A phase II, open-label trial of bortezomib (VELCADE®) in combination with gemcitabine and cisplatin in patients with locally advanced or metastatic non-small cell lung cancer

Kontopodis, E.; Κotsakis, Athanasios; Kentepozidis, Nikolaos; Syrigos, Kostas; Ziras, Nikolaos; Moutsos, Michael; Filippa, Georgia; Mala, Anastasia; Vamvakas, L.; Mavroudis, Dimitris; Georgoulias, Vassilis; Agelaki, Sofia

doi:10.1007/s00280-016-2997-7

Cited by 15 publications

(19 citation statements)

References 25 publications

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“…Finally atherosclerotic plaque forms a complicated lesion where hypoxia emplifies HIF expression and activation. (Befani et al, 2012;Chen et al, 2011;Cortes et al, 2004;Iskandarani et al, 2016;Kontopodis et al, 2016;Mian et al, 2016) were more prominent in SCLC (Jacoby et al, 2010;Jordan et al, 2005)…”

Section: Figure Legendsmentioning

confidence: 98%

Hypoxia inducible factor as a therapeutic target for atherosclerosis

Jain

Nikolopoulou

et al. 2018

Pharmacology & Therapeutics

166

139

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Atherosclerosis is a highly prevalent disease that can significantly increase the risk of major vascular events, such as myocardial or cerebral infarctions. The anoxemia theory states that a disparity between oxygen supply and demand contributes to atherosclerosis. Hypoxia inducible factor-1 (HIF-1) is a heterodimeric protein, part of the basic helix-loop-helix family and one of the main regulators of cellular responses in a low‑oxygen environment. It plays a key role in the development of atherosclerosis through cell-specific responses, acting on endothelial cells, vascular smooth muscle cells (SMCs) and macrophages. Through the upregulation of VEGF, NO, ROS and PDGF, HIF-1 is able to cause endothelial cell dysfunction, proliferation, angiogenesis and inflammation. Activation of the NF-kB pathway in endothelial cells is an important contributor to inflammation and positively feedbacks to HIF-1. HIF-1 also plays a significant role in both the proliferation and migration of smooth muscle cells - two important features of atherosclerosis, while the formation of foam cells (lipid-laden macrophages) is also a critical step in atherosclerosis and mediated by HIF-1 through various mechanisms such as dysfunctional efflux pathways in macrophages. Overall, HIF-1 exerts its effect on the pathogenesis of atherosclerosis via a variety of molecular and cellular events in the process. In this review article, we examine the effects HIF-1 on vascular cells and macrophages in the development of atherosclerosis, highlighting the environmental cues and signalling pathways that control HIF-1 expression/activation within the vasculature. We will highlight the potential of HIF-1 as a therapeutic target on the disease development.

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Section: Figure Legendsmentioning

confidence: 98%

Hypoxia inducible factor as a therapeutic target for atherosclerosis

Jain

Nikolopoulou

et al. 2018

Pharmacology & Therapeutics

166

139

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“…337 Previous studies have proven that bortezomib can inhibit proliferation and induce cell apoptosis by blocking the NF-κB pathway, activating the c-Jun/AP-1 pathway and increasing cyclin-CDK inhibitors (p21 and p27) in various tumor cell lines, such as squamous cell carcinoma, multiple myeloma (MM), mantle cell lymphoma (MCL), hepatocellular carcinoma and non-small-cell lung cancer (NSCLC). [338][339][340][341][342][343] In the clinic, it is the first approved PI by the U.S. Food and Drug Administration (FDA) for relapsed MM 344 and MCL. 345 Later, it was expanded for use in patients with NSCLC and pancreatic cancer.…”

Section: Nanog Ubiquitinationmentioning

confidence: 99%

The role of ubiquitination in tumorigenesis and targeted drug discovery

Deng

Meng

Chen

et al. 2020

Sig Transduct Target Ther

415

308

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Ubiquitination, an important type of protein posttranslational modification (PTM), plays a crucial role in controlling substrate degradation and subsequently mediates the "quantity" and "quality" of various proteins, serving to ensure cell homeostasis and guarantee life activities. The regulation of ubiquitination is multifaceted and works not only at the transcriptional and posttranslational levels (phosphorylation, acetylation, methylation, etc.) but also at the protein level (activators or repressors). When regulatory mechanisms are aberrant, the altered biological processes may subsequently induce serious human diseases, especially various types of cancer. In tumorigenesis, the altered biological processes involve tumor metabolism, the immunological tumor microenvironment (TME), cancer stem cell (CSC) stemness and so on. With regard to tumor metabolism, the ubiquitination of some key proteins such as RagA, mTOR, PTEN, AKT, c-Myc and P53 significantly regulates the activity of the mTORC1, AMPK and PTEN-AKT signaling pathways. In addition, ubiquitination in the TLR, RLR and STING-dependent signaling pathways also modulates the TME. Moreover, the ubiquitination of core stem cell regulator triplets (Nanog, Oct4 and Sox2) and members of the Wnt and Hippo-YAP signaling pathways participates in the maintenance of CSC stemness. Based on the altered components, including the proteasome, E3 ligases, E1, E2 and deubiquitinases (DUBs), many molecular targeted drugs have been developed to combat cancer. Among them, small molecule inhibitors targeting the proteasome, such as bortezomib, carfilzomib, oprozomib and ixazomib, have achieved tangible success. In addition, MLN7243 and MLN4924 (targeting the E1 enzyme), Leucettamol A and CC0651 (targeting the E2 enzyme), nutlin and MI-219 (targeting the E3 enzyme), and compounds G5 and F6 (targeting DUB activity) have also shown potential in preclinical cancer treatment. In this review, we summarize the latest progress in understanding the substrates for ubiquitination and their special functions in tumor metabolism regulation, TME modulation and CSC stemness maintenance. Moreover, potential therapeutic targets for cancer are reviewed, as are the therapeutic effects of targeted drugs.Signal Transduction and Targeted Therapy (2020) 5:11; https://doi.

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“…Combination therapies of BTZ with paclitaxel/carboplatin/radiation, irinotecan, radiation and the HDAC inhibitor vorinostat showed promising results in NSCLC therapy [ 42 , 82 – 85 ]. However, cisplatin with, or without gemcitabine, did not improve the efficacy of BTZ [ 86 , 87 ]. Moreover, the addition of BTZ to the current NSCLC chemotherapeutic regimen of gemcitabine and cisplatin did not improve the results of gemcitabine and cisplatin alone [ 86 , 88 ] even though in vitro studies with NSCLC cells demonstrated a schedule-dependent effect of BTZ increasing the expression of deoxycytidine kinase, the activating enzyme for gemcitabine, and concomitantly levels of the active metabolite of gemcitabine [ 89 ].…”

Section: Proteasome Inhibitors In Solid Malignanciesmentioning

confidence: 99%

Positioning of proteasome inhibitors in therapy of solid malignancies

Roeten

Cloos

Jansen

2017

Cancer Chemother Pharmacol

123

109

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Targeting of the protein degradation pathway, in particular, the ubiquitin-proteasome system, has emerged as an attractive novel cancer chemotherapeutic modality. Although proteasome inhibitors have been most successfully applied in the treatment of hematological malignancies, they also received continuing interest for the treatment of solid tumors. In this review, we summarize the current positioning of proteasome inhibitors in the treatment of common solid malignancies (e.g., lung, colon, pancreas, breast, and head and neck cancer), addressing topics of their mechanism(s) of action, predictive factors and molecular mechanisms of resistance.

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A phase II, open-label trial of bortezomib (VELCADE®) in combination with gemcitabine and cisplatin in patients with locally advanced or metastatic non-small cell lung cancer

Abstract: The incorporation of bortezomib into the gemcitabine/cisplatin regimen, in the dose and schedule used in this study, could not improve the efficacy of the chemotherapy regimen and has not to be further investigated.

Cited by 15 publications

References 25 publications

Hypoxia inducible factor as a therapeutic target for atherosclerosis

Hypoxia inducible factor as a therapeutic target for atherosclerosis

The role of ubiquitination in tumorigenesis and targeted drug discovery

Positioning of proteasome inhibitors in therapy of solid malignancies

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