Caffeic Acid Phenethyl Ester (CAPE) Inhibits Hepatocellular Carcinoma Growth and Angiogenesis via Vascular Endothelial Growth Factor Suppression: A Preclinical Evidence

INTRODUCTION: Caffeic acid phenethyl ester (CAPE), a natural compound, has shown antitumor potential, but its efficacy and mechanism in hepatocellular carcinoma (HCC) require further validation, particularly in vivo. This study systematically investigated the antitumor efficacy and safety profile of CAPE against HCC through comprehensive in vitro and in vivo experiments. METHODS: In vitro, the anti-proliferative effect of CAPE (0-160 μM) on the human HCC cell line Bel-7402 was evaluated using the CCK-8 assay. The anti-angiogenic potential was assessed by measuring the migration of human umbilical vein endothelial cells (HUVECs) using a Transwell assay and by quantifying Vascular Endothelial Growth Factor (VEGF) secretion via enzyme-linked immunosorbent assay (ELISA). In vivo, a subcutaneous xenograft model using Bel-7402 cells in BALB/c nude mice was established. Mice were randomized to receive vehicle or CAPE (10 mg/kg/day) for 4 weeks. Tumor growth was monitored, and microvessel density (MVD) in tumor tissues was quantified by Factor VIII immunohistochemistry. An acute toxicity study was conducted in healthy Kunming mice with a single high dose (5 g/kg) of CAPE. RESULTS: CAPE exhibited significant anti-proliferative effects on Bel-7402 cells (IC50 = 17.6 μM) and inhibited HUVECs in a dose-dependent manner. In the xenograft model, CAPE suppressed tumor growth. CAPE demonstrated no acute toxicity in mice, suggesting preliminary safety for further investigation. Furthermore, it inhibited angiogenesis in vivo, impeded MVD in HCC specimens, and decreased VEGF secretion. DISCUSSION: This preclinical study provides evidence that CAPE exerts antitumor effects against HCC by inhibiting cell proliferation and suppressing angiogenesis. CONCLUSION: These findings, coupled with a good preliminary safety profile, support CAPE as a promising candidate for further mechanistic investigation and development in HCC therapy.