Elevated Levels of Serum Thymidine Kinase 1 Predict Poor Survival for Patients with Metastatic Prostate Cancer.

Background And Objective: Prostate-specific antigen (PSA) is of limited value as a surrogate marker for overall survival (OS) in prostate cancer (PC). Serum thymidine kinase 1 (sTK1) is an enzyme expressed by actively dividing cells. Our aim was to evaluate the value of sTK1 as prognostic biomarker in metastatic hormone-sensitive PC (mHSPC) and metastatic castration-resistant PC (mCRPC).

Zebrafish tumour xenograft models: a prognostic approach to epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is the gynaecological malignancy with highest mortality. Although adjuvant treatment with carboplatin and paclitaxel leads to an objective response in ~80% of these patients, a majority will relapse within two years. Better methods for assessing long-term treatment outcomes are needed.

Corrigendum: Antiproliferative effects of the natural oxadiazine Nocuolin A are associated with impairment of mitochondrial oxidative phosphorylation.

[This corrects the article DOI: 10.3389/fonc.2019.

The deubiquitinase USP8 regulates ovarian cancer cell response to cisplatin by suppressing apoptosis.

The identification of therapeutic approaches to improve response to platinum-based therapies is an urgent need for ovarian carcinoma. Deubiquitinases are a large family of ubiquitin proteases implicated in a variety of cellular functions and may contribute to tumor aggressive features through regulation of processes such as proliferation and cell death. Among the subfamily of ubiquitin-specific peptidases, USP8 appears to be involved in modulation of cancer cell survival by still poorly understood mechanisms.

Comprehensive Target Screening and Cellular Profiling of the Cancer-Active Compound b-AP15 Indicate Abrogation of Protein Homeostasis and Organelle Dysfunction as the Primary Mechanism of Action.

Dienone compounds have been demonstrated to display tumor-selective anti-cancer activity independently of the mutational status of TP53. Previous studies have shown that cell death elicited by this class of compounds is associated with inhibition of the ubiquitin-proteasome system (UPS). Here we extend previous findings by showing that the dienone compound b-AP15 inhibits proteasomal degradation of long-lived proteins.

Caffeic acid phenethyl ester targets ubiquitin-specific protease 8 and synergizes with cisplatin in endometrioid ovarian carcinoma cells.

Deubiquitinases (DUBs) mediate the removal of ubiquitin from diverse proteins that participate in the regulation of cell survival, DNA damage repair, apoptosis and drug resistance. Previous studies have shown an association between activation of cell survival pathways and platinum-drug resistance in ovarian carcinoma cell lines. Among the strategies available to inhibit DUBs, curcumin derivatives appear promising, thus we hypothesized their use to enhance the efficacy of cisplatin in ovarian carcinoma preclinical models.

Sensitivity of Acute Myelocytic Leukemia Cells to the Dienone Compound VLX1570 Is Associated with Inhibition of the Ubiquitin-Proteasome System.

Dienone compounds with a 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore have been widely reported to show tumor cell selectivity. These compounds target the ubiquitin-proteasome system (UPS), known to be essential for the viability of tumor cells. The induction of oxidative stress, depletion of glutathione, and induction of high-molecular-weight (HMW) complexes have also been reported.

Targeting Mitochondrial Metabolism in Clear Cell Carcinoma of the Ovaries.

Ovarian clear cell carcinoma (OCCC) is a rare but chemorefractory tumor. About 50% of all OCCC patients have inactivating mutations of , a member of the SWI/SNF chromatin-remodeling complex. Members of the SWI/SNF remodeling have emerged as regulators of the energetic metabolism of mammalian cells; however, the role of ARID1A as a modulator of the mitochondrial metabolism in OCCCs is yet to be defined.

Identification of proteasome inhibitors using analysis of gene expression profiles.

Inhibitors of the 20S proteasome such as bortezomib (Velcade) and carfilzomib (Kypriolis) are in clinical use for the treatment of patients with multiple myeloma and mantle cell lymphoma. In an attempt to identify novel inhibitors of the ubiquitin-proteasome system (UPS) we used the connectivity map (CMap) resource, based on alterations of gene expression profiles by perturbagens, and performed COMPARE analyses of drug sensitivity patterns in the NCI panel. Cmap analysis identified a large number of small molecules with strong connectivity to proteasome inhibition, including both well characterized inhibitors of the 20S proteasome and molecules previously not described to inhibit the UPS.

Dienone Compounds: Targets and Pharmacological Responses.

The biological responses to dienone compounds with a 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore have been studied extensively. Despite their expected general thiol reactivity, these compounds display considerable degrees of tumor cell selectivity. Here we review and preclinical studies of dienone compounds including b-AP15, VLX1570, RA-9, RA-190, EF24, HO-3867, and MCB-613.

Induction of ER Stress in Acute Lymphoblastic Leukemia Cells by the Deubiquitinase Inhibitor VLX1570.

The proteasome is a validated target of cancer therapeutics. Inhibition of proteasome activity results in the activation of the unfolded protein response (UPR) characterized by phosphorylation of eukaryotic initiation factor 2α (eIF2α), global translational arrest, and increased expression of the proapoptotic CHOP (C/EBP homologous protein) protein. Defects in the UPR response has been reported to result in altered sensitivity of tumor cells to proteasome inhibitors.

-3-Oxo-Dodecanoyl-Homoserine Lactone Impacts Mitochondrial Networks Morphology, Energetics, and Proteome in Host Cells.

Mitochondria play crucial roles in cellular metabolism, signaling, longevity, and immune defense. Recent evidences have revealed that the host microbiota, including bacterial pathogens, impact mitochondrial behaviors and activities in the host. The pathogenicity of requires quorum sensing (QS) cell-cell communication allowing the bacteria to sense population density and collectively control biofilm development, virulence traits, adaptation and interactions with the host.

Drug Development Targeting the Ubiquitin-Proteasome System (UPS) for the Treatment of Human Cancers.

Cancer cells are characterized by a higher rate of protein turnover and greater demand for protein homeostasis compared to normal cells. In this scenario, the ubiquitin-proteasome system (UPS), which is responsible for the degradation of over 80% of cellular proteins within mammalian cells, becomes vital to cancer cells, making the UPS a critical target for the discovery of novel cancer therapeutics. This review systematically categorizes all current reported small molecule inhibitors of the various essential components of the UPS, including ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), ubiquitin ligases (E3s), the 20S proteasome catalytic core particle (20S CP) and the 19S proteasome regulatory particles (19S RP), as well as their mechanism/s of action and limitations.

Phase 1 study of the protein deubiquitinase inhibitor VLX1570 in patients with relapsed and/or refractory multiple myeloma.

This phase 1 study sought to characterize the safety, tolerability, and pharmacokinetic behavior of VLX1570, a small molecule inhibitor of the deubiquitinases (DUBs) that remove sterically bulky ubiquitin chains from proteins during processing in the19S regulatory subunit of the proteasome, in patients with relapsed and refractory multiple myeloma (MM). Fourteen patients were treated with escalating doses of VLX1570 ranging from 0.05 to 1.

Portoamides A and B are mitochondrial toxins and induce cytotoxicity on the proliferative cell layer of in vitro microtumours.

Cyanobacteria are known to produce many toxins and other secondary metabolites. The study of their specific mode of action may reveal the biotechnological potential of such compounds. Portoamides A and B (PAB) are cyclic peptides isolated from the cyanobacteria Phormidium sp.

Author Correction: Cytotoxic unsaturated electrophilic compounds commonly target the ubiquitin proteasome system.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Analysis of determinants for in vitro resistance to the small molecule deubiquitinase inhibitor b-AP15.

Background: b-AP15/VLX1570 are small molecule inhibitors of the ubiquitin specific peptidase 14 (USP14) and ubiquitin carboxyl-terminal hydrolase 5 (UCHL5) deubiquitinases (DUBs) of the 19S proteasome. b-AP15/VLX1570 have been shown to be cytotoxic to cells resistant to bortezomib, raising the possibility that this class of drugs can be used as a second-line therapy for treatment-resistant multiple myeloma. Limited information is available with regard to potential resistance mechanisms to b-AP15/VLX1570.

A novel tumor spheroid model identifies selective enhancement of radiation by an inhibitor of oxidative phosphorylation.

There is a need for preclinical models that can enable identification of novel radiosensitizing drugs in clinically relevant high-throughput experiments. We used a new high-throughput compatible total cell kill spheroid assay to study the interaction between drugs and radiation in order to identify compounds with radiosensitizing activity. Experimental drugs were compared to known radiosensitizers and cytotoxic drugs clinically used in combination with radiotherapy.

Cytotoxic unsaturated electrophilic compounds commonly target the ubiquitin proteasome system.

A large number of natural products have been advocated as anticancer agents. Many of these compounds contain functional groups characterized by chemical reactivity. It is not clear whether distinct mechanisms of action can be attributed to such compounds.

Oxidative Stress Induced by the Deubiquitinase Inhibitor b-AP15 Is Associated with Mitochondrial Impairment.

Inhibitors of the 20S proteasome such as bortezomib are cytotoxic to tumor cells and have been proven to be valuable for the clinical management of multiple myeloma. The therapeutic efficacy of bortezomib is, however, hampered by the emergence of acquired resistance. Available data suggest that blocking proteasome activity at the level of proteasome-associated deubiquitinases (DUBs) provides a mechanism to overcome resistance to bortezomib and also to other cancer therapies.

Antiproliferative Effects of the Natural Oxadiazine Nocuolin A Are Associated With Impairment of Mitochondrial Oxidative Phosphorylation.

Natural products are interesting sources for drug discovery. The natural product oxadiazine Nocuolin A (NocA) was previously isolated from the cyanobacterial strain sp. LEGE 06071 and here we examined its cytotoxic effects against different strains of the colon cancer cell line HCT116 and the immortalized epithelial cell line hTERT RPE-1.

Repurposing of auranofin: Thioredoxin reductase remains a primary target of the drug.

Auranofin is a gold (I)-containing compound used for the treatment of rheumatic arthritis. Auranofin has anticancer activity in animal models and is approved for clinical trials for lung and ovarian carcinomas. Both the cytosolic and mitochondrial forms of the selenoprotein thioredoxin reductase (TrxR) are well documented targets of auranofin.

Proteasome inhibitor b-AP15 induces enhanced proteotoxicity by inhibiting cytoprotective aggresome formation.

Proteasome inhibitors have been shown to induce cell death in cancer cells by triggering an acute proteotoxic stress response characterized by accumulation of poly-ubiquitinated proteins, ER stress and the production of reactive oxygen species. The aggresome pathway has been described as an escape mechanism from proteotoxicity by sequestering toxic cellular aggregates. Here we show that b-AP15, a small-molecule inhibitor of proteasomal deubiquitinase activity, induces poly-ubiquitin accumulation in absence of aggresome formation.

Targeting Mitochondria for Treatment of Chemoresistant Ovarian Cancer.

Ovarian cancer is the leading cause of death from gynecologic malignancy in the Western world. This is due, in part, to the fact that despite standard treatment of surgery and platinum/paclitaxel most patients recur with ultimately chemoresistant disease. Ovarian cancer is a unique form of solid tumor that develops, metastasizes and recurs in the same space, the abdominal cavity, which becomes a unique microenvironment characterized by ascites, hypoxia and low glucose levels.

A drug screening assay on cancer cells chronically adapted to acidosis.

Background: Drug screening for the identification of compounds with anticancer activity is commonly performed using cell lines cultured under normal oxygen pressure and physiological pH. However, solid tumors are characterized by a microenvironment with limited access to nutrients, reduced oxygen supply and acidosis. Tumor hypoxia and acidosis have been identified as important drivers of malignant progression and contribute to multicellular resistance to different forms of therapy.