Pros and Cons of the Cannabinoid System in Cancer: Focus on Hematological Malignancies

Abstract

The endocannabinoid system (ECS) is a composite cell-signaling system that allows endogenous cannabinoid ligands to control cell functions through the interaction with cannabinoid receptors. Modifications of the ECS might contribute to the pathogenesis of different diseases, including cancers. However, the use of these compounds as antitumor agents remains debatable. Pre-clinical experimental studies have shown that cannabinoids (CBs) might be effective for the treatment of hematological malignancies, such as leukemia and lymphoma. Specifically, CBs may activate programmed cell death mechanisms, thus blocking cancer cell growth, and may modulate both autophagy and angiogenesis. Therefore, CBs may have significant anti-tumor effects in hematologic diseases and may synergistically act with chemotherapeutic agents, possibly also reducing chemoresistance. Moreover, targeting ECS might be considered as a novel approach for the management of graft versus host disease, thus reducing some symptoms such as anorexia, cachexia, fatigue, anxiety, depression, and neuropathic pain. The aim of the present review is to collect the state of the art of CBs effects on hematological tumors, thus focusing on the essential topics that might be useful before moving into the clinical practice.

Keywords: anti-tumor effects; bone marrow transplantation; cannabinoids; hematological malignancies; leukemia; lymphoma; medical cannabis.

Figure 1

Antitumor mechanisms of CBs.CBs have a pro-apoptotic effect via an action on apoptosis regulators (Bcl-2 and BAX) as well as an effect on oxidative stress. CBs stimulate ceramide generation and cell death in tumor cells but not in normal cells, reduce angiogenesis, and exert an antiproliferative effect acting on the AKT/mTOR pathway. Finally, CBs can stimulate ER stress, thus stimulating both an AMP-activated protein kinase and the calcium/calmodulin-dependent protein kinase, kinase 2, which in turn activates autophagy. Abbreviations: CBs: Cannabinoids; BAX: bcl-2-like protein 4; Bcl-2: B-cell lymphoma 2; VEGF: vascular endothelial growth factor; Ang-2: Angiopoietin-2; PIGF: placental growth factor; AKT/mTOR: Protein kinase B/mechanistic target of rapamycin; ER: Endoplasmic reticulum.

Figure 2

Differential effects of CBs on normal and neoplastic cells.

Figure 3

Pros and cons of the endocannabinoid system as a promising antitumor therapeutic strategy.