Gangemi, Giuseppina (2013) Targeting the endocannabinoid system in colorectal cancer. [Tesi di dottorato]

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Tipologia del documento: Tesi di dottorato
Lingua: English
Titolo: Targeting the endocannabinoid system in colorectal cancer
Autori:
AutoreEmail
Gangemi, Giuseppinagiuseppinagangemi@libero.it
Data: 2 Aprile 2013
Numero di pagine: 176
Istituzione: Università degli Studi di Napoli Federico II
Dipartimento: Medicina Molecolare e Biotecnologie Mediche
Scuola di dottorato: Medicina molecolare
Dottorato: Oncologia ed endocrinologia molecolare
Ciclo di dottorato: 25
Coordinatore del Corso di dottorato:
nomeemail
Santoro, Massimomasantor@unina.it
Tutor:
nomeemail
Bifulco, Mauriziombifulco@unisa.it
Data: 2 Aprile 2013
Numero di pagine: 176
Parole chiave: endocannabinoid, FAAH, CRC
Settori scientifico-disciplinari del MIUR: Area 06 - Scienze mediche > MED/04 - Patologia generale
Depositato il: 11 Apr 2013 14:08
Ultima modifica: 15 Lug 2014 13:14
URI: http://www.fedoa.unina.it/id/eprint/9422

Abstract

The endogenous cannabinoid system, comprising the cannabinoid receptors, their endogenous ligands (e.g. anandamide) and the enzymes regulating endocannabinoid biosynthesis and degradation, is an almost ubiquitous signaling system involved in the control of several physio-pathological conditions. Modulation of endocannabinoid tone has proven to hold several therapeutic promise in the treatment of a wide range of pathological processes. In this framework, given the ubiquity of the endocannabinoids and their receptors and their regulating action on proteins involved in cell fate control, there has been increasing evidence for a role of the endocannabinoid system also into neoplastic transformation and an interest to exploit it for a potential therapeutic application. However, despite several reports on endocannabinoids’ properties, little is known concerning the endogenous function of the endocannabinoid system and in particular of CB1 signaling in the regulation of tumor growth. A deregulation of the endocannabinoid system occurs in colorectal cancer (CRC). Loss of cannabinoid receptor 1 expression has been associated with colon tumor progression through a mechanism of epigenetic silencing, suggesting a role for CB1 as a tumor suppressor. A stable analogue of the endocannabinoid anandamide was utilized as a critical tool to characterize the basal functions of endocannabinoid system and CB1 signaling in CRC. Anandamide emerged as suppressor of colon tumor growth, since up regulation of CB1 receptor expression based on transcriptional regulation acting on its gene promoter affected CRC proliferation. However, a rapid anandamide metabolism has been identified in CRC, thus limiting this protective mechanism. As a consequence, an indirect targeting of anandamide degradative enzyme fatty acid amide hydrolase to maintain a local endocannabinoid tone has been proved. FAAH inhibition has been demonstrated to affect CRC proliferation through cell cycle machinery deregulation, DNA damage signaling pathway activation and late programmed cell death induction. Oxaliplatin in combination with 5-Fluorouracil and leucovorin (FOLFOX) has been approved for metastatic CRC therapy. Despite clinical success, patients who initially respond to chemotherapeutics may subsequently become refractory, directing the attention towards alternative strategies, including the use of combined therapies. A combinatorial approach has proven effective since FAAH inhibition sensitizes CRC cells to targeted therapies, thus representing a valid strategy to overcome drug resistance and side effects.

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