Natural Phenolic Acid, Product of the Honey Bee, for the Control of Oxidative Stress, Peritoneal Angiogenesis, and Tumor Growth in Mice.

Dyana Odeh,Daniela Ančić,Marina Kukolj,Nada Oršolić,Martina Kunštić

doi:10.3390/molecules25235583

Abstract

Tumor-associated macrophages (TAM) are key regulators of the link between inflammation and cancer, and the interplay between TAM and tumor cells represents a promising target of future therapeutic approaches. We investigated the effect of gallic acid (GA) and caffeic acid (CA) as strong antioxidant and anti-inflammatory agents on tumor growth, angiogenesis, macrophage polarization, and oxidative stress on the angiogenic model caused by the intraperitoneal (ip) inoculation of Ehrlich ascites tumor (EAT) cells (2.5 × 106) in Swiss albino mouse. Treatment with GA or CA at a dose of 40 mg/kg and 80 mg/kg ip was started in exponential tumor growth phase on days 5, 7, 9, and 11. On day 13, the ascites volume and the total number and differential count of the cells present in the peritoneal cavity, the functional activity of macrophages, and the antioxidant and anti-angiogenic parameters were determined. The results show that phenolic acids inhibit the processes of angiogenesis and tumor growth, leading to the increased survival of EAT-bearing mice, through the protection of the tumoricidal efficacy of M1 macrophages and inhibition of proangiogenic factors, particularly VEGF, metalloproteinases -2 and -9, and cyclooxygenase-2 activity.

Highlights

Angiogenesis is the process of the formation of new capillary blood vessels from pre-existing ones and is considered essential for tumor growth and metastasis [1]
Because gallic acid (GA) and caffeic acid (CA) showed an inhibition of tumor growth and decreased ascites fluid volume, which is closely related to angiogenesis, we investigated the number of peritoneal vessels and the key factors in the process of angiogenesis, such as the vascular endothelial growth factor (VEGF) and metalloproteinase activity
In order to find a potent antiangiogenic, anti-inflammatory, and antioxidant drug, we investigated the effect of CA and GA on growth and angiogenesis in the exponential tumor growth phase of Ehrlich ascites tumor-bearing mice; ip EAT cell inoculation induces a strong local inflammatory response with increased vascular permeability, leading to an intense edema formation, cell migration, rapid proliferation, and an increase in ascites fluid formation (Table 1, Supplementary File, Figure S1)

Summary

Introduction

Angiogenesis is the process of the formation of new capillary blood vessels from pre-existing ones and is considered essential for tumor growth and metastasis [1]. A growing tumor needs an extensive network of capillaries to provide nutrients and oxygen. In this process, tumor-associated macrophages (TAMs) play an important role. TAMs are key regulators of the link between inflammation and cancer. TAMs with other immune cells that infiltrate tumors are involved in dynamic interaction with tumor cells, and this interaction leads to tumorigenesis, metastasis, and drug resistance [2,3]. The interplay between TAMs and neoplastic cells represents a promising target of future therapeutic approaches. By the production of numerous enzymes, including matrix metalloproteinases

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