Mechanism of anti-glioma activity and in vivo efficacy of the cannabinoid ligand KM-233

Abstract

Glioblastoma multiforme (GBM) is the most common and devastating form of primary central nervous system malignancy. The prognosis for patients diagnosed with GBM is poor, having a median survival rate of 12-15 months. Despite modern advances in the development of antineoplastic agents, the efficacy of newer anti-cancer agents in the treatment of GBM is yet to be determined. Thus, there remains a significant unmet need for new therapeutic strategies against GBM. A promising chemotherapeutic intervention has emerged from studies of cannabinoid receptor agonists wherein tetrahydrocannabinol has been the most extensively studied. The novel cannabinoid ligand KM-233 was developed as a lead platform for future optimization of biopharmaceutical properties of classical based cannabinoid ligands. Treatment of U87MG human GBM cells with KM-233 caused a time dependent change in the phosphorylation profiles of MEK, ERK1/2, Akt, BAD, STAT3, and p70S6K. Almost complete mitochondrial depolarization was observed 6 h post-treatment followed by a rapid increase in cleaved caspase 3 and significant cytoskeletal contractions. Treatment with KM-233 also resulted in a redistribution of the Golgi-endoplasmic reticulum structures. Dose escalation studies in the orthotopic model using U87MG cells revealed an 80 % reduction in tumor size after 12 mg/kg daily dosing for 20 days. The evaluation of KM-233 against primary tumor tissue in the side flank model revealed a significant decrease in the rate of tumor growth. These findings indicate that structural refinement of KM-233 to improve its biopharmaceutical properties may lead to a novel and efficacious treatment for GBM.

The influence of biomechanical properties and cannabinoids on tumor invasion

“…Cannabinoids are in general associated with a reduced invasiveness for various tumor types. 17,19,20,25,37 In contrast, one study reported an increased invasiveness after treatment with cannabinoids in a cannabinoid receptor independent way. 38 The experiments conducted for the present study revealed differentiated effects of cannabinoids.…”

“…16 This indicates that the eCB system is part of the (anti)tumor signaling. Most of the studies analyzing the effects of cannabinoids on tumor cells have focused on apoptosis [17][18][19] or cell cycle arrest. 18,20 Changes and disruptions of the cytoskeleton in a quantitative manner and thus mechanical parameters have been investigated only sparsely.…”

Cannabinoids as therapeutic agents in cancer: current status and future implications

“…The submaximal doses of Δ 9 -THC and CBD in combination with TMZ produced a strong antitumoral action in both TMZ-sensitive and TMZ-resistant tumors [108]. Treatment of KM-233 (novel cannabinoid ligand) caused a time dependent change in the phosphorylation profiles of MEK, ERK1/2, Akt, BAD, STAT3, and p70S6K in U87MG human GBM cells [109]. At 12mg/kg daily dose of KM-233 for 20 days revealed around 80% reduction in tumor size in the orthotopic model of U87MG [109].…”

“…Treatment of KM-233 (novel cannabinoid ligand) caused a time dependent change in the phosphorylation profiles of MEK, ERK1/2, Akt, BAD, STAT3, and p70S6K in U87MG human GBM cells [109]. At 12mg/kg daily dose of KM-233 for 20 days revealed around 80% reduction in tumor size in the orthotopic model of U87MG [109]. Glioma cells develop resistance to cannabinoid treatment due to the upregulation of Amphiregulin (EGFR family ligand) and the growth factor midkine (Mdk) [110-111].…”

Synthesis and biological evaluation of (3′,5′-dichloro-2,6-dihydroxy-biphenyl-4-yl)-aryl/alkyl-methanone selective CB2 inverse agonist

“…[1][2][3] Both receptors, either individually or in combination, have been identified as potential targets for intervention of human diseases including neurodegenerative [4][5][6] and cardiovascular disease, 7-9 diabetes, [10][11][12] and cancer. [13][14][15][16] Within this spectrum of diseases, intervention in neurodegenerative disorders using CB2 agonists and inverse agonists is arguably one of the most exciting developments in the cannabinoid field. Specifically, microglia, the resident immune and inflammatory mediators in the central nervous system (CNS), express CB2 in Alzheimer's 17,18 and Parkinson's disease 19 and amyotrophic lateral sclerosis.…”