Cannabichromene: Integrative modulation of apoptosis, ferroptosis, and endocannabinoid signaling in pancreatic cancer therapy

Cannabichromene (CBC: C21H3O2, M.W.: 314.46 g) is a non-psychotropic phytocannabinoid derived from Cannabis sativa (Hemp) and has been increasing attention for its potential therapeutic properties. CBC has demonstrated strong anti-inflammatory effects in animal models with edema through non-CB receptor mechanisms; however, there are still required on pharmacological studies in cancer models. In this study, we investigated the molecular mechanisms on anti-cancer activity of CBC in human pancreatic cancer cells. Through mRNA-seq analysis, we observed that many genes involved in cell death pathways were upregulated and also downregulated by CBC treatment, including ferroptosis-related genes such as HMOX1. We confirmed the functional validation of apoptosis and ferroptosis induction following CBC treatment using a variety of molecular assays. In addition, we found that CBC treatment preferentially increased the expression of TRPV1 and CB2 receptors. The cell death was reversed by inhibitor treatment on TRPV1 and CB2, suggesting that receptor expression is necessary for induction of apoptotic cell death. Finally, we confirmed the consistent regulation on apoptosis, ferroptosis, and the endocannabinoid receptors during tumor growth inhibition by CBC treatment in in-vivo xenograft models. Therefore, we propose that CBC exhibits pharmacological activity via integrative modulation for multiple cell death pathways in the pancreatic cancer therapy.