New Biocompatible ß-Phosphorylated Linear Nitrones Targeting Mitochondria: Protective Effect in Apoptotic Cells.

The mitochondrion, an essential organelle involved in cellular respiration, energy production, and cell death, is the main cellular source of reactive oxygen species (ROS), including superoxide. Mitochondrial diseases resulting from uncontrolled/excess ROS generation are an emerging public health concern and there is current interest in specific mitochondriotropic probes to get information on in-situ ROS production. As such, nitrones vectorized by the triphenylphosphonium (TPP) cation have recently drawn attention despite reported cytotoxicity. Herein, we describe the synthesis of 13 low-toxic derivatives of N-benzylidene-1-diethoxyphosphoryl-1-methylethylamine N-oxide (PPN) alkyl chain-grafted to a pyridinium, triethylammonium or berberinium lipophilic cation. These nitrones showed in-vitro superoxide quenching activity and EPR/spin-trapping efficiency towards biologically relevant free radicals, including superoxide and hydroxyl radicals. Their mitochondrial penetration was confirmed by 31 P NMR spectroscopy, and their anti-apoptotic properties were assessed in Schwann cells treated with hydrogen peroxide. Two pyridinium-substituted PPNs were identified as potentially better alternatives to TPP nitrones conjugates for studying mitochondrial oxidative damage.

Inhibitor of Apoptosis Proteins Determines Glioblastoma Stem-Like Cell Fate in an Oxygen-Dependent Manner.

In glioblastomas, apoptosis inhibitor proteins (IAPs) are involved in apoptotic and nonapoptotic processes. We previously showed that IAP inhibition induced a loss of stemness and glioblastoma stem cells differentiation by activating nuclear factor-κB under normoxic conditions. Hypoxia has been shown to modulate drug efficacy. Here, we investigated how IAPs participate in glioblastoma stem-like cell maintenance and fate under hypoxia. We showed that in a hypoxic environment, IAPs inhibition by GDC-0152, a small-molecule IAPs inhibitor, triggered stem-like cell apoptosis and decreased proliferation in four human glioblastoma cell lines. We set up a three-dimensional glioblastoma spheroid model in which time-of-flight secondary ion mass spectrometry analyses revealed a decrease in oxygen levels between the periphery and core. We observed low proliferative and apoptotic cells located close to the hypoxic core of the spheres and glial fibrillary acidic protein+ cells at their periphery. These oxygen-dependent GDC-0152 antitumoral effects have been confirmed on human glioblastoma explants. Notably, serine-threonine kinase activation analysis revealed that under hypoxic conditions, IAP inhibition activated ataxia telangiectasia and Rad3-related protein signaling. Our findings provide new insights into the dual mechanism of action of IAP inhibitors that depends on oxygen level and are relevant to their therapeutic application in tumors. Stem Cells 2019;37:731-742.

Gemcitabine: An Alternative Treatment for Oxaliplatin-Resistant Colorectal Cancer.

Resistance to treatments is one of the leading causes of cancer therapy failure. Oxaliplatin is a standard chemotherapy used to treat metastatic colorectal cancer. However, its efficacy is greatly reduced by the development of resistances. In a previous study, we deciphered the mechanisms leading to oxaliplatin resistance and highlighted the roles played by ROS production and the p38 MAPK pathway in this phenomenon. In this report, we studied the effects of different chemotherapy molecules on our oxaliplatin-resistant cells to identify alternative treatments. Among all the studied molecules, gemcitabine was the only one to present a major cytotoxic effect on oxaliplatin-resistant cancer cells both in vivo and in vitro. However, the combination of oxaliplatin and gemcitabine did not present any major interest. Indeed, the study of combination efficiency using Chou and Talalay's method showed no synergy between oxaliplatin and gemcitabine. Using PamGene technology to decipher gemcitabine's effects on oxaliplatin-resistant cells, we were able to show that gemcitabine counteracts chemoresistance by strongly inhibiting the Akt and src/p38 MAPK pathways, leading to apoptosis induction and cell death. In view of these results, gemcitabine could be an interesting alternative therapy for patients with colorectal cancer not responding to oxaliplatin-based protocols such as FOLFOX.

Emerging biomarkers for neoadjuvant immune checkpoint inhibitors in operable non-small cell lung cancer.

The advent of immune checkpoint inhibitors (ICIs) has dramatically changed the treatment of patients with locally advanced unresectable and metastatic non-small cell lung cancer (NSCLC). Now, ICIs are undergoing evaluation as neoadjuvant therapy in patients with early-stage, resectable NSCLC using candidate surrogate endpoints of clinical efficacy, i.e., major pathologic response (MPR, ≤10% viable tumor cells in resected tumors). The initial results from early, small-scale trials are encouraging; however, they also reveal that a substantial number of patients with operable disease may not benefit from neoadjuvant ICIs. Consequently, much investigative effort is currently directed toward identifying mechanisms of resistance to ICI therapy in resectable NSCLC. There is also an urgent need for biomarkers that could be used to guide the clinical decision-making process and maximize the clinical benefit of ICIs in patients with early-stage, resectable NSCLC. Here, we summarize the initial results from the trials of neoadjuvant ICIs in patients with early-stage and locally advanced operable NSCLC and review the findings of studies investigating emerging biomarkers associated with those trials.

The NADPH Oxidase Family and Its Inhibitors.

Significance: The oxidative stress, resulting from an imbalance in the production and scavenging of reactive oxygen species (ROS), is known to be involved in the development and progression of several pathologies. The excess of ROS production is often due to an overactivation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) and for this reason these enzymes became promising therapeutic targets. However, even if NOX are now well characterized, the development of new therapies is limited by the lack of highly isoform-specific inhibitors. Recent Advances: In the past decade, several groups and laboratories have screened thousands of molecules to identify new specific inhibitors with low off-target effects. These works have led to the characterization of several new potent NOX inhibitors; however, their specificity varies a lot depending on the molecules. Critical Issues: Here, we are reviewing more than 25 known NOX inhibitors, focusing mainly on the newly identified ones such as APX-115, NOS31, Phox-I1 and 2, GLX7013114, and GSK2795039. To have a better overall view of these molecules, the inhibitors were classified according to their specificity, from pan-NOX inhibitors to highly isoform-specific ones. We are also presenting the use of these compounds both in vitro and in vivo. Future Directions: Several of these new molecules are potent and very specific inhibitors that could be good candidates for the development of new drugs. Even if the results are very promising, most of these compounds were only validated in vitro or in mice models and further investigations will be required before using them as potential therapies.

Pan Aurora Kinase Inhibitor: A Promising Targeted-Therapy in Dedifferentiated Liposarcomas With Differential Efficiency Depending on Sarcoma Molecular Profile.

Soft tissue sarcoma (STS) are rare and aggressive tumours. Their classification includes numerous histological subtypes of frequent poor prognosis. Liposarcomas (LPS) are the most frequent type among them, and the aggressiveness and deep localization of dedifferentiated LPS are linked to high levels of recurrence. Current treatments available today lead to five-year overall survival has remained stuck around 60%-70% for the past three decades. Here, we highlight a correlation between Aurora kinasa A (AURKA) and AURKB mRNA overexpression and a low metastasis - free survival. AURKA and AURKB expression analysis at genomic and protein level on a 9-STS cell lines panel highlighted STS heterogeneity, especially in LPS subtype. AURKA and AURKB inhibition by RNAi and drug targeting with AMG 900, a pan Aurora Kinase inhibitor, in four LPS cell lines reduces cell survival and clonogenic proliferation, inducing apoptosis and polyploidy. When combined with doxorubicin, the standard treatment in STS, aurora kinases inhibitor can be considered as an enhancer of standard treatment or as an independent drug. Kinome analysis suggested its effect was linked to the inhibition of the MAP-kinase pathway, with differential drug resistance profiles depending on molecular characteristics of the tumor. Aurora Kinase inhibition by AMG 900 could be a promising therapy in STS.

Correction: Reversion of resistance to oxaliplatin by inhibition of p38 MAPK in colorectal cancer cell lines: involvement of the calpain / Nox1 pathway.

[This corrects the article DOI: 10.18632/oncotarget.21780.].

Reversion of resistance to oxaliplatin by inhibition of p38 MAPK in colorectal cancer cell lines: involvement of the calpain / Nox1 pathway.

Oxaliplatin is a major treatment for metastatic colorectal cancer, however its effectiveness is greatly diminished by the development of resistances. Our previous work has shown that oxaliplatin efficacy depends on the reactive oxygen species (ROS) produced by Nox1. In this report, we investigated Nox1 involvement in the survival mechanisms of oxaliplatin resistant cell lines that we have selected. Our results show that basal ROS production by Nox1 is increased in resistant cells. Whereas the transitory Nox1-dependent production of superoxide contributes to the cytotoxicity of oxaliplatin in sensitive cells, oxaliplatin treatment of resistant cells leads to a decrease in the production of superoxide associated with an increase of H2O2 and a decreased cytotoxicity of oxaliplatin. We have shown that calpains regulate differently Nox1 according to the sensitivity of the cells to oxaliplatin. In sensitive cells, calpains inhibit Nox1 by cleaving NoxA1 leading to a transient ROS production necessary for oxaliplatin cytotoxic effects. In contrast, in resistant cells calpain activation is associated with an increase of Nox1 activity through Src kinases, inducing a strong and maintained ROS production responsible for cell survival. Using a kinomic study we have shown that this overactivation of Nox1 results in an increase of p38 MAPK activity allowing the resistant cells to escape apoptosis. Our results show that the modulation of Nox1 activity in the context of anticancer treatment remains complex. However, a strategy to maximize Nox1 activation while inhibiting the p38 MAPK-dependent escape routes appears to be an option of choice to optimize oxaliplatin efficiency.