A SIRT6 Inhibitor, Marine-Derived Pyrrole-Pyridinimidazole Derivative 8a, Suppresses Angiogenesis

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Angiogenesis, the formation of new blood vessels, is crucial for tumor growth and metastasis.
• Sirtuin6 (SIRT6), a NAD+-dependent deacetylase, influences various cellular processes, including angiogenesis.
• Targeting angiogenesis is a key strategy in cancer therapy, yet the antiangiogenic effects of SIRT6 inhibitors remain unexplored.

Purpose of the Study:

• To investigate the antiangiogenic potential of a novel SIRT6 inhibitor, compound 8a.
• To elucidate the molecular mechanisms underlying the antiangiogenic effects of 8a.
• To evaluate the efficacy of 8a in preclinical models of cancer.

Main Methods:

• In vitro assays using human umbilical vein endothelial cells (HUVECs) to assess migration and tube formation.
• Western blot analysis to quantify protein expression (VEGF, HIF-1α, p-VEGFR2, N-cadherin, CD31) and pathway activation (AKT, ERK).
• In vivo studies using zebrafish embryos and a pancreatic cancer xenograft mouse model to evaluate antiangiogenic effects.

Main Results:

• Compound 8a significantly inhibited HUVEC migration and tube formation.
• 8a treatment downregulated key angiogenesis markers (VEGF, HIF-1α, p-VEGFR2, N-cadherin) and suppressed AKT/ERK signaling.
• In vivo studies confirmed 8a's ability to block angiogenesis in zebrafish and reduce CD31 expression in pancreatic tumors.

Conclusions:

• Compound 8a functions as a potent SIRT6 inhibitor with significant antiangiogenic activity.
• 8a effectively suppresses angiogenesis through multiple molecular pathways.
• These findings position 8a as a promising candidate for developing novel antiangiogenic and anticancer therapeutics.