Integrative Therapies in Human Pancreatic Ductal Adenocarcinoma: a preclinical investigation

Over the last decades, the interest in additional therapeutic approaches to increase usual anticancer therapy efficacy, reducing side effects and improving patients’ quality of life, is growing. An increasing number of cancer patients use, together with traditional anticancer therapies, herbal and dietary supplements. Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and despite the therapeutic improvements, its prognosis is very poor. Firstly, it was evaluated the effect of Cannabigerol (CBG), a non-psychotropic cannabinoid from cannabis Sativa in two human PDAC cell lines, PANC-1 and MIAPaCa-2. CBG activity was investigated on cell viability, cell death and on EGFR-RAS-associated signaling. Moreover, CBG effect in combination with gemcitabine (GEM) and paclitaxel (PTX) was investigated. Data showed that CBG induced apoptosis and reduced EGFR/Akt/mTOR and Ras pathways, supporting the ability of cannabinoids in interfering with several pro-tumoral pathways. Moreover, GEM and PTX activity was increased by CBG addition. Subsequently, the effect of a combination of Cannabidiol (CBD), Melatonin (MLT) and Oxygen-Ozone (O2/O3) was analysed in in vitro and in xenograft mouse model of PDAC. CBD is the most studied non-psychotropic cannabinoid in preclinical and clinical studies for its anticancer properties. MLT effect is being assessed for preventing or treating chemotherapy and radiotherapy side effects and there are some evidences about its anticancer effect in several preclinical cancer models. O2/O3 therapy is considered an integrative opportunity for cancer patients for its effect in reducing pain, fatigue and musculoskeletal symptoms, but it is actually little investigated as direct anticancer molecule. Results evidenced that the different treatments inhibited PDAC cell lines viability, modulating also Ras signaling pathway, and inhibited PDAC growth in mice, alone and combined with GEM. Data suggest that these different treatments could be an interesting approach in supporting PDAC therapy