Cannabidiol inhibits RAD51 and sensitizes glioblastoma to temozolomide in multiple orthotopic tumor models

Abstract

Background Cannabidiol (CBD), a non-psychoactive cannabinoid with a low toxicity profile, has been shown to produce antitumor activity across cancers in part through selective production of reactive oxygen species (ROS) in tumor cells. The alkylating agent, temozolomide (TMZ), is standard of care for treatment of glioblastoma (GBM). It can trigger increased ROS to induce DNA damage. It has also been reported that down-regulating the expression of RAD51, an important DNA damage repair protein, leads to sensitization of glioblastoma to TMZ. Methods We determined the extent to which CBD enhanced the antitumor activity of TMZ in multiple orthotopic models of glioblastoma. In addition, we investigated the potential for CBD to enhance the antitumor activity of TMZ through production of ROS and modulation of DNA repair pathways. Results CBD enhanced the activity of TMZ in U87 MG and U251 GBM cell lines and in patient-derived primary GBM163 cells leading to stimulation of ROS, activation of the ROS sensor AMPK, and upregulation of the autophagy marker LC3A. CBD produced a sensitization of U87 and GBM163-derived intracranial (i.c.) tumors to TMZ and significantly increased survival of tumor-bearing mice. However, these effects were not observed in orthotopic models derived from GBM with intact methylguanine methyltransferase (MGMT) expression. We further demonstrate that CBD inhibited RAD51 expression in MGMT-methylated models of GBM, providing a potential mechanism for tumor sensitization to TMZ by CBD. Conclusion These data support the potential therapeutic benefits of using CBD to enhance the antitumor activity of TMZ in GBM patients.

Integrative rare disease biomedical profile based network supporting drug repurposing or repositioning, a case study of glioblastoma

“…[ 62 ] Cannabidiol, another ALS treatment, sensitizes GBM to TMZ in multiple orthotopic tumor models. [ 63 ] Inhalant cannabidiol has also been shown to inhibit the progression of GBM through regulation of the tumor environment. [ 64 ] Finally, stem cell therapy has shown potential for treating neuron and glial cell damage in the brain or spinal cord that results from neurological conditions such as GBM.…”

Surprising Long Term Survival in Glioblastoma Patients Treated with Cannabidiol

“…CBD enhanced also p53-mediated induction of apoptosis [8]. In combination with TMZ, the activity against GBM cell lines was improved in vitro, and the survival of tumor-bearing mice was prolonged, possibly via inhibition of the expression of RAD51, a DNA repair protein in MGMT-metylated tumors [10]. Moreover, CBD is able to modify DNA methylation in the brain by regulating the activity of the respective enzymes [11][12][13].…”

New Avenues and Major Achievements in Phytocompounds Research for Glioblastoma Therapy

“…Not only ∆9-THC, but also CBD has been evaluated in clinical trials in the context of GBM treatment. The molecular mechanisms responsible for the anti-tumor effect exerted by CBD include, among others, targeting glioma stem cells and cancer-related signaling pathways [107,108], influencing the tumor microenvironment (TME) [109], and producing reactive oxygen species (ROS) in tumor cells [110]. Overall, numerous in vitro and in vivo studies showing beneficial effects of CBD against GBM cells (just to mention a few most recent studies [107,[109][110][111][112]) paved the way for clinical trials evaluating the impact of this cannabinoid on humans.…”