycolytic activity and generate high amounts of lactate production. These phenomenon have some resemblance like the Warburg effect common seen in a variety of cancers. Thus, we hypothesize that targeting the elevated glycolytic activity may induce remarkable apoptosis of PDAC. In addition, combination of the first-line anticancer drug, Gemcitabine, with anti-glycolytic drugs will be anticipated to get the therapeutic effect of PDAC in cells and animals. In order to examine our hypothesis, BM038 and BM050 were screened by MTT assay to determine the potency of these selected drugs. Lung and PDAC adenocarcinoma cells were previously served as targets in our pre-screening experiments. Among the various derivatives, BM038 and BM050 have been shown to have at least 10-fold cytotoxicity. In this study, we will focus on the following research tasks: 1). Determining their IC50 in various PDAC cells with different metabolic subtypes, and HPDE cells serve as normal control; 2). Determining the alteration condition of the cellular energy metabolic status when cells are treated with BM038 and BM050; 3).Determining if the cytotoxic effect of BM038 and BM050 is enhanced by combination of Gemcitabine; 4). Determining whether the major targeting effect of BM038 and BM050 appear in either glycolytic or mitochondria activity. Herein, we’ll anticipate the outcome of this study will provide a novel therapeutic strategy and more clear disease vision for PDAC in the near future.