title: 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.
authors.affiliation: Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Steven N
authors.initials: SN
authors.lastname: Gurley
authors.forename: Ammaar H
authors.initials: AH
authors.lastname: Abidi
authors.forename: Patrick
authors.initials: P
authors.lastname: Allison
authors.forename: Peihong
authors.initials: P
authors.lastname: Guan
authors.forename: Christopher
authors.initials: C
authors.lastname: Duntsch
authors.forename: Jon H
authors.initials: JH
authors.lastname: Robertson
authors.forename: Stanley D
authors.initials: SD
authors.lastname: Kosanke
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Keir
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Elberger
authors.forename: Bob M
authors.initials: BM
authors.lastname: Moore
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002186:Cannabinoids / Q000627:therapeutic use*; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D010750:Phosphoproteins / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D002186:Cannabinoids; C512823:KM-233; D010750:Phosphoproteins; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D053148:Caspase 3