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1.
Chalcone Derivatives: Role in Anticancer Therapy.
Ouyang, Y, Li, J, Chen, X, Fu, X, Sun, S, Wu, Q
Biomolecules. 2021;(6)
Abstract
Chalcones (1,3-diaryl-2-propen-1-ones) are precursors for flavonoids and isoflavonoids, which are common simple chemical scaffolds found in many naturally occurring compounds. Many chalcone derivatives were also prepared due to their convenient synthesis. Chalcones as weandhetic analogues have attracted much interest due to their broad biological activities with clinical potentials against various diseases, particularly for antitumor activity. The chalcone family has demonstrated potential in vitro and in vivo activity against cancers via multiple mechanisms, including cell cycle disruption, autophagy regulation, apoptosis induction, and immunomodulatory and inflammatory mediators. It represents a promising strategy to develop chalcones as novel anticancer agents. In addition, the combination of chalcones and other therapies is expected to be an effective way to improve anticancer therapeutic efficacy. However, despite the encouraging results for their response to cancers observed in clinical studies, a full description of toxicity is required for their clinical use as safe drugs for the treatment of cancer. In this review, we will summarize the recent advances of the chalcone family as potential anticancer agents and the mechanisms of action. Besides, future applications and scope of the chalcone family toward the treatment and prevention of cancer are brought out.
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First-in-human phase I/Ib open-label dose-escalation study of GWN323 (anti-GITR) as a single agent and in combination with spartalizumab (anti-PD-1) in patients with advanced solid tumors and lymphomas.
Piha-Paul, SA, Geva, R, Tan, TJ, Lim, DW, Hierro, C, Doi, T, Rahma, O, Lesokhin, A, Luke, JJ, Otero, J, et al
Journal for immunotherapy of cancer. 2021;(8)
Abstract
BACKGROUND GWN323 is an IgG1 monoclonal antibody (mAb) against the glucocorticoid-induced tumor necrosis factor receptor-related protein. This first-in-human, open-label phase I/Ib study aimed to investigate the safety and tolerability and to identify the recommended doses of GWN323 with/without spartalizumab, an anti-programmed cell death receptor-1 agent, for future studies. Pharmacokinetics, preliminary efficacy and efficacy biomarkers were also assessed. METHODS Patients (aged ≥18 years) with advanced/metastatic solid tumors with Eastern Cooperative Oncology Group performance status of ≤2 were included. GWN323 (10-1500 mg) or GWN323+spartalizumab (GWN323 10-750 mg+spartalizumab 100-300 mg) were administered intravenously at various dose levels and schedules during the dose-escalation phase. Dose-limiting toxicities (DLTs) were assessed during the first 21 days in a single-agent arm and 42 days in a combination arm. Adverse events (AEs) were graded per National Cancer Institute-Common Toxicity Criteria for Adverse Events V.4.03 and efficacy was assessed using Response Evaluation Criteria in Solid Tumors V.1.1. RESULTS Overall, 92 patients (single-agent, n=39; combination, n=53) were included. The maximum administered doses (MADs) in the single-agent and combination arms were GWN323 1500 mg every 3 weeks (q3w) and GWN323 750 mg+spartalizumab 300 mg q3w, respectively. No DLTs were observed with single-agent treatment. Three DLTs (6%, all grade ≥3) were noted with combination treatment: blood creatine phosphokinase increase, respiratory failure and small intestinal obstruction. Serious AEs were reported in 30.8% and 34.0%, and drug-related AEs were reported in 82.1% and 77.4% of patients with single-agent and combination treatments, respectively. Disease was stable in 7 patients and progressed in 26 patients with single-agent treatment. In combination arm patients, 1 had complete response (endometrial cancer); 3, partial response (rectal cancer, adenocarcinoma of colon and melanoma); 14, stable disease; and 27, disease progression. GWN323 exhibited a pharmacokinetic profile typical of mAbs with a dose-dependent increase in the pharmacokinetic exposure. Inconsistent decreases in regulatory T cells and increases in CD8+ T cells were observed in the combination arm. Gene expression analyses showed no significant effect of GWN323 on interferon-γ or natural killer-cell signatures. CONCLUSIONS GWN323, as a single agent and in combination, was well tolerated in patients with relapsed/refractory solid tumors. The MAD was 1500 mg q3w for single-agent and GWN323 750 mg+spartalizumab 300 mg q3w for combination treatments. Minimal single-agent activity and modest clinical benefit were observed with the spartalizumab combination. TRIAL REGISTRATION NUMBER NCT02740270.
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Human gut-microbiome interplay: Analysis of clinical studies for the emerging roles of diagnostic microbiology in inflammation, oncogenesis and cancer management.
Jiang, Z, Li, L, Chen, J, Wei, G, Ji, Y, Chen, X, Liu, J, Huo, J
Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases. 2021;:104946
Abstract
Microorganisms have been known to coexist in various parts of human body including the gut. The interactions between microbes and the surrounding tissues of the host are critical for fine fettle of the gut. The incidence of such microorganisms tends to vary among specific type of cancer affected individuals. Such microbial communities of specific tumor sites in cancer affected individuals could plausibly be used as prognostic and/or diagnostic markers for tumors associated with that specific site. Microorganisms of intestinal and non-intestinal origins including Helicobacter pylori can target several organs, act as carcinogens and promote cancer. It is interesting to note that diets causing inflammation can also increase the cancer risk. Yet, dietary supplementation with prebiotics and probiotics can reduce the incidence of cancer. Therefore, both diet and microbial community of the gut have dual roles of prevention and oncogenesis. Hence, this review intends to summarize certain important details related to gut microbiome and cancer.
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Plant-derived glucose transport inhibitors with potential antitumor activity.
Shriwas, P, Chen, X, Kinghorn, AD, Ren, Y
Phytotherapy research : PTR. 2020;(5):1027-1040
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Abstract
Glucose, a key nutrient utilized by human cells to provide cellular energy and a carbon source for biomass synthesis, is internalized in cells via glucose transporters that regulate glucose homeostasis throughout the human body. Glucose transporters have been used as important targets for the discovery of new drugs to treat cancer, diabetes, and heart disease, owing to their abnormal expression during these disease conditions. Thus far, several glucose transport inhibitors have been used in clinical trials, and increasing numbers of natural products have been characterized as potential anticancer agents targeting glucose transport. The present review focuses on natural product glucose transport inhibitors of plant origin, including alkaloids, flavonoids and other phenolic compounds, and isoprenoids, with their potential antitumor properties also discussed.
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p53 tumor suppressor and iron homeostasis.
Zhang, J, Chen, X
The FEBS journal. 2019;(4):620-629
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Iron is an essential nutrient for all living organisms and plays a vital role in many fundamental biochemical processes, such as oxygen transport, energy metabolism, and DNA synthesis. Due to its capability to produce free radicals, iron has deleterious effects and thus, its level needs to be tightly controlled in the body. Deregulation of iron metabolism is known to cause diseases, including anemia by iron deficiency and hereditary hemochromatosis by iron overload. Interestingly, dysregulated iron metabolism occurs frequently in tumor cells and contributes to tumorigenesis. In this review, we will discuss the role of p53 tumor suppressor in iron homeostasis.
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Advances in nanomaterials for use in photothermal and photodynamic therapeutics (Review).
Yang, Z, Sun, Z, Ren, Y, Chen, X, Zhang, W, Zhu, X, Mao, Z, Shen, J, Nie, S
Molecular medicine reports. 2019;(1):5-15
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Nanomaterials play crucial roles in the diagnosis and treatment of diseases. Photothermal and photodynamic therapy, as two minimally invasive therapeutic methods, have promising potential in the diagnosis and prevention of cancer. Recently, many photothermal materials (such as noble metal material, transition metal sulfur oxides, carbon material and upconversion nanomaterial) and photodynamic materials (such as phthalein cyanogen, porphyrins and other dye molecules) have been applied in photothermal therapy (PTT) and photodynamic therapy (PDT). Moreover, as nanomaterials have suitable biocompatibility, these materials have been applied in cancer therapy. In the present review, we summarized the effects of different material types, synthesis methods, material morphologies and surface modifications on the outcomes of cancer therapy. The application of nanomaterials in PTT and PDT was introduced and the advantages and disadvantages of PTT and PDT in the prevention of cancer were discussed. Finally, we discussed the application of nanomaterials in the combination of PTT and PDT in cancer treatment.
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Black phosphorus based fiber optic biosensor for ultrasensitive cancer diagnosis.
Zhou, L, Liu, C, Sun, Z, Mao, H, Zhang, L, Yu, X, Zhao, J, Chen, X
Biosensors & bioelectronics. 2019;:140-147
Abstract
We propose the first black phosphorus (BP) - fiber optic biosensor for ultrasensitive diagnosis of human neuron-specific enolase (NSE) cancer biomarkers. A novel optical-nano configuration has been exploited by integrating BP nanosheets with a largely tilted fiber grating (BP-TFG), where the BP is bio-functionalized by the poly-L-lysine acting as a critical cross-linker to facilitate bio-nano-photonic interface with extremely enhanced light-matter interaction. BP nanosheets are synthesized by a liquid ultrasonication-based exfoliation and deposited on fiber device by an in-situ layer-by-layer method. The BP-induced optical modulation effects in terms of thickness-tunable feature, polarization-dependence and enhanced light-matter interaction are experimentally investigated. The anti-NSE immobilized BP-TFG biosensor has been implemented to detect NSE biomarkers demonstrating ultrahigh sensitivity with limit of detection down to 1.0 pg/mL, which is 4 orders magnitude lower than NSE cut-off value of small cell lung cancer. The enhanced sensitivity of BP-TFG is 100-fold higher than graphene oxide or AuNPs based biosensors. We believe that BP-fiber optic configuration opens a new bio-nano-photonic platform for the applications in healthcare, biomedical, food safety and environmental monitoring.
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Emerging Strategies of Cancer Therapy Based on Ferroptosis.
Shen, Z, Song, J, Yung, BC, Zhou, Z, Wu, A, Chen, X
Advanced materials (Deerfield Beach, Fla.). 2018;(12):e1704007
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Ferroptosis, a new form of regulated cell death that is iron- and reactive oxygen species dependent, has attracted much attention in the research communities of biochemistry, oncology, and especially material sciences. Since the first demonstration in 2012, a series of strategies have been developed to induce ferroptosis of cancer cells, including the use of nanomaterials, clinical drugs, experimental compounds, and genes. A plethora of research work has outlined the blueprint of ferroptosis as a new option for cancer therapy. However, the published ferroptosis-related reviews have mainly focused on the mechanisms and pathways of ferroptosis, which motivated this contribution to bridge the gap between biological significance and material design. Therefore, it is timely to summarize the previous efforts on the emerging strategies for inducing ferroptosis and shed light on future directions for using such a tool to fight against cancer. Here, the current strategies of cancer therapy based on ferroptosis will be elaborated, the design considerations and the advantages and limitations are highlighted, and finally a future perspective on this emerging field is given.
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Rigid nanoparticle-based delivery of anti-cancer siRNA: challenges and opportunities.
Wang, Z, Liu, G, Zheng, H, Chen, X
Biotechnology advances. 2014;(4):831-43
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Abstract
Gene therapy is a promising strategy to treat various genetic and acquired diseases. Small interfering RNA (siRNA) is a revolutionary tool for gene therapy and the analysis of gene function. However, the development of a safe, efficient, and targetable non-viral siRNA delivery system remains a major challenge in gene therapy. An ideal delivery system should be able to encapsulate and protect the siRNA cargo from serum proteins, exhibit target tissue and cell specificity, penetrate the cell membrane, and release its cargo in the desired intracellular compartment. Nanomedicine has the potential to deal with these challenges faced by siRNA delivery. The unique characteristics of rigid nanoparticles mostly inorganic nanoparticles and allotropes of carbon nanomaterials, including high surface area, facile surface modification, controllable size, and excellent magnetic/optical/electrical properties, make them promising candidates for targeted siRNA delivery. In this review, recent progresses on rigid nanoparticle-based siRNA delivery systems will be summarized.