Anticancer effects of cannabidiol and oxygen- ozone combination in human pancreatic ductal adenocarcinoma cell lines

Introduction: Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive and lethal malignancy. Surgical resection followed by adjuvant chemotherapy is the main therapeutic strategy, but it is less effective in high-grade patients, so new therapies are necessary [1]. The use of cannabidiol (CBD), was evaluated in in vitro and in vivo models in several human cancers [2]. Oxygen- ozone (O2/O3) therapy is an emerging alternative tool use to ame- liorate mechanisms promoting chronic pain and inflammation. Aim: To evaluate the anticancer effects of CBD and O2/O3, alone and in combination with chemotherapeutic drugs, in 2 human PDAC cell lines. Expression profile of CBD-target receptors (CBD- TRs) and their correlation with Overall Survival (OS) and Recurrence Free Survival (RFS) in PDAC patients. Methods: Cytotoxicity was evaluated by MTT assay. Cell death mechanism by cytofluorimetric and western blot analysis. PDAC gene profile modulation was evaluated with TaqMan Array. CBD-TRs gene and protein expression levels were evaluated by RT-PCR and west- ern blot analysis. By Pan-cancer database, OS and RFS associated to CBD-TRs expression in PDAC patients were determined. Results: CBD and O2/O3 induced cell death in PANC-1 and MIAPaCa-2. Moreover, CBD and O2/O3 increased chemothera- peutic drugs efficacy. CBD and O2/O3 modulate the expression profile of PDAC involved genes. The expression profile of CBD- TRs in PDAC cell lines was determined: PANC-1 showed a higher expression of TRPV2 receptor, while in MIAPaCa-2 TRPV4 was the higher CBD-TRs expressed. Finally, database results showed a significant correlation between OS and RFS, and specific CBD-TRs expression levels. Conclusions: These preliminary data suggest that CBD and O2/O3 combined therapy could be used as adjuvant to chemotherapy and specific CBD-TRs should be potential targets as diagnostic markers and in PDAC therapy. Keywords: Pancreatic cancer, cannabidiol, TRPV channels, chemotherapy, oxygen- ozone.