Journal of Neuro-Oncology

, Volume 110, Issue 2, pp 163–177 | Cite as

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

  • Steven N. Gurley
  • Ammaar H. Abidi
  • Patrick Allison
  • Peihong Guan
  • Christopher Duntsch
  • Jon H. Robertson
  • Stanley D. Kosanke
  • Stephen T. Keir
  • Darell D. Bigner
  • Andrea J. Elberger
  • Bob M. MooreII
Laboratory Investigation

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.

Keywords

Brain malignancy Cannabinoid Chemotherapeutic Glioma Therapy 

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Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • Steven N. Gurley
    • 1
  • Ammaar H. Abidi
    • 1
  • Patrick Allison
    • 1
  • Peihong Guan
    • 1
  • Christopher Duntsch
    • 2
  • Jon H. Robertson
    • 2
  • Stanley D. Kosanke
    • 3
  • Stephen T. Keir
    • 4
  • Darell D. Bigner
    • 5
  • Andrea J. Elberger
    • 6
  • Bob M. MooreII
    • 1
  1. 1.Department of Pharmaceutical SciencesThe University of Tennessee Health Science CenterMemphisUSA
  2. 2.Department of NeurosurgeryThe University of Tennessee Health Science CenterMemphisUSA
  3. 3.Department of PathologyUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA
  4. 4.Department of SurgeryDuke UniversityDurhamUSA
  5. 5.Department of PathologyDuke UniversityDurhamUSA
  6. 6.Department of Anatomy and NeurobiologyThe University of Tennessee Health Science CenterMemphisUSA

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