|Pun, Ho Yuen
|Analysis of the anti-tumor effects of novel compounds (83b1, 160a, DpC and Dp44mT) against human esophageal, prostate and colorectal carcinomas
|Tang, Cheuk-on Johnny (ABCT)
|Hong Kong Polytechnic University -- Dissertations
Cancer -- Treatment
|Department of Applied Biology and Chemical Technology
|247 pages : color illustrations
|Cancer is one of the most common and lethal diseases worldwide including esophageal, prostate and colorectal cancers. Nowadays, although there are different approaches for treating these cancers, the incidence and mortality are still elevating. More effective and efficient therapeutics for treating these cancers are urgently needed. To address such critical issues, the anti-cancer effects of two novel quinoline derivatives 83b1 and 160a, and two novel thiosemicarbazone derivatives DpC and Dp44mT were first studied in attempt to identify novel anti-cancer compounds for future drug development. For the first part of the present study, the anti-cancer effects of the novel quinoline derivative, 83b1, on mainly esophageal cancer were studied, it showed significant cytotoxic effects on esophageal squamous cell carcinoma (ESCC) cell lines and tumor-xenograft models. Through the in silico assessment and isothermal titration calorimetry (ITC), it was demonstrated that Peroxisome Proliferator-activated Receptor Delta (PPARD), which is a cancer-promoting protein over-expressed in cancer cells, was targeted by 83b1 and it resulted in reduction of the number of cancer cells by downregulating cyclooxygenase-2 (COX-2) and COX-2 derived prostaglandin E2 (PGE2). Moreover, 83b1 also showed the anti-cancer effects on other cancer types including breast, lung, liver and colorectal cancers. Furthermore, the possible signaling pathways affected by 83b1 in esophageal cancer cell lines were also studied including the signaling proteins AKT-1, JNK-1, ATF-2, MAPK, HSP-27 and MEK. For the second part, the anti-cancer effects of another quinoline derivative 160a on esophageal cancers were also studied and 160a demonstrated significant cytotoxic effects on ESCC cell lines. By using the in silico assessment, it implicated that 160a can target on p-glycoprotein (P-gp) and reverse drug resistance conferred by P-gp via blocking the P-gp binding site to its substrate. 160a also showed the synergistic effects with the use of P-gp substrate doxorubicin. Furthermore, the anti-cancer effects of two novel thiosemicarbazone derivatives DpC and Dp44mT were also demonstrated on prostate and colorectal cancer cell lines. DpC and Dp44mT also acted as the iron-chelators, and they showed the anti-tumor effects through up-regulation of NDRG1 and down-regulation of LYRIC. By down-regulation of LYRIC, they could also suppress the TNFα-mediated EMT and cell migration; they also showed the ability to reduce the expression of the onco-proteins downstream of LYRIC. To conclude, the novel anti-tumor compounds used in this study showed the good potentials for treating cancers through the involvement of different molecular mechanisms. Further studies include the investigation their pharmacokinetics and toxicities in animal models.
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