Cancer mortality and senescence: Is redox therapy an option?

Patient genomics and mouse functional genetics have revealed that senescence is a barrier to metastatic progression of prostate cancer. Many efforts focus on eliminating senescent cells, whereas others aim to elucidate distinct characteristics that set them apart from normal and aging cells. Here, we discuss how exploration of the redox state of senescent cells could help define new markers and pro-oxidant vulnerabilities, drawing analogy to what is known about the redox sensitivity of proliferating cancer cells.

Pleiotropic tumor suppressive functions of PTEN missense mutations during gliomagenesis.

PTEN plays a crucial role in preventing the development of glioblastoma (GBM), a severe and untreatable brain cancer. In GBM, most PTEN deficiencies are missense mutations that have not been thoroughly examined. Here, we leveraged genetically modified mice and isogenic astrocyte cell cultures to investigate the role of clinically relevant mutations (G36E, L42R, C105F, and R173H) in the development of EGFR-driven GBM.

Dietary pro-oxidant therapy by a vitamin K precursor targets PI 3-kinase VPS34 function.

Men taking antioxidant vitamin E supplements have increased prostate cancer (PC) risk. However, whether pro-oxidants protect from PC remained unclear. In this work, we show that a pro-oxidant vitamin K precursor [menadione sodium bisulfite (MSB)] suppresses PC progression in mice, killing cells through an oxidative cell death: MSB antagonizes the essential class III phosphatidylinositol (PI) 3-kinase VPS34-the regulator of endosome identity and sorting-through oxidation of key cysteines, pointing to a redox checkpoint in sorting.

Comparative analysis of clonal evolution among patients with right- and left-sided colon and rectal cancer.

Tumor multiregion sequencing reveals intratumor heterogeneity (ITH) and clonal evolution playing a key role in tumor progression and metastases. Large-scale high-depth multiregional sequencing of colorectal cancer, comparative analysis among patients with right-sided colon cancer (RCC), left-sided colon cancer (LCC), and rectal cancer (RC), as well as the study of lymph node metastasis (LN) with extranodal tumor deposits (ENTDs) from evolutionary perspective remain weakly explored. Here, we recruited 68 patients with RCC (18), LCC (20), and RC (30).

Family-Based Whole Genome Sequencing Identified Novel Variants in ABCA5 Gene in a Patient with Idiopathic Ventricular Tachycardia.

Idiopathic ventricular tachycardia (IVT) is the major cause of sudden cardiac death. Patients with IVT were usually manifested without structural heart disease. In this present study, we performed family-based whole genome sequencing (WGS) and Sanger sequencing for a 5-year-old Chinese boy with IVT and all the unaffected family members in order to identify the candidate gene and disease-causing mutation underlying the disease phenotype.

Identification and functional characterization of mutations in LPL gene causing severe hypertriglyceridaemia and acute pancreatitis.

Hypertriglyceridaemia is a very rare disorder caused by the mutations of LPL gene, with an autosomal recessive mode of inheritance. Here, we identified two unrelated Chinese patients manifested with severe hypertriglyceridaemia and acute pancreatitis. The clinical symptoms of proband 1 are more severe than proband 2.

Sorafenib kills liver cancer cells by disrupting SCD1-mediated synthesis of monounsaturated fatty acids the ATP-AMPK-mTOR-SREBP1 signaling pathway.

Sorafenib is a multikinase inhibitor that is effective in treating advanced liver cancer. Although its mechanism of action through several established cancer-related protein kinase targets is well-characterized, sorafenib induces variable responses among human tumors, and the cause for this variation is yet unknown. To investigate the underlying mechanisms, we applied mass spectrometry-based proteomic analysis to Huh7.

The natural compound GL22, isolated from Ganoderma mushrooms, suppresses tumor growth by altering lipid metabolism and triggering cell death.

Cancer cells rewire their metabolism to satisfy the demands of uncontrolled proliferation and survival. The reprogramming of lipid metabolism supports tumor growth, metastasis, and therapy-resistance. Therefore, targeting lipid metabolic reprogramming is a potential cancer treatment strategy.

Marine Bacterial Polysaccharide EPS11 Inhibits Cancer Cell Growth via Blocking Cell Adhesion and Stimulating Anoikis.

Tumor cells that acquire metastatic potential have developed resistance to anoikis, a cell death process, after detachment from their primary site to the second organ. In this study, we investigated the molecular mechanisms of a novel marine bacterial polysaccharide EPS11 which exerts its cytotoxic effects through affecting cancer cell adhesion and anoikis. Firstly, we found that EPS11 could significantly affect cell proliferation and block cell adhesion in A549 cells.

Mansouramycin C kills cancer cells through reactive oxygen species production mediated by opening of mitochondrial permeability transition pore.

Cancer is one of the deadliest diseases in the world and the search for novel anticancer agents is urgently required. Marine-derived isoquinolinequinones have exhibited promising anticancer activities. However, the exact mechanisms of cytotoxic activities of these isoquinolinequinones are poorly characterized.

Cucurbitacin I inhibits STAT3, but enhances STAT1 signaling in human cancer cells in vitro through disrupting actin filaments.

STAT1 and STAT3 are two important members of the STAT (signal transducers and activators of transcription) protein family and play opposing roles in regulating cancer cell growth. Suppressing STAT3 and/or enhancing STAT1 signaling are considered to be attractive anticancer strategies. Cucurbitacin I (CuI) isolated from the cucurbitacin family was reported to be an inhibitor of STAT3 signaling and a disruptor of actin cytoskeleton.

Synthesis of Biotinylated 2-methoxystypandrone and Identification of JAK2 and IKK as its Targets.

Background: 2-Methoxystypandrone (2-MS), isolated from the roots of Polygonum cuspidatum, is a potent dual inhibitor of the STAT3 and NF-κB pathways.

Objective: To investigate the molecular targets and mechanisms of 2-MS.

Method: A biotin-conjugated 2-MS analog, named 2-MS-Biotin, was designed and synthesized.

Antagonistic Activity and Mode of Action of Phenazine-1-Carboxylic Acid, Produced by Marine Bacterium PA31x, Against and in a Zebrafish Model.

Phenazine and its derivatives are very important secondary metabolites produced from spp. and have exhibited broad-spectrum antifungal and antibacterial activities. However, till date, there are few reports about marine derived and its production of phenazine metabolites.

A novel polysaccharide from Sargassum integerrimum induces apoptosis in A549 cells and prevents angiogensis in vitro and in vivo.

Many polysaccharides isolated from plants have exhibited promising antitumor activities. The aim of this study is to investigate the antitumor activity of the novel polysaccharide named SPS from Sargassum integerrimum, elucidate the underlying anticancer mechanism in a human lung cancer cell line A549, and evaluate its anti-angiogenic activity both in vitro and in vivo. The results show that SPS significantly reduces A549 cells viability in a dose- and time-dependent manner via MTT method.

Complete genome sequence of hypervirulent and outbreak-associated Acinetobacter baumannii strain LAC-4: epidemiology, resistance genetic determinants and potential virulence factors.

Acinetobacter baumannii is an important human pathogen due to its multi-drug resistance. In this study, the genome of an ST10 outbreak A. baumannii isolate LAC-4 was completely sequenced to better understand its epidemiology, antibiotic resistance genetic determinants and potential virulence factors.

Bigelovin inhibits STAT3 signaling by inactivating JAK2 and induces apoptosis in human cancer cells.

Aim: To study the function and mechanism of bigelovin, a sesquiterpene lactone from the flower of Chinese herb Inula hupehensis, in regulating JAK2/STAT3 signaling and cancer cell growth.

Methods: HepG2 cells stably transfected with the STAT3-responsive firefly luciferase reporter plasmid (HepG2/STAT3 cells), and a panel of human cancer cell lines were used to identify active compounds. Cell viability was measured using MTT assay.

2-Methoxystypandrone inhibits signal transducer and activator of transcription 3 and nuclear factor-κB signaling by inhibiting Janus kinase 2 and IκB kinase.

Constitutive activation of the signal transducer and activator of transcription 3 (STAT3) or the nuclear factor-κB (NF-κB) pathway occurs frequently in cancer cells and contributes to oncogenesis. The activation of Janus kinase 2 (JAK2) and IκB kinase (IKK) are key events in STAT3 and NF-κB signaling, respectively. We have identified 2-methoxystypandrone (2-MS) from a traditional Chinese medicinal herb Polygonum cuspidatum as a novel dual inhibitor of JAK2 and IKK.

Wedelolactone, a naturally occurring coumestan, enhances interferon-γ signaling through inhibiting STAT1 protein dephosphorylation.

Signal transducers and activators of transcription 1 (STAT1) transduces signals from cytokines and growth factors, particularly IFN-γ, and regulates expression of genes involved in cell survival/death, proliferation, and migration. STAT1 is activated through phosphorylation on its tyrosine 701 by JAKs and is inactivated through dephosphorylation by tyrosine phosphatases. We discovered a natural compound, wedelolactone, that increased IFN-γ signaling by inhibiting STAT1 dephosphorylation and prolonging STAT1 activation through specific inhibition of T-cell protein tyrosine phosphatase (TCPTP), an important tyrosine phosphatase for STAT1 dephosphorylation.

Small-molecule STAT3 signaling pathway modulators from Polygonum cuspidatum.

Constitutively activated STAT3 plays a pivotal role in oncogenesis and metastasis in many human cancers, and STAT3 has been validated as a novel anticancer drug target. Thus, the identification of small molecules that modulate STAT3 activity could be of great therapeutic importance. The aim of this study was to isolate novel modulators of the STAT3 signaling pathway from the roots of Polygonum cuspidatum by bioassay-guided fractionation using a STAT3 reporter gene assay.

A novel sulfonamide agent, MPSP-001, exhibits potent activity against human cancer cells in vitro through disruption of microtubule.

Aim: To evaluate the anti-cancer effects of a new sulfonamide derivative, 2-(N-(3-chlorophenyl)-4-methoxyphenylsulfonamido)-N-hydroxypropanamide (MPSP-001).

Methods: Human cancer cell lines (HepG2, THP-1, K562, HGC-27, SKOV3, PANC-1, SW480, Kba, HeLa, A549, MDA-MB-453, and MCF-7) were examined. The cytotoxicity of MPSP-001 was evaluated using the WST-8 assay.

CSA-enabled spin diffusion leads to MAS rate-dependent T1's at high field.

A surprisingly strong spin rate dependence of (15)N and (13)C NMR T(1) times in magic angle spinning experiments on solid peptides is demonstrated. Using a variety of isotopomers, the phenomenon is shown to be the result of chemical shift anisotropy-mediated spin diffusion. This effect has the potential to be used to detect long-range distance constraints in macromolecular systems.