Next-generation proteasome inhibitor oprozomib synergizes with modulators of the unfolded protein response to suppress hepatocellular carcinoma

Hepatocellular carcinoma (HCC) responds poorly to conventional systemic therapies. The first-in-class proteasome inhibitor bortezomib has been approved in clinical use for hematologic malignancies and has shown modest activity in solid tumors, including HCC. However, a considerable proportion of patients fail to respond and experience important adverse events. Recently, the next-generation orally bioavailable irreversible proteasome inhibitor oprozomib was developed. Here, we assessed the efficacy of oprozomib and its effects on the unfolded protein response (UPR), a signaling cascade activated through the ATF6, PERK and IRE1 pathways by accumulation of unfolded proteins in the endoplasmic reticulum, in HCC. The effects of oprozomib and the role of the UPR were evaluated in HCC cell lines and in diethylnitrosamine-induced and xenograft mouse models for HCC. Oprozomib dose-dependently reduced the viability and proliferation of human HCC cells. Unexpectedly, oprozomib-treated cells displayed diminished cytoprotective ATF6-mediated signal transduction as well as unaltered PERK and IRE1 signaling. However, oprozomib increased pro-apoptotic UPR-mediated protein levels by prolonging their half-life, implying that the proteasome acts as a negative UPR regulator. Supplementary boosting of UPR activity synergistically improved the sensitivity to oprozomib via the PERK pathway. Oral oprozomib displayed significant antitumor effects in the orthotopic and xenograft models for HCC, and importantly, combining oprozomib with different UPR activators enhanced the antitumor efficacy by stimulating UPR-induced apoptosis without cumulative toxicity. In conclusion, next-generation proteasome inhibition by oprozomib results in dysregulated UPR activation in HCC. This finding can be exploited to enhance the antitumor efficacy by combining oprozomib with clinically applicable UPR activators

Differential Biological Effects of Dietary Lipids and Irradiation on the Aorta, Aortic Valve, and the Mitral Valve

peer reviewedAimsDietary cholesterol and palmitic acid are risk factors for cardiovascular diseases (CVDs) affecting the arteries and the heart valves. The ionizing radiation that is frequently used as an anticancer treatment promotes CVD. The specific pathophysiology of these distinct disease manifestations is poorly understood. We, therefore, studied the biological effects of these dietary lipids and their cardiac irradiation on the arteries and the heart valves in the rabbit models of CVD.Methods and ResultsCholesterol-enriched diet led to the thickening of the aortic wall and the aortic valve leaflets, immune cell infiltration in the aorta, mitral and aortic valves, as well as aortic valve calcification. Numerous cells expressing α-smooth muscle actin were detected in both the mitral and aortic valves. Lard-enriched diet induced massive aorta and aortic valve calcification, with no detectable immune cell infiltration. The addition of cardiac irradiation to the cholesterol diet yielded more calcification and more immune cell infiltrates in the atheroma and the aortic valve than cholesterol alone. RNA sequencing (RNAseq) analyses of aorta and heart valves revealed that a cholesterol-enriched diet mainly triggered inflammation-related biological processes in the aorta, aortic and mitral valves, which was further enhanced by cardiac irradiation. Lard-enriched diet rather affected calcification- and muscle-related processes in the aorta and aortic valve, respectively. Neutrophil count and systemic levels of platelet factor 4 and ent-8-iso-15(S)-PGF2α were identified as early biomarkers of cholesterol-induced tissue alterations, while cardiac irradiation resulted in elevated levels of circulating nucleosomes.ConclusionDietary cholesterol, palmitic acid, and cardiac irradiation combined with a cholesterol-rich diet led to the development of distinct vascular and valvular lesions and changes in the circulating biomarkers. Hence, our study highlights unprecedented specificities related to common risk factors that underlie CVD

Innovations technologiques en radiothérapie-oncologie

peer reviewedInnovatIve technologIes In radIatIon oncology SUMMARY : At present, radiation oncology is again flourishing thanks to the development of highly accurate techniques as intensity modulated radiation therapy, stereotactic radiation therapy and hadrontherapy. These therapeutic modalities are made possible by the advent of image guided radiation therapy and respiratory gating that allows a better patient repositioning during the irradiation and between fractions. Nowadays, thanks to these recent technological advances, one can more easily conceive dose escalation, hypofractionation and combined treatment of radiation with sensitizing drugs and this together with a better protection of normal tissue aiming at, simultaneously, improved tumour control and better quality of life. This article describes these innovative technologies that, when integrated to other anti-tumoral therapeutic modalities, seem to be very promising. Keywords : -RÉSUMÉ : La radiothérapie connaît actuellement un nouvel essor grâce au développement de techniques de haute précision telles que la radiothérapie par modulation d’intensité, la radiothérapie stéréotaxique et l’hadronthérapie. Ces modalités thérapeutiques sont rendues possibles par l’avènement de traitements guidés par l’image et par l’asservissement respiratoire qui permettent d’assurer un meilleur contrôle sur le positionnement du patient et celui de la tumeur au cours de l’irradiation et d’une séance de traitement à l’autre. Grâce à ces avancées technologiques, on est à même de proposer une escalade de dose, des doses par fraction plus élevées (traitement accéléré hypofractionné), des associations radiothérapie et radiosensibilisateurs et, simultanément, une protection des tissus sains dans le but non seulement d’améliorer le contrôle tumoral, mais aussi de préserver la qualité de vie des patients. Cette revue décrit ces technologies innovantes qui, intégrées aux autres modalités thérapeutiques anti-tumorales, semblent très prometteuses

Accélération de l'irradiation partielle du sein: state of the art état de l'art

Accélération irradiation partielle du sein peuvent être appliquées au moyen de différentes techniques. It Il offers an opportunity for reducing the treatment duration considerably and harbours the offre une opportunité pour réduire considérablement la durée du traitement et les ports de la potential for less exposure of healthy tissue to higher radiation doses. potentiel de moins d'exposition des tissus sains à des doses de rayonnement supérieures. However, evidence Toutefois, les preuves issued from randomized trials is limited. émis par des essais randomisés est limité. European and American experts call our attention Des experts européens et américains appellent notre attention to the potential dangers of widespread implementation of these techniques without any aux dangers potentiels de la mise en œuvre généralisée de ces techniques sans aucune long-term data on outcome and ask for complete information of patients on the potential données à long terme sur les résultats et demande des informations complètes sur les patients sur le potentiel hazards and risks if accelerated partial breast irradiation is used instead of whole breast dangers et des risques, si l'accélération irradiation partielle du sein est utilisé au lieu du sein au complet irradiation. l'irradiationAccelerated partial breast irradiation can be applied by means of different techniques. It offers an opportunity for reducing the treatment duration considerably and harbours the potential for less exposure of healthy tissue to higher radiation doses. However, evidence issued from randomized trials is limited. European and American experts call our attention to the potential dangers of widespread implementation of these techniques without any long-term data on outcome and ask for complete information of patients on the potential hazards and risks if accelerated partial breast irradiation is used instead of whole breast irradiation