Identification and development of novel anti-lymphangiogenic compounds as cancer therapeutics
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1
Cancer Research Malaysia, Malaysia
Background
Cancer metastasis is the leading cause of death in cancer patients as it accounts for approximately 90% of human cancer death. It is well reported that blood and/or lymphatic vessels, play key roles in cancer metastasis by providing nutrient and conduits for cancer cell dissemination. Consequently, many anti-angiogenic agents are developed and currently used in clinics. Although promising, these are nevertheless associated with side effects. Alternatively, the intimate relationship between cancer metastasis and lymphangiogenesis has stimulated researchers to seek for novel anti-lymphangiogenic drugs as therapeutic options for cancer metastasis. Though there are few anti-lymphangiogenic agents which are currently under clinical evaluation, there are still no FDA approved selective agents designed to prevent lymphatic vessel growth, highlighting an important clinical niche. In this study, we aim to identify novel anti-lymphangiogenic compounds as novel therapeutic agents for metastatic human cancer.
Methods
Zebrafish is an established in vivo model for vascular biology and had contributed in identifying various novel anti-(lymph)angiogenic compounds. Here, we utilised the Tg(lymphatic vessel endothelial hyaluronic receptor 1b (lyve1b):Discosoma sp. Red fluorescent protein 2 (DsRed2))nz101 transgenic that express DsRed2 in all lymphatic/venous endothelial cells, to screen for anti-(lymph)angiogenic compounds from our compound libraries consisted natural and semi-synthetic compounds. The thoracic duct development in zebrafish was quantified using fluorescent microscope to measure lymphatic vessel development.
Results
Approximately 300 compounds were screened and we identified 2 semi synthetic compounds which able to inhibit thoracic duct development specifically. Subsequent biochemical analysis revealed inhibition of phosphorylated ERK1/2 expression, the down-stream target of vascular endothelial growth factor (VEGF) pathway in human lymphatic endothelial cells upon compound treatments, suggesting anti-lymphangiogenic activity through inhibition of VEGF pathway.
Conclusion
Novel anti-lymphangiogenic compounds can be identified using the zebrafish model and potential therapeutics can be developed against cancer metastasis, by targeting lymphangiogenesis.
Keywords:
Lymphangiogenesis,
Angiogenesis,
Zebrafish,
Matastasis,
Cancer
Conference:
International Conference on Drug Discovery and Translational Medicine 2018 (ICDDTM '18)
“Seizing Opportunities and Addressing Challenges of Precision Medicine”, Putrajaya, Malaysia, 3 Dec - 5 Feb, 2019.
Presentation Type:
Oral Presentation
Topic:
Cancer
Citation:
Okuda
KS,
Ng
M,
Samat
N,
Ruslan
N,
Tan
P and
Patel
V
(2019). Identification and development of novel anti-lymphangiogenic compounds as cancer therapeutics.
Front. Pharmacol.
Conference Abstract:
International Conference on Drug Discovery and Translational Medicine 2018 (ICDDTM '18)
“Seizing Opportunities and Addressing Challenges of Precision Medicine”.
doi: 10.3389/conf.fphar.2018.63.00122
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Received:
07 Nov 2018;
Published Online:
17 Jan 2019.
*
Correspondence:
Dr. Pei Jean Tan, Cancer Research Malaysia, Subang Jaya, Malaysia, peijean.tan@cancerresearch.my