Antitumor Cannabinoid Chemotypes: Structural Insights

Abstract

Cannabis has long been known to limit or prevent nausea and vomiting, lack of appetite, and pain. For this reason, cannabinoids have been successfully used in the treatment of some of the unwanted side effects caused by cancer chemotherapy. Besides their palliative effects, research from the past two decades has demonstrated their promising potential as antitumor agents in a wide variety of tumors. Cannabinoids of endogenous, phytogenic, and synthetic nature have been shown to impact the proliferation of cancer through the modulation of different proteins involved in the endocannabinoid system such as the G protein–coupled receptors CB1, CB2, and GRP55, the ionotropic receptor TRPV1, or the fatty acid amide hydrolase (FAAH). In this article, we aim to structurally classify the antitumor cannabinoid chemotypes described so far according to their targets and types of cancer. In a drug discovery approach, their in silico pharmacokinetic profile has been evaluated in order to identify appropriate drug-like profiles, which should be taken into account for further progress toward the clinic. This analysis may provide structural insights into the selection of specific cannabinoid scaffolds for the development of antitumor drugs for the treatment of particular types of cancer.

Cannabinoids in the Pathophysiology of Skin Inflammation

“…The skin ECS contributes to the regulation of cell differentiation and proliferation through AEA and FAAH that maintain homeostasis through cannabinoid receptor signaling [37,51,124,153]. Both non-melanoma and melanoma skin cancer cells express CB1 and CB2 receptors, alongside other receptors that cannabinoids can activate [154,155]. Cannabinoids have revealed pro-apoptotic and anti-proliferative in various cancers such as prostate, digestive tract and breast carcinomas, with CBD demonstrating the strongest anti-tumor effects [156].…”

The Highs and Lows of Cannabis in Cancer Treatment and Bone Marrow Transplantation

“…Recent studies suggested that some cannabinoid-based treatments might have antitumor properties. [2][3][4][5] Cannabinoids were found to modulate key cell signaling pathways involved in the control of cancer cell proliferation and survival. [6][7][8] However, most of these studies utilized in vitro methods, a few were done in immune-competent animal models, and the data from human patients are anecdotal.…”

Cannabinoid Receptor CB2 Subtype: A Novel Pharmacological Target in Cancer and Neurodegenerative Diseases

“…Nevertheless, several studies have evaluated the antitumor effect of different types of CB2R molecules already used in cancer therapy for their well-established palliative effects. Several works have underlined that endogenous, phytogenic, synthetic cannabinoids, and modulators of endocannabinoid biosynthesis, are able to inhibit the proliferation of a wide spectrum of tumor cells with mechanism not totally unravelled [11]. Velasco, et al suggested at least four anticancer mechanisms: 1) the suppression of mitogenic signal; 2) the induction of apoptosis; 3) the inhibition of tumor angiogenesis; 4) induction of metastasis [11].…”

“…Several works have underlined that endogenous, phytogenic, synthetic cannabinoids, and modulators of endocannabinoid biosynthesis, are able to inhibit the proliferation of a wide spectrum of tumor cells with mechanism not totally unravelled [11]. Velasco, et al suggested at least four anticancer mechanisms: 1) the suppression of mitogenic signal; 2) the induction of apoptosis; 3) the inhibition of tumor angiogenesis; 4) induction of metastasis [11]. Concerning to CB2R agonists, among phytocannabinoid, morin, a flavonoid structurally closely related to quercetin, showed an apoptotic effect by a mechanism not fully resolved [10].…”

“…Concerning to CB2R agonists, among phytocannabinoid, morin, a flavonoid structurally closely related to quercetin, showed an apoptotic effect by a mechanism not fully resolved [10]. Interestingly, synthetic compounds as WIN55,212-2, JWH-015, JWH-133 were found able to induce cannabinoid receptor dependent anti-proliferative and pro-apoptotic effects both in vitro and in vivo assays [7,[11][12][13][14][15]. Recently, researchers have discovered the ability of CB2R to form heteromers with other GPCRs, as CXCR4 or GPR55.…”