The antitumour drug ABTL0812 impairs neuroblastoma growth through endoplasmic reticulum stress-mediated autophagy and apoptosis

Abstract

Neuroblastoma is the leading cause of cancer death in children aged 1 to 4 years. Particularly, five-year overall survival for high-risk neuroblastoma is below 50% with no curative options when refractory or relapsed. Most of current therapies target cell division and proliferation, thereby inducing DNA damage and programmed cell death. However, aggressive tumours often present alterations of these processes and are resistant to therapy. Therefore, exploring alternative pathways to induce tumour cell death will provide new therapeutic opportunities for these patients. In this study we aimed at testing the therapeutic potential of ABTL0812, a novel anticancer drug that induces cytotoxic autophagy to eliminate cancer cells, which is currently in phase II clinical trials of adult tumours. Here, we show that ABTL0812 impaired the viability of clinical representative neuroblastoma cell lines regardless of genetic alterations associated to bad prognosis and resistance to therapy. Oral administration of ABTL0812 to mice bearing neuroblastoma xenografts impaired tumour growth. Furthermore, our findings revealed that, in neuroblastoma, ABTL0812 induced cancer cell death via induction of endoplasmic reticulum stress, activation of the unfolded protein response, autophagy and apoptosis. Remarkably, ABTL0812 potentiated the antitumour activity of chemotherapies and differentiating agents such as irinotecan and 13-cis-retinoic acid. In conclusion, ABTL0812 distinctive mechanism of action makes it standout to be used alone or in combination in high-risk neuroblastoma patients.

ABTL0812 enhances antitumor effect of paclitaxel and reverts chemoresistance in triple‐negative breast cancer models

“…Therefore, the aggressiveness and poor prognosis of TNBC call for new and more effective therapies.ABTL0812 is a novel first-in-class anticancer agent. It was initially selected for preclinical development based on its anti-proliferative effect on different human cancer cell lines and its safety profile in animal models as both single therapy and in combination with chemotherapy [4][5][6][7][8]. A first-in-human phase I clinical trial with ABTL0812 was successfully completed, showing a high safety profile and signs of efficacy in patients with advanced solid tumors who had received ABTL0812 orally after several chemotherapy lines (NCT02201823).…”

“…It can induce endoplasmic reticular (ER) stress and inhibit the protein kinase B (Akt)/mechanistic target of rapamycin (mTOR) axis via the overexpression of tribbles homolog 3 (TRIB3). These two actions converge to strongly induce cytotoxic autophagy that can cause cancer cell death, while non‐tumor cells are spared [ 4 , 5 , 6 , 7 , 8 ]. Deregulation of the phosphoinositide 3‐kinase (PI3K)/Akt/mTOR (PAM) signaling pathway is a common oncogenic aberration observed in TNBC that frequently leads to chemoresistance [ 1 ].…”

Oxidative Stress Activated by Sorafenib Alters the Temozolomide Sensitivity of Human Glioma Cells Through Autophagy and JAK2/STAT3-AIF Axis

“…We further confirmed that the autophagy inhibitors 3-MA and CQ moderately reversed the inhibitory effect of the combination of sorafenib and TMZ on the cell apoptosis rate ( Figure 6D ), indicating that the combined therapy induces cell apoptosis through the induction of autophagy. Autophagy and apoptosis can trigger cell death through synergistic action and complementary cooperation ( París-Coderch et al, 2020 ). The proapoptotic effect of autophagy caused by the combined therapy also indicated that autophagy and apoptosis caused by combined therapy had synergistic effects.…”

Lipids in Pathophysiology and Development of the Membrane Lipid Therapy: New Bioactive Lipids

“…Following the rational drug design, C2-hydroxylated fatty acids have been developed to treat several conditions. Examples of advanced clinical development in this regard are 2-hydroxyoleic acid (LAM561), which has shown safety and promising therapeutic activity against glioma and other types of tumor in humans [50,113], and 2-hydroxylinoleic acid (ABTL0812), which has demonstrated safety and efficacy against endometrial and lung cancers [143,144] (reviewed below). On the other hand, another DHA hydroxylated analog with therapeutic properties is 2-hydroxydocosahexaenoic acid (DHA-H), which has been demonstrated to have neuroprotective and neuroregenerative activity, and to be safe and efficacious in mouse models of AD and Parkinson's disease (PD) in preclinical studies (PCS) [114,145] (reviewed below).…”

“…Similarly, 2-hydroxylinoleic acid (ABTL0812) has been demonstrated to be safe and efficacious against endometrial and lung cancers, both in model systems and in clinical trials (NCT02201823, NCT03366480, NCT03417921, NCT04431258), producing specific cancer cell death. Thus, ABTL0812 binding to the membrane inhibits Akt/mTORC1, enhances sphingolipid dihydroceramide activity, provoking ER stress and autophagic cell death without inducing undesired side effects [143,144].…”