Cannabinoids suppress chemotherapy- and ionizing radiation-induced apoptosis of glioblastoma cells

Abstract

Abstract Cancer patients are increasingly exposed to cannabinoids, the bioactive molecules produced by the Cannabis sativa La. plant. This trend is being driven by several factors: expanding cannabis legalization, FDA approval of select cannabinoids for the treatment of seizures and cancer therapy–induced toxicities, and prior reports suggesting that cannabinoids may have direct anti-cancer effects. Despite the growing frequency of cannabinoid exposure during cancer treatment, it remains unknown whether cannabinoids influence tumor cell responses to standard anti-cancer therapies. Using multiple glioblastoma multiforme (GBM) cell line models, we found that treatment with a range of cannabinoids including CP-55,940 (a synthetic cannabinoid that mimics the effects of naturally occurring THC), cannabigerovarin (CBGV), cannabichromene (CBC), cannabicyclol (CBL), cannabidiol (CBD) and cannabielsoin (CBE) generally does not affect GBM cell viability, except in a limited number of cases at doses of 20 μM or higher. Strikingly, we instead find that cannabinoid treatment suppresses therapy-induced GBM cell death, including the apoptosis induced by the GBM standard-of-care treatments temozolomide and ionizing radiation. This suppression of therapy-induced apoptosis was also evident in assays of clonal outgrowth following combination treatment. Mechanistically, cannabinoid exposure decreased apoptotic priming and increased expression of the pro-survival protein BCL-X L in U251-MG GBM cells. In addition, cannabinoid treatment shifted the response of U251-MG cells to cancer therapies away from apoptosis and toward G1 cell cycle arrest, in association with induction of p21. Finally, we observed higher rates of apoptosis in immortalized human neural progenitor cells (ReNcells) than in GBM cells at equivalent doses of CBD, suggesting that the relatively high cannabinoid doses required to induce GBM apoptosis may also be toxic to normal neural cells. Overall, these findings raise the possibility that cannabinoids could negatively affect tumor responses to chemotherapy and radiation, underscoring the need to carefully evaluate these effects in future clinical trials.