Oleuropein-Rich Leaf Extract as a Broad Inhibitor of Tumour and Macrophage iNOS in an Apc Mutant Rat Model.

Jessica Ruzzolini,Annalisa Romani,Giovanna Caderni,Silvia Urciuoli,Francesca Bianchini,Cristina Luceri,Elena Andreucci,Katia Tortora,Sofia Chioccioli,Silvia Peppicelli,Chiara Nediani,Lido Calorini,Noemi Monaco

doi:10.3390/antiox10101577

Abstract

Oleuropein, the major compound found in olive leaves, has been reported to exert numerous pharmacological properties, including anti-inflammatory, anti-diabetic and anti-cancer effects. The purpose of this study was to evaluate, for the first time, the effect of oleuropein-rich leaf extracts (ORLE) in already-developed colon tumours arising in Apc (adenomatous polyposis coli) mutated PIRC rats (F344/NTac-Apcam1137). Here, we were able to investigate in parallel the anti-cancer effect of ORLE, both in vivo and in vitro, and its anti-inflammatory effect on macrophages, representing a critical and abundant population in most solid tumour microenvironment. We found that in vivo ORLE treatment promoted apoptosis and attenuated iNOS activity both in colon tumours as in peritoneal macrophages of PIRC rats. We this confirmed in vitro using primary RAW264.7 cells: ORLE reduced iNOS activity in parallel with COX-2 and pro-inflammatory cytokines, such as IL-1β, IL-6 and TGF-β. These findings suggest that ORLE possess a strong anti-inflammatory activity, which could be crucial for dampening the pro-tumourigenic activity elicited by a chronic inflammatory state generated by either tumour cells or tumour-associated macrophages.

Highlights

Cancer is currently the second leading cause of death worldwide and highly efficient anti-cancer drugs are currently used to counteract the uncontrolled proliferative activity of neoplastic cells
We found that an oleuropein-rich leaf extracts (ORLE) enriched diet reduces cell proliferation and increases cell apoptosis in tumours and reduces nitric oxide synthase in colon tumour lesions and peritoneal macrophages of PIRC rats
One-year old PIRC rats with consolidated colon tumours were fed for one week with

Summary

Introduction

Cancer is currently the second leading cause of death worldwide and highly efficient anti-cancer drugs are currently used to counteract the uncontrolled proliferative activity of neoplastic cells. The effectiveness of most chemotherapeutic agents is accompanied by systemic toxicity, since anti-cancer agents discriminate poorly between normal and cancerous cells. Among alternative therapies for cancer treatment, there is a growing interest in the anti-cancer action of natural substances, that are non-toxic, affordable, readily accessible, and, some of which, present in large amounts in byproducts from agro-food chains [1]. Natural products are well-established to have pharmacological or biological activities that can be of therapeutic benefits for cancer therapy. More recently the use of natural compounds as differentiation inducing agents leading maturation of low differentiated cancer cells rendering them less aggressive and more sensitive to conventional treatments has emerged [3]

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