新穎性長鏈烴基醯胺衍生物WMJ-S-001之抗腫瘤機轉與介白質-6誘導淋巴管新生之作用探討

To date, cancer remains a major cause of death worldwide. Despite advances in drug discovery and the use of targeted therapies in recent years, the prognosis for many advanced cancers remains poor. Therefore, developing novel agents or therapies is an ongoing urgent need for cancer treatment. Recent development in drug discovery has highlighted the broad pharmacological properties of a key pharmacophore, hydroxamate, although the exact mechanisms remain unclear. We have synthesized a series of aliphatic hydroxamate derivatives, the WMJ-S compounds, and evaluated their anti-tumor activities. Among these WMJ-S compounds, WMJ-S-001 exhibits the most potent cytotoxicity in cancer cells. We thus selected WMJ-S-001 and investigated the mechanisms by which WMJ-S-001 induces HCT116 colorectal cancer cell death (Part I). We have demonstrated that the death of HCT116 colorectal cancer cells exposed to WMJ-S-001 may involve AMPK-p38MAPKp53-survivin cascade. These results support the role of WMJ-S-001 as a potential drug candidate and warrant the clinical development in the treatment of cancer. On the other hand, the dilemma of anti-cancer agent development is attributed to the complexity of tumor progression. An understanding of the mechanisms underlying tumor progression is another major issue for cancer research. Growing evidences have shown that elevated serum IL-6 is associated with advanced stages and poor prognosis of colorectal cancer. Moreover, IL-6 has been shown to promote tumor lymphangiogenesis and metastasis through vascular endothelial growth factor-C (VEGF-C) induction in tumor cells. Whether IL-6 induces VEGF-C expression in lymphatic endothelial cells (LECs) and its underlying mechanisms remain unclear. In this study, we also investigate the precise mechanisms underlying IL-6-induced VEGF-C expression in LECs (Part II). We report a Src-FAK-mediated STAT3, C/EBPβ and p65 activation leading to VEGF-C expression and lymphangiogenesis in IL-6/sIL-6R-exposed SV-LECs. The identification of mechanisms underlying IL-6/sIL-6R-associated tumor lymphangiogenesis will aid in future development of new selective-targeting strategies in the treatment of cancer.