Pharmacological advances in cannabinoid-based therapies for pancreatic cancer: preclinical efficacy of CCL-106 and its epimers.

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal form of cancer with limited treatment options and poor survival rates. Cannabinoids have demonstrated antiproliferative and proapoptotic effects in various cancer types, including PDAC, making them promising therapeutic agents. However, clinical efficacy remains underexplored, particularly for cannabinoids like cannabidiol and tetrahydrocannabinol, which show limited activity against pancreatic cancer.

Materials and methods: We synthesized novel cannabinoid analogues, including CCL-106 and its epimers CCL-114 and CCL-115, which exhibit superior antitumor activity in both two-dimensional and three-dimensional pancreatic cancer models.

Results: These compounds demonstrated substantially lower concentration that causes 50% inhibition of growth (IC₅₀) values in human pancreatic cancer cell lines and enhanced tumor inhibition in pancreatic cancer cell-derived xenograft model without inducing systemic toxicity. Mechanistic studies revealed that the antiproliferative effects of these compounds are primarily mediated through CB2 and GPR55 receptor activation, alongside the generation of reactive oxygen species. Further, CCL-106 has been shown to significantly enhance the efficacy of the standard-of-care chemotherapeutic regimen gemcitabine/nab-paclitaxel in vitro. Moreover, the combination of CCL-106 with gemcitabine/nab-paclitaxel exhibited synergistic effects on growth inhibition of PDAC cells. Additionally, using a patient-derived xenograft model of PDAC, the antitumor efficacy of CCL-115 and CCL-114 in combination with gemcitabine and nab-paclitaxel was demonstrated.

Conclusions: These findings suggest that CCL-106 and its epimers hold potential as effective and less-toxic therapeutic options for PDAC treatment. Further clinical studies are warranted to explore their translational application.