The Novel Antitumor Compound HCA Promotes Glioma Cell Death by Inducing Endoplasmic Reticulum Stress and Autophagy

SIMPLE SUMMARY: Melitherapy is an innovative therapeutic approach to treat different diseases, including cancer, and it is based on the regulation of cell membrane composition and structure, which modulates relevant signal pathways. In this context, 2-hydroxycervonic acid (HCA) was designed for patients with cancer or other pathologies who have received ineffective and safe treatment. Here, we have tested the effects of HCA on glioblastoma cells and xenograft tumors (mice). HCA appeared to enhance endoplasmic reticulum stress/unfolded protein response signaling, which consequently induced autophagic cell death of the glioblastoma tumor cells. In light of the data obtained, it would clearly be worthwhile to undertake more clinically orientated studies to fully assess the potential of HCA to combat glioblastoma in patients. ABSTRACT: Glioblastoma (GBM) is the most common and aggressive type of primary brain tumor in adults, and the median survival of patients with GBM is 14.5 months. Melitherapy is an innovative therapeutic approach to treat different diseases, including cancer, and it is based on the regulation of cell membrane composition and structure, which modulates relevant signal pathways. Here, we have tested the effects of 2-hydroxycervonic acid (HCA) on GBM cells and xenograft tumors. HCA was taken up by cells and it compromised the survival of several human GBM cell lines in vitro, as well as the in vivo growth of xenograft tumors (mice) derived from these cells. HCA appeared to enhance ER stress/UPR signaling, which consequently induced autophagic cell death of the GBM tumor cells. This negative effect of HCA on GBM cells may be mediated by the JNK/c-Jun/CHOP/BiP axis, and it also seems to be provoked by the cellular metabolite of HCA, C21:5n-3 (heneicosapentaenoic acid). These results demonstrate the efficacy of the melitherapeutic treatment used and the potential of using C21:5n-3 as an efficacy biomarker for this treatment. Given the safety profile in animal models, the data presented here provide evidence that HCA warrants further clinical study as a potential therapy for GBM, currently an important unmet medical need.