Exploring the therapeutic potential of cannabinoids in cancer by modulating signaling pathways and addressing clinical challenges

Abstract

For centuries, cannabinoids have been utilized for their medicinal properties, particularly in Asian and South-Asian countries. Cannabis plants, known for their psychoactive and non-psychoactive potential, were historically used for spiritual and remedial healing. However, as cannabis became predominantly a recreational drug, it faced prohibition. Recently, the therapeutic potential of cannabinoids has sparked renewed research interest, extending their use to various medical conditions, including cancer. This review aims to highlight current data on the involvement of cannabinoids in cancer signaling pathways, emphasizing their potential in cancer therapy and the need for further investigation into the underlying mechanisms. A comprehensive literature review was conducted using databases such as PubMed/MedLine, Google Scholar, Web of Science, Scopus, and Embase. The search focused on peer-reviewed articles, review articles, and clinical trials discussing the anticancer properties of cannabinoids. Inclusion criteria included studies in English on the mechanisms of action and clinical efficacy of cannabinoids in cancer. Cannabinoids, including Δ9-THC, CBD, and CBG, exhibit significant anticancer activities such as apoptosis induction, autophagy stimulation, cell cycle arrest, anti-proliferation, anti-angiogenesis, and metastasis inhibition. Clinical trials have demonstrated cannabinoids' efficacy in tumor regression and health improvement in palliative care. However, challenges such as variability in cannabinoid composition, psychoactive effects, regulatory barriers, and lack of standardized dosing remain. Cannabinoids show promising potential as anticancer agents through various mechanisms. Further large-scale, randomized controlled trials are essential to validate these findings and establish standardized therapeutic protocols. Future research should focus on elucidating detailed mechanisms, optimizing dosing, and exploring cannabinoids as primary chemotherapeutic agents.

Keywords: Anticancer effects; Apoptosis; CBD; Cannabinoids; Metastasis; Pharmacological mechanisms; Δ9-THC.

Fig. 1

Different typed of Cannabinoids synthesized by cannabis plant [8, 19]

Fig. 2

Classification and roles of cannabinoids. The figure illustrates the three primary classifications of cannabinoids based on their origins: endocannabinoids, phytocannabinoids, and synthetic cannabinoids. Endocannabinoids, synthesized within the human body, include N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG). They regulate pain, depression, appetite, and various neuropsychological processes. Phytocannabinoids, derived from Cannabis sativa and Cannabis indica plants, include Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), and are used therapeutically for neurological disorders. Synthetic cannabinoids, such as JWH-018 and JWH-073, are chemically engineered for research and analgesic purposes. The diagram shows the interaction of these cannabinoids with endocannabinoid receptors and their respective roles in medical and therapeutic contexts

Fig. 3

Distribution and roles of cannabinoid receptors CB1R and CB2R in the human body. The diagram illustrates the two main types of G-protein coupled cannabinoid receptors: cannabinoid receptor 1 (CB1R) and cannabinoid receptor 2 (CB2R). CB1R are predominantly found in the brain and spinal cord, where they play vital roles in neurological functions such as synaptic remodeling, neurogenesis, neuron migration, axonal targeting, and synaptogenesis. These receptors are distributed across various regions of the central nervous system, including the hypothalamus, hippocampus, basal ganglia, amygdala, cortex, and cerebellum. In contrast, CB2R are primarily located in the cells and tissues of the immune system, where they significantly modulate immune responses. They are present in immune cells like macrophages in the spleen and tonsils, aiding the immunosuppressive functions of the endocannabinoid system. The diagram emphasizes the specific locations and functions of CB1R and CB2R, highlighting their critical roles in both neurological and immune system processes

Fig. 4

Structural model of cannabinoid receptors. This image depicts the structural model of cannabinoid receptors, specifically highlighting the seven transmembrane α-helices (TM1 to TM7). These helices span the cell membrane, forming a bundle that is essential for the receptor’s function. The loops connecting these transmembrane segments extend into both the intracellular and extracellular environments. The receptor features an extracellular N-terminus and an intracellular C-terminus, which includes a short helical segment known as Helix 8. This structural configuration is typical of class A G-protein coupled receptors (GPCRs), including cannabinoid receptors CB1R and CB2R. These receptors are pivotal in various physiological processes, mediating the effects of endogenous and exogenous cannabinoids by interacting with G proteins and triggering intracellular signaling pathways

Fig. 5

Molecular pathways mediated by cannabinoid receptors in cancer cells. This figure illustrates the molecular pathways mediated by cannabinoid receptors CB1 and CB2, as well as TRPV1, TRPV2, and TRPM8, in cancer cells. The interaction of cannabinoids, such as THC, CBD, and CBG, with these receptors initiates various intracellular signaling cascades that influence cell fate decisions. Activation of CB1 and CB2 receptors by THC and CBD can lead to the modulation of several signaling pathways. The activation of the ERK1/2 pathway results in the upregulation of cyclin-dependent kinase inhibitors p21 and p27, leading to cell cycle arrest by preventing the phosphorylation of the retinoblastoma protein (pRb). This process halts the progression of the cell cycle. Additionally, the activation of the PI3K/AKT pathway influences cell proliferation and autophagy through mTORC1. Prolonged activation of the PI3K/AKT pathway can lead to endoplasmic reticulum (ER) stress and the activation of ATF4, TRIB3, and CHOP, which are markers of cellular stress and can trigger apoptosis. CBG interacts with TRPV1, TRPV2, and TRPM8 receptors, leading to the production of reactive oxygen species (ROS). The accumulation of ROS induces the activation of proapoptotic proteins, promoting programmed cell death (apoptosis). Abbreviations: AKT Protein kinase B, ATF4 Activating transcription factor 4, CB1R Cannabinoid receptor type 1, CB2R Cannabinoid receptor type 2, CBD Cannabidiol, CBG Cannabigerol, CHOP C/EBP homologous protein, ER Endoplasmic reticulum, ERK1/2 Extracellular signal-regulated kinases 1 and 2, mTORC1 Mechanistic target of rapamycin complex 1, PI3K Phosphoinositide 3-kinase, pRb Retinoblastoma protein, ROS Reactive oxygen species, THC Δ9-tetrahydrocannabinol, TRIB3 Tribbles pseudokinase 3, TRPM8 Transient receptor potential cation channel subfamily M member 8, TRPV1 Transient receptor potential vanilloid 1, TRPV2 Transient receptor potential vanilloid 2