Abstract
T-Acute Lymphoblastic Leukemia (T-ALL) is less frequent than B-ALL, but it has poorer outcome. For this reason new therapeutic approaches are needed to treat this malignancy.The Endocannabinoid/Endovanilloid (EC/EV) system has been proposed as possible target to treat several malignancies, including lymphoblastic diseases. The EC/EV system is composed of two G-Protein Coupled Receptors (CB1 and CB2), the Transient Potential Vanilloid 1 (TRPV1) channel, their endogenous and exogenous ligands and enzymes. CB1 is expressed mainly in central nervous system while CB2 predominantly on immune and peripheral cells, therefore we chose to selectively stimulate CB2 and TRPV1.We treated T-ALL lymphoblasts derived from 4 patients and Jurkat cells with a selective agonist at CB2 receptor: JWH-133 [100 nM] and an agonist at TRPV1 calcium channel: RTX [5 uM] at 6, 12 and 24 hours. We analyzed the effect on apoptosis and Cell Cycle Progression by a cytofluorimetric assays and evaluated the expression level of several target genes (Caspase 3, Bax, Bcl-2, AKT, ERK, PTEN, Notch-1, CDK2, p53) involved in cell survival and apoptosis, by Real-Time PCR and Western Blotting.We observed a pro-apoptotic, anti-proliferative effect of these compounds in both primary lymphoblasts obtained from patients with T-ALL and in Jurkat cell line. Our results show that both CB2 stimulation and TRPV1 activation, can increase the apoptosis in vitro, interfere with cell cycle progression and reduce cell proliferation, indicating that a new therapeutic approach to T-cell ALL might be possible by modulating CB2 and TRPV1 receptors.
Highlights
Leukemias encompass 30% of all pediatric cancers, and acute lymphoblastic leukemia (ALL) is the most common leukemia in the pediatric population; it comprises 75% of all pediatric leukemia cases [1, 2]
Cannabinoids have been shown to induce apoptosis in human leukemia and lymphoma cell lines via cannabinoid receptor type 2 (CB2), the cannabinoid receptor normally expressed in the immune system [14,15,16, 33, 34]
Transient Potential Vanilloid 1 (TRPV1) has been found to be functionally expressed in CD4+ T cells and it contributes to T cell receptor (TCR)-induced Ca2+ channel influx [35]
Summary
Leukemias encompass 30% of all pediatric cancers, and acute lymphoblastic leukemia (ALL) is the most common leukemia in the pediatric population; it comprises 75% of all pediatric leukemia cases [1, 2]. Children with T-ALL tend to experience more induction failures and extramedullary relapses www.oncotarget.com than their B-ALL counterparts and frequently present with unfavorable clinical features, such as male gender, older age, high white blood cell count (WBC), bulky extramedullary disease, and CNS involvement [8, 9]. Intracellular calcium overload mediate cell apoptosis through different mechanism interfering with cell energy production and metabolism, drugs acting on the TRPV receptors, potentially can act as target to reduce cell proliferation and survival in cancer [22, 23]. Cannabinoid receptors have been shown to modulate several signaling pathways involved in the control of cell proliferation and survival [28,29,30,31]. We have recently demonstrated an anti-proliferative, pro-apoptotic and anti-invasive effect induced by EC/EV compounds in human osteosarcoma [32]
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