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

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.

HCA (2-Hydroxy-Docosahexaenoic Acid) Induces Apoptosis and Endoplasmic Reticulum Stress in Pancreatic Cancer Cells

“…During these experiments none of the mice lost more than 10% of their body weight (data not shown), and the oral administration of HCA was well tolerated. Indeed, HCA had been seen not to produce any toxicity in mice in earlier studies at studied doses [ 11 , 12 , 13 , 14 ].…”

“…Previous studies observed that HCA activated ER/UPR stress signaling pathways in glioma cells [ 11 ]. Since RE/UPR stress can trigger cell death, key proteins were studied.…”

“…Although our results point out to a different mechanism of action for the metabolite than the parent molecule as an antitumoral drug in pancreatic cancer cells, C21:5n-3 is still the main metabolite of HCA, and its presence can be detected in both cells and animals after HCA administration [ 11 , 30 ]. In that context, its safety was assessed following the Irwin test.…”

“…Epidemiological studies have shown that a high intake of fish oil or ω3 polyunsaturated fatty acids (e.g., DHA) reduces the risk of pancreatic cancers, and that DHA has anti-tumorigenic properties in this type of cancer, although no long-term clinical studies are currently available [ 10 ]. HCA is an anti-tumor compound that promotes glioma cell death by inducing endoplasmic reticulum (ER) stress and autophagy [ 11 ] and also presents pharmacological safety previously demonstrated in zebrafish, Drosophila melanogaster , and mice [ 12 , 13 , 14 ].…”

A Face-To-Face Comparison of Tumor Chicken Chorioallantoic Membrane (TCAM) In Ovo with Murine Models for Early Evaluation of Cancer Therapy and Early Drug Toxicity

“…Indeed, we did not observe a therapeutic effect of cisplatin in the resistant PC-9 cell line lung tumor model xenograft in TCAM or in mouse ( Figure 3 ). Moreover, we demonstrated, through the U118MG GBM cell line described to be poorly responsive to TMZ in the mouse xenograft model [ 54 ], that TMZ induced tumor reduction in both mouse and TCAM models with a similar tumor growth inhibition pattern ( Figure 3 ). Thus, the TCAM might represent an interesting alternative to murine models in order to decipher drug resistance [ 18 ].…”