A Combined Preclinical Therapy of Cannabinoids and Temozolomide against Glioma

Abstract

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. D 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 þ 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. Mol Cancer Ther; 10(1); 90-103. Ó2011 AACR.

Potentiation of the antitumor activity of adriamycin against osteosarcoma by cannabinoid WIN-55,212-2

“…Notably, the present data also demonstrated that the combined administration of ADM and cannabinoid exerted an enhanced antiproliferation effect on MG-63 cells. Similar synergistic effects of drugs were also observed with cannabinoids and TMA against glioblastoma multiforme (22). Cannabinoids have been shown to be devoid of the strong side-effects associated with other chemotherapeutic agents (25,26) and no overt toxic effects of cannabinoids in patients have been reported in clinical trials for various applications (8,27).…”

“…In line with this hypothesis, trials have been conducted to investigate the synergistic antitumor effect of multiple drugs. It has been reported that the combined administration of cannabinoids and temozolomide (TMA) exert a strong antitumor action in glioblastoma multiforme (22). Combinations of thymoquinone and diosgenin have also shown potent antiproliferative and apoptotic effects on squamous cell carcinoma (20).…”

microRNA-17 regulates the expression of ATG7 and modulates the autophagy process, improving the sensitivity to temozolomide and low-dose ionizing radiation treatments in human glioblastoma cells

“…In order to perform in vitro studies to modulate chemotherapy and IR resistance, two different human glioblastoma cell lines were assayed: T98G as TMZ resistant 37 and U373-MG as radioresistant cells. 31 Importantly, many evidences reported that both treatments lead to autophagy activation 34,36,51,52 and that, a further activation of the autophagy process, by means of drugs like rapamycin or cannabinoids, lead to an enhanced sensitization of glioblastoma cells to chemotherapy and IR treatments. 53 We observed that the in vitro combination of miR-17 inhibition and TMZ treatment was highly effective in a relatively long period of cell culture time, further decreasing the threshold resistance at low TMZ doses in T98G cells.…”

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

“…Furthermore, ⌬ 9 -THC promotes autophagy-mediated apoptosis by inducing ceramide accumulation and eukaryotic translation initiation factor 2␣ phosphorylation, thereby activating an ER stress response that promotes autophagy via the tribbles homolog 3-dependent inhibition of the Akt/mammalian target of mTORC1 complex axis in human glioma (768) and in hepatocellular carcinoma (875) cells. Enhancement of autophagy by the combined administration of ⌬ 9 -THC and temozolomide exerts a strong antitumoral action in glioma xenografts (857).…”