A combined preclinical therapy of cannabinoids and temozolomide against glioma

• Published in: Molecular cancer therapeutics Vol. 10; no. 1; pp. 90 - 103
• Main Authors: Torres, Sofía, Lorente, Mar, Rodríguez-Fornés, Fátima, Hernández-Tiedra, Sonia, Salazar, María, García-Taboada, Elena, Barcia, Juan, Guzmán, Manuel, Velasco, Guillermo
• Format: Journal Article
• Language: English
• Published: United States 01.01.2011
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Autophagy - drug effects; Brain Neoplasms - drug therapy; Brain Neoplasms - pathology; Cell Growth Processes - drug effects; Cell Line, Tumor; Cell Survival - drug effects; Dacarbazine - administration & dosage; Dacarbazine - analogs & derivatives; Dacarbazine - pharmacology; Dronabinol - administration & dosage; Dronabinol - pharmacology; Drug Resistance, Neoplasm; Drug Synergism; Glioblastoma - drug therapy; Glioblastoma - pathology; Humans; Mice; Mice, Nude; Random Allocation; Transfection; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.mct-10-0688

Glioblastoma multiforme (GBM) is highly resistant to current anticancer treatments, which makes it crucial to find new therapeutic strategies aimed at improving the poor prognosis of patients suffering from this disease. Δ(9)-Tetrahydrocannabinol (THC), the major active ingredient of marijuana, and other cannabinoid receptor agonists inhibit tumor growth in animal models of cancer, including glioma, an effect that relies, at least in part, on the stimulation of autophagy-mediated apoptosis in tumor cells. Here, we show that the combined administration of THC and temozolomide (TMZ; the benchmark agent for the management of GBM) exerts a strong antitumoral action in glioma xenografts, an effect that is also observed in tumors that are resistant to TMZ treatment. Combined administration of THC and TMZ enhanced autophagy, whereas pharmacologic or genetic inhibition of this process prevented TMZ + THC-induced cell death, supporting that activation of autophagy plays a crucial role on the mechanism of action of this drug combination. Administration of submaximal doses of THC and cannabidiol (CBD; another plant-derived cannabinoid that also induces glioma cell death through a mechanism of action different from that of THC) remarkably reduces the growth of glioma xenografts. Moreover, treatment with TMZ and submaximal doses of THC and CBD produced a strong antitumoral action in both TMZ-sensitive and TMZ-resistant tumors. Altogether, our findings support that the combined administration of TMZ and cannabinoids could be therapeutically exploited for the management of GBM.