Secalonic Acid-D Represses HIF1α/VEGF-Mediated Angiogenesis by Regulating the Akt/mTOR/p70S6K Signaling Cascade

Area of Science:

• Oncology
• Pharmacology
• Mycology

Background:

• Tumor angiogenesis is a key target for cancer therapy.
• Existing antiangiogenic agents require improved disease selectivity.
• Novel therapeutic compounds are needed to combat cancer effectively.

Purpose of the Study:

• To isolate and characterize secalonic acid-D (SAD) from a novel source.
• To evaluate the antiangiogenic and antitumor potential of SAD.
• To elucidate the molecular mechanisms underlying SAD's activity.

Main Methods:

• In vitro assays using human umbilical vascular endothelial cells and human MCF-7 breast tumor xenografts.
• In vivo assays including rat aortic ring assay and Matrigel plug assay in mice.
• Analysis of signaling pathways (Akt/mTOR/p70S6K), apoptosis, and cell cycle progression.

Main Results:

• SAD potently inhibited HIF1α/VEGF-mediated angiogenesis and tumor growth.
• SAD suppressed VEGF-induced microvessel sprouting and blood vessel formation.
• SAD induced apoptosis and cell-cycle arrest by affecting key proteins and pathways, including Akt/mTOR/p70S6K, HIF1α, and VEGFR.
• No apparent toxicities were observed in preclinical mouse models at effective doses.

Conclusions:

• Secalonic acid-D exhibits significant antiangiogenic and antitumor properties.
• SAD acts through inhibition of the Akt/mTOR/p70S6K pathway and downstream proangiogenic factors.
• SAD demonstrates preclinical efficacy and safety, suggesting its potential as a novel cancer-selective therapeutic agent.