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

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Gurley, SN; Abidi, AH; Allison, P; Guan, P; Duntsch, C; Robertson, JH; Kosanke, SD; Keir, ST; Bigner, DD; Elberger, AJ; Moore, BM

Published Date

  • November 2012

Published In

Volume / Issue

  • 110 / 2

Start / End Page

  • 163 - 177

PubMed ID

  • 22875710

Electronic International Standard Serial Number (EISSN)

  • 1573-7373

Digital Object Identifier (DOI)

  • 10.1007/s11060-012-0958-5

Language

  • eng

Conference Location

  • United States