JWH-051

Chemotherapeutic agent-induced organ toxicities, including cardiotoxicity, nephrotoxicity, hepatotoxicity, and neurotoxicity, remain significant challenges in cancer treatment, often limiting therapeutic utility, effectiveness and patient quality of life (QOL). These toxicities arise from numerous mechanisms such as oxidative stress, inflammation, and apoptosis, driven by chemotherapeutic agents like doxorubicin, cisplatin, cyclophosphamide, and methotrexate. Various strategies are being explored to mitigate these toxicities without compromising the effectiveness of the treatment. Polypharmacological or dual-targeting agents that combat cancer cells, sensitize resistant cancer types, and minimize organ damage show enormous promise in therapeutics. Among emerging therapeutic targets, the endocannabinoid system, comprising cannabinoid receptors and metabolizing enzymes, offers potential in both cancer chemotherapy and reducing organ toxicities. The therapeutic potential of cannabinoids is attributed to their role in modulating inflammation, oxidative stress, and cell survival which are the common components of cancer pathogenesis and organ toxicities. Preclinical studies demonstrate that cannabinoid receptor-agonists, such as JWH-133 and beta-caryophyllene, mitigate organ damage by suppressing pro-inflammatory cytokines, reducing reactive oxygen species (ROS) production, and inhibiting apoptotic pathways. For instance, cannabinoid receptor 2 (CB2) activation has been shown to attenuate doxorubicin-induced cardiotoxicity by enhancing antioxidant defenses and reducing myocardial inflammation. Similarly, in cisplatin-induced nephrotoxicity, cannabinoids alleviate renal injury by decreasing tubular cell apoptosis and inflammatory infiltrates. Despite these promising findings, challenges remain, including the development of highly selective cannabinoid receptor agonists, understanding tissue-specific responses, and addressing translational gaps between animal models and human pathophysiology. This review highlights the mechanistic overview of cannabinoid receptor agonists in mitigating chemotherapy-induced organ toxicities and adverse effects, summarizes preclinical evidence, and discusses the potential for clinical application. By elucidating the therapeutic potential of the activation of cannabinoid receptors, this work underscores its viability as a novel strategy to enhance the effectiveness of chemotherapeutic regimens and improve patient outcomes, however, further research is the need of the hour to advance cannabinoid-mediated therapies into clinical practice.

Cannabidiol (CBD), a phytocannabinoid with pleiotropic effects, exhibits complex mechanisms of action that remain incompletely understood, particularly its role as an allosteric modulator of G protein-coupled receptor (GPCR) heteromers. Among these, the adenosine A_2A-cannabinoid CB₂ receptor heteromer (A_2AR-CB₂R) is a functionally relevant complex implicated in diverse physiological processes. This study aimed to characterize the modulatory effects of CBD on A_2AR-CB₂R heteromers. A multi-technique approach was employed using HEK-293T cells co-transfected with A_2AR and CB₂R. Real-time NanoBRET assays at 37 °C were used to assess receptor interaction kinetics. Functional consequences were evaluated via β-arrestin II recruitment assays, and complex formation was visualized and quantified using proximity ligation assays (PLA). CBD acted as a potent allosteric modulator, enhancing the kinetics of agonist-induced A_2AR-CB₂R interaction. Notably, this effect was accompanied by functional dissociation: CBD inhibited β-arrestin II recruitment in a probe-dependent manner, with significant modulatory effects at concentrations of 100 nM, and showed a greater inhibition of the selective CB₂R agonist JWH-133-induced signaling than that induced by CGS 21680, a selective A_2AR agonist. PLA data confirmed that this functional modulation occurred without altering the extent of heteromer complex formation. These findings reveal that CBD operates as a biased allosteric modulator of the A_2AR-CB₂R heteromer. Rather than disrupting heteromer formation, CBD selectively induces a conformational state that uncouples physical receptor interaction from β-arrestin II signaling. This defines a distinct mechanism of action for CBD and highlights A_2AR-CB₂R heteromers as promising targets for biased signaling-based therapeutics.