Cannabidiol and Oxygen-Ozone Combination Induce Cytotoxicity in Human Pancreatic Ductal Adenocarcinoma Cell Lines

Abstract

Pancreatic cancer (PC) is related to lifestyle risks, chronic inflammation, and germline mutations in BRCA1/2, ATM, MLH1, TP53, or CDKN2A. Surgical resection and adjuvant chemotherapy are the main therapeutic strategies but are less effective in patients with high-grade tumors. Oxygen-ozone (O2/O3) therapy is an emerging alternative tool for the treatment of several clinical disorders. O2/O3 therapy has been found to ameliorate mechanisms promoting chronic pain and inflammation, including hypoxia, inflammatory mediators, and infection. The advantages of using cannabinoids have been evaluated in vitro and in vivo models of several human cancers. Regarding PDAC, activation of cannabinoid receptors was found to induce pancreatic cancer cell apoptosis without affecting the normal pancreas cells. In a murine model of PDAC, a combination of cannabidiol (CBD) and gemcitabine increased survival length by nearly three times. Herein, we evaluate the anticancer effect of CBD and O2/O3, alone or in combination, on two human PDAC cell lines, PANC-1 and MiaPaCa-2, examining expression profiles of 92 pancreatic adenocarcinoma associated genes, cytotoxicity, migration properties, and cell death. Finally, we assess the combination effects with gemcitabine and paclitaxel. Summarizing, for the first time the antitumoral effect of combined therapy with CBD and oxygen-ozone therapy in PDAC is evidenced.

Targeting the Endocannabinoid System: From the Need for New Therapies to the Development of a Promising Strategy. What About Pancreatic Cancer?

“…In vitro studies in MiaPaCa2 and Panc1 cell lines reported that cannabinoid administration led to apoptosis, reduced cell viability and augmented the levels of ceramide and caspase 3. The combination of cannabinoid and O 2 /O 3 induced cytotoxicity and augmented chemosensitivity to gemcitabine and paclitaxel (63). Moreover, mRNA levels of the p8 protein, which is associated with stress, were up-regulated (19).…”

“…Other studies investigated cannabinoid receptors in pancreatic cancer both in vitro and in vivo (18,63). Researchers showed that cannabinoid receptors are more highly expressed in human pancreatic tumor cell lines and tumor biopsies than in normal pancreatic tissue.…”

Antitumor Effects of Cannabinoids in Human Pancreatic Ductal Adenocarcinoma Cell Line (Capan-2)-Derived Xenograft Mouse Model

“…Tumor cells xenografts transplanted subcutaneously into the immunodeficiency mice have been widely tested in the preclinical studies for identifying or developing the new anticancer drugs (19). The immunodeficient mice such as BALB/c nude mice were the mice that lack T-cell lymphocytes, allowing tumor cell lines to be proliferated and propagated into a solid mass in the subcutaneous region (20,21). The current experiment selected the xenograft tumor model to evaluate the effects of cannabinoid compounds in pancreatic adenocarcinoma transplanted mice.…”

Oxidative Stress and Multi-Organel Damage Induced by Two Novel Phytocannabinoids, CBDB and CBDP, in Breast Cancer Cells

“…Recently, it was found that the co-administration of cannabinoids with chemotherapeutic drugs enhanced their efficiency, especially in chemotherapy-refractory tumors [ 10 , 11 ]. Phytocannabinoids may act via dependent and/or independent cannabinoid receptor mechanisms [ 12 , 13 ]. CB1 and CB2 are the first cannabinoids receptors described.…”

“…These are G-protein coupled receptors (GPCR) that can be activated by endogenous and exogenous cannabinoids. More recently, studies have shown that cannabinoids can activate other receptors, i.e., GPR55, TRPM8 as well as other ion channels of the transient receptor potential superfamily as vanilloid type 1–4 (TRPV1, TRPV2, TRPV3 and TRPV4) [ 12 , 14 , 15 , 16 , 17 ]. In the context of breast cancer, the biological role of CBD in the regulation of epithelial tumor pathophysiology has clearly emerged [ 18 , 19 ].…”