Abstract
Multiple myeloma (MM) is characterized by aberrant bone marrow plasma cell (PC) proliferation and is one of the most common hematological malignancies. The potential effect of cannabinoids on the immune system and hematological malignancies has been poorly characterized. Cannabidiol (CBD) may be used to treat various diseases. CBD is known to exert immunomodulatory effects through the activation of cannabinoid receptor 2 (CB2), which is expressed in high levels in the hematopoietic system. Cytokine-induced killer (CIK) cells are a heterogeneous population of polyclonal T lymphocytes obtained via ex vivo sequential incubation of peripheral blood mononuclear cells (PBMCs) with interferon-γ (IFN-γ), anti CD3 monoclonal antibody, and IL-2. They are characterized by the expression of CD3+ and CD56+, which are surface markers common to T lymphocytes and natural killer (NK) cells. CIK cells are mainly used in hematological patients who suffer relapse after allogeneic transplantation. Here, we investigated their antitumor effect in combination with pure cannabidiol in KMS-12 MM cells by lactate dehydrogenase LDH cytotoxicity assay, CCK-8 assay, and flow cytometry analysis. The surface and intracellular CB2 expressions on CIK cells and on KMS-12 and U-266 MM cell lines were also detected by flow cytometry. Our findings confirm that the CB2 receptor is highly expressed on CIK cells as well as on MM cells. CBD was able to decrease the viability of tumor cells and can have a protective role for CIK cells. It also inhibits the cytotoxic activity of CIKs against MM at high concentrations, so in view of a clinical perspective, it has to be considered that the lower concentration of 1 µM can be used in combination with CIK cells. Further studies will be required to address the mechanism of CBD modulation of CIK cells in more detail.
Highlights
The human endocannabinoid system (ECS), which includes the cannabinoid receptors, endocannabinoids, and their metabolizing enzymes, has been considered as a pharmacological target for the treatment of various cancer types including multiple myeloma
Two major cannabinoids extracted from Cannabis sativa plant, called phytocannabinoids, (-)delta9-tetrahydrocannabinol (THC) [1] and cannabidiol (CBD) [2] which bind to cannabinoid receptors, are the most researched compounds and have been recently used for the treatment of cancer for their palliative effects like the treatment of pain and inhibition of vomiting associated with chemotherapy and as antitumor drugs based on their potential antitumor activity
It has been demonstrated that cannabinoids can induce a selective apoptosis in MM cell lines and plasma cell (PC) of MM patients which was mediated by caspase activation, mainly caspase-2, without harming normal cells and that blockage of the cannabinoid receptor 2 (CB2) inhibited cannabinoid-induced apoptosis [13]
Summary
The human endocannabinoid system (ECS), which includes the cannabinoid receptors, endocannabinoids, and their metabolizing enzymes, has been considered as a pharmacological target for the treatment of various cancer types including multiple myeloma. CBD can interact with other molecular targets like vanilloid receptors (e.g., the transient receptor potential vanilloid type-1 and 2 TRPV1-2) [7], G protein-coupled receptor 55 (GPR55) [8], and peroxisome proliferator-activated receptor gamma (PPARgamma) [9]. It is of particular interest since it is not psychoactive but has significant relaxing, anti-inflammatory, pain-relieving, and immunomodulatory properties [10,11]. The mechanism of CIK-associated tumor cytotoxicity has not been fully elucidated yet, including the efficiency of combining CIK and cannabidiol on tumor cells
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