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.
journal_name
J Neurooncoljournal_title
Journal of neuro-oncologyauthors
Gurley SN,Abidi AH,Allison P,Guan P,Duntsch C,Robertson JH,Kosanke SD,Keir ST,Bigner DD,Elberger AJ,Moore BM 2nddoi
10.1007/s11060-012-0958-5subject
Has Abstractpub_date
2012-11-01 00:00:00pages
163-77issue
2eissn
0167-594Xissn
1573-7373journal_volume
110pub_type
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journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/BF00182138
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journal_title:Journal of neuro-oncology
pub_type: 临床试验,杂志文章
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journal_title:Journal of neuro-oncology
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pub_type: 临床试验,杂志文章
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journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-017-2442-8
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journal_title:Journal of neuro-oncology
pub_type: 杂志文章
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journal_title:Journal of neuro-oncology
pub_type: 杂志文章,随机对照试验
doi:10.1007/s11060-017-2601-y
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pub_type: 杂志文章,评审
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journal_title:Journal of neuro-oncology
pub_type: 历史文章,杂志文章,评审
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