Cancer is an increasingly prevalent health problem and remains a major cause of mortality around the world. The metastatic spread of tumor cells is associated with resistance to conventional therapy and is the leading cause of death for cancer patients. Tumor cells produce a range of growth factors and/or cytokines that promote tumor metastasis by directly or indirectly stimulating angiogenesis and lymphangiogenesis, which is one of the major routes for tumor invasion and metastasis. It thus represents a rational target for therapeutic intervention. Hydroxanates and its derivatives have attracted considerable attention, due to their pharmacological, toxicological and pathological properties. Hydroxamates have a wide spectrum of activities including anti-tumor, anti-microbial, anti-tuberculus activities. Several hydroxamates have been advanced into clinical trials as pharmaceutical agents for the treatment of several diseases. In an effort to develop novel inhibitors to suppress angiogenesis, lymphangiogenesis and tumor growth, we selected WMJ-S-001, a novel aliphatic hydroxamate, and characterized its anti-angiogenic and anti-lymphangiogenic activities. In our preliminary studies, we found that WMJ-S-001 inhibited vascular endothelial growth factor (VEGF)-induced proliferation, migration and endothelial tube formation in human umbilical vascular endothelial cells (HUVECs). WMJ-S-001 also attenuated VEGF-induced microvessel sprouting from aortic rings ex vivo. On the other hand, WMJ-S-001 also suppressed cell proliferation and endothelial tube formation in lymphatic endothelial cells. Furthermore, WMJ-S-001 inhibited the phosphorylation of VEGFR2, Akt and ERK in HUVECs exposed to VEGF. WMJ-S-001 was also shown to inhibit cell proliferation in HCT116, MCF-7 and KOSC3 cells. Taken together, these results suggested that WMJ-S-001 may modulate vascular or lymphatic endothelial cell remodeling and leads to the inhibition of tumor angiogenesis and lymphangiogenesis. The central hypothesis of this project is that WMJ-S-001 inhibits angiogenesis and lymphangiogenesis, leading to the suppression of tumor progression and metastasis. Understanding the anti-angiogenic and anti-lymphangiogenic mechanisms of WMJ-S-001 will aid in future development of selective-targeting strategies for WMJ-S-001 or its derivatives in the treatment of cancer.
|Effective start/end date||8/1/13 → 7/31/14|
- vascular endothelial growth factor (VEGF)