Regulation of Inflammatory and Proliferative Pathways by Fotemustine and Dexamethasone in Endometriosis.

Tiziana Genovese,Emanuela Raffone,Enrico Gugliandolo,Angela Trovato Salinaro,Ramona D’Amico,Alessio Filippo Peritore,Rosalia Crupi,Daniela Impellizzeri,Roberta Fusco,Marika Cordaro,Salvatore Cuzzocrea,Rosanna Di Paola,Rosalba Siracusa

doi:10.3390/ijms22115998

Tiziana Genovese, Emanuela Raffone + Show 11 more

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https://doi.org/10.3390/ijms22115998

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Abstract

Endometriosis is a common disease. Its pathogenesis still remains uncertain, but it is clear that cell proliferation, apoptosis and chronic inflammation play an important role in its development. This paper aimed to investigate the anti-proliferative and anti-inflammatory effects of a combined therapy with fotemustine and dexamethasone. Endometriosis was induced by intraperitoneal injections of uterine fragments from donor animals to recipient animals. Next, the pathology was allowed to develop for 7 days. On the seventh day, fotemustine was administered once and dexamethasone was administered daily for the next 7 days. On Day 14, the animals were sacrificed, and peritoneal fluids and lesions were explanted. In order to evaluate the gastrointestinal side effects of the drugs, stomachs were harvested as well. The combined therapy of fotemustine and dexamethasone reduced the proinflammatory mediator levels in the peritoneal fluid and reduced the lesions’ area and diameter. In particular, fotemustine and dexamethasone administration reduced the heterogeneous development of endometrial stroma and glands (histological analysis of lesions) and hyperproliferation of endometriotic cells (immunohistochemical analysis of Ki67 and Western blot analysis of PCNA) through the mitogen-activated protein kinase (MAPK) signaling pathway. Combined fotemustine and dexamethasone therapy showed anti-inflammatory effects by inducing the synthesis of anti-inflammatory mediators at the transcriptional and post-transcriptional levels (Western blot analysis of NFκB, COX-2 and PGE2 expression). Fotemustine and dexamethasone administration had anti-apoptotic activity, restoring the impaired mechanism (TUNEL assay and Western blot analysis of Bax and Bcl-2). Moreover, no gastric disfunction was detected (histological analysis of stomachs). Thus, our data showed that the combined therapy of fotemustine and dexamethasone reduced endometriosis-induced inflammation, hyperproliferation and apoptosis resistance.

Highlights

Endometriosis is an invasive disease which affects women of reproductive age
This paper evaluated the combined effect of FT and DM on endometriosis, evaluating the association between anti-proliferative and anti-inflammatory approaches
The relationship between inflammation and endometriosis was seen in infertile women, in whom intraperitoneal inflammation was observed [27], and was thought to be partially due to retrograde menstruation [28,29]

Summary

Introduction

Endometriosis is an invasive disease which affects women of reproductive age. The hallmarks of the pathology are growth of the endometrial stroma and glands outside the uterine cavity. The symptoms described by the patients are severe dysmenorrhea, chronic pelvic pain and infertility. This pathology, largely affects women of reproductive age. Sampson’s hypothesis of retrograde menstruation is the most widely accepted. According to this theory, endometriosis derives from fragments of the endometrial glands. The first theory proposes that cellular fragments from embryonic Mullerian ducts evolve into endometriotic foci at the beginning of puberty through the influence of sex hormones. The second theory proposes that endometrial and peritoneal cells would both have their origin from the coelomic epithelium, during the disease, healthy peritoneal tissue would transform into ectopic endometrium [1]. Menstrual fragments are composed of both living and necrotic cells [4,5]

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