Targeting Glioma Initiating Cells with A combined therapy of cannabinoids and temozolomide

Abstract

Glioblastoma multiforme (GBM) is the most frequent and aggressive type of brain tumor due, at least in part, to its poor response to current anticancer treatments. These features could be explained, at least partially, by the presence within the tumor mass of a small population of cells termed Glioma Initiating Cells (GICs) that has been proposed to be responsible for the relapses occurring in this disease. Thus, the development of novel therapeutic approaches (and specifically those targeting the population of GICs) is urgently needed to improve the survival of the patients suffering this devastating disease. Previous observations by our group and others have shown that Δ-Tetrahydrocannabinol (THC, the main active ingredient of marijuana) and other cannabinoids including cannabidiol (CBD) exert antitumoral actions in several animal models of cancer, including gliomas. We also found that the administration of THC (or of THC + CBD at a 1:1 ratio) in combination with temozolomide (TMZ), the benchmark agent for the treatment of GBM, synergistically reduces the growth of glioma xenografts. In this work we investigated the effect of the combination of TMZ and THC:CBD mixtures containing different ratios of the two cannabinoids in preclinical glioma models, including those derived from GICs. Our findings show that TMZ + THC:CBD combinations containing a higher proportion of CDB (but not TMZ + CBD alone) produce a similar antitumoral effect as the administration of TMZ together with THC and CBD at a 1:1 ratio in xenografts generated with glioma cell lines. In addition, we also found that the administration of TMZ + THC:CBD at a 1:1 ratio reduced the growth of orthotopic xenografts generated with GICs derived from GBM patients and enhanced the survival of the animals bearing these intracranial xenografts. Remarkably, the antitumoral effect observed in GICs-derived xenografts was stronger when TMZ was administered together with cannabinoid combinations containing a higher proportion of CBD. These findings support the notion that the administration of TMZ together with THC:CBD combinations - and specifically those containing a higher proportion of CBD - may be therapeutically explored to target the population of GICs in GBM.

Peptidylarginine Deiminase Isozyme-Specific PAD2, PAD3 and PAD4 Inhibitors Differentially Modulate Extracellular Vesicle Signatures and Cell Invasion in Two Glioblastoma Multiforme Cell Lines

“…In LN229 cell-derived EVs, only PAD3 inhibitor significantly increased relative levels of miR126 while PAD2 and PAD4 inhibitors slightly (but significantly) decreased miR126; therefore, only PAD3 inhibitor achieved the "protective" anti-oncogenic response by elevating relative levels of miR126 in LN229 cell-derived EVs. Interestingly, cannabidiol, which is effective in GBM treatment [78,79] and was also recently identified as an potent EV modulatory agent [37,38], has also been found to elevate miR126 and reduce miR21 EV-cargos from LN18 and LN229 cells, possibly explaining some of its protective functions in GBM [37]. miR210 has previously been identified as a major miR induced under hypoxia and has important roles in mitochondrial metabolism, DNA damage response, cell proliferation and apoptosis [80].…”

The Endocannabinoid System: A Target for Cancer Treatment

“…This highlights the need for new therapeutic strategies. In the last few years, CBs, and in particular ∆9-THC and CBD, have exhibited anticancer activity in preclinical models of cancer and specifically in glioma [108]. The CB1 receptor is expressed mainly in the brain at very high levels in the basal ganglia, hippocampus, cerebellum, and cortex.…”

Cannabinoid Combination Induces Cytoplasmic Vacuolation in MCF-7 Breast Cancer Cells

“…These properties have gained traction in the cancer field, since the activation of cannabinoid receptor can be exploited to influence several hallmarks of tumor progression. The anti-cancer effects of phytocannabinoids have been observed in several cancer types, including gliomas and carcinomas of the skin, liver, colon, prostate, and breast [ 8 , 9 , 10 , 11 , 12 ]. Breast cancer is particularly difficult to treat due to its heterogeneity [ 13 ].…”