Frontiers in Pharmacology
·
2025
·
IF 4.8
Hailiang Li,Zheng Ma,Wanfu Yang,Yifan Zhang,Jinping Sun,Haifeng Jiang,Faxuan Wang,Li Hou,Hechun Xia
Introduction Glioblastoma multiform (GBM) is considered the deadliest brain cancer. Standard therapies are followed by poor patient’s survival outcomes, so novel and more efficacious therapeutic strategies are imperative to tackle this scourge. Metformin has been reported to have anti-cancer effects. However, the precise mechanism underlying these effects remains elusive. A better understanding of its underlying mechanism will inform future experimental designs exploring metformin as a potential adjuvant therapy for GBM. This research aimed to elucidate the potential molecular mechanism of metformin in GBM by integrating proteomics and transcriptomics. Methods The study examined the effects of metformin on GBM cell lines using various methods. The U87, U251 and HA1800 were cultured and modified through PER2 knockdown and overexpression. Cell viability was assessed using the CCK8 assay, and G6PDH activity and intracellular NADPH + levels were measured with specific kits. ROS levels, mitochondrial membrane potential, cell cycle distribution and apoptosis were analyzed by flow cytometry. RNA was extracted for transcriptomic analysis through RNA sequencing, while proteomic analysis was performed on total protein from treated cells. WB detected specific proteins, and RT-qPCR quantified gene expression. In vivo experiments, GBM xenograft on nude mice treated with metformin combining radiotherapy was evaluated and received IHC and TUNEL staining for protein expression and apoptosis assessment. Statistical analyses were conducted using Prism software to identify significant group differences. Results We found that differential expressional genes and proteins relating to circadian rhythm were enriched in proteomic or transcriptomic. The expression of PER2, the key circadian gene, was up-regulated in GBM cell lines when treated with metformin. Furthermore, the expression of silent information regulator 2(SIRT2) was down-regulated, while the expression of the G6PD protein just slightly increased in GBM cell lines. Meanwhile, NADPH+ production and G6PDH enzyme activity significantly decreased. Further study validated that metformin inhibited the cell growth of GBM cell lines through up-regulating PER2 and inhibited SIRT2/G6PD signaling pathway, enhancing radiotherapy(RT) sensitivity. We also found that the inhibition of SIRT2 caused by metformin is mediated by PER2. Discussion We found the pivotal role of metformin as an effective circadian rhythm regulator. Targeting circadian clock gene to modify and rescue the dysfunctional circadian clock of GBM cells at molecular level might be an innovative way to administer cancer chronotherapy and maintain metabolic homeostasis in real world practice.
研究领域:
肿瘤学
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2021
·
IF 5.858
Mingming Sun,Hao Sheng,Tingfeng Wu,Jiaqi Song,Huanran Sun,Yingzhi Wang,Jiyan Wang,Zhen Li,Huifang Zhao,Junzhen Tan,Yanping Li,Guo Chen,Qingrong Huang,Yuan Zhang,Bei Lan,Shuangping Liu,Changliang Shan,Shuai Zhang
Reprogramming of energy metabolism is a hallmark of cancer, and the pentose phosphate pathway (PPP) is a major glucose metabolic pathway important for meeting the cellular demands of biosynthesis and anti-oxidant defense. Our previous study showed that phosphoinositide 3-kinase enhancer-activating Akt (PIKE-A) plays an important role in glioblastoma cell survival and growth under cellular energy stress condition. However, the crucial functions of PIKE-A in cancer energy metabolism are poorly understood. In the present study, we show that PIKE-A promotes DNA biosynthesis, NADPH production and inhibits reactive oxygen species (ROS) production, leading to increasing proliferation and growth of glioblastoma cell and suppressing cellular senescence. Mechanistically, PIKE-A binds to STAT3 and stimulates its phosphorylation mediated by tyrosine kinase Fyn , which enhances transcription of the rate-limitting enzyme glucose-6-phosphate dehydrogenase (G6PD) in the PPP. Finally, targeting PIKE-A-G6PD axis sensitizes glioblastoma to temozolomide (TMZ) treatment. This study reveals that STAT3 is a novel binding partner of PIKE-A which recruits Fyn to phosphorylate STAT3, contributing to the expression of G6PD, leading to promoting tumor growth and suppressing cellular senescence. Thus, the PIKE-A/STAT3/G6PD axis strongly links the PPP to carcinogenesis and may become a promising cancer therapeutic target.
研究领域:
癌症生物学
·
分子生物学
·
细胞生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Heliyon
·
2024
·
IF 3.4
Qi Wu,Xue-li Ge,Zi-kai Geng,Hao Wu,Jing-yi Yang,Shi-rong Cao,Ai-lin Yang
HuaChanSu is active water extracts from the skin of Bufo bufo gargarizans Cantor. It has been already used to treat clinical cancers including HCC (Hepatocellular carcinoma, HCC), however, the molecular mechanisms under HuaChanSu's anti-cancer effects remain unclear. PPP (Pentose phosphate pathway, PPP), the major source of ribose and NADPH (Nicotinamide adenine dinucleotide phosphate, NADPH), is always over-activated and particularly critical for tumor cells growth. In this study, firstly, we illustrate that HuaChanSu restrains the growth of human hepatoma cells. More importantly, we demonstrate that the expression of G6PD (Glucose-6-phosphate dehydrogenase, G6PD), the first rate-limiting enzyme of the PPP, is restrained in human hepatoma cells after treatment with HuaChanSu. Additionally, our results show that G6PD enzyme activity and dimer formation are inhibited by HuaChanSu. Furthermore, we find that HuaChanSu could inhibit NADPH production and nucleotide level. In addition, we identify that expression of PLK1 (Polo-like kinase 1, PLK1) is also reduced in response to HuaChanSu, and knockdown of PLK1 restrains enzyme activity and dimer formation of G6PD, but has no effect on G6PD protein level. Subsequently, we demonstrate that inhibition of G6PD could restrain the proliferation of tumor cells and enhance the inhibitory effect of HuaChanSu on cell proliferation of human hepatoma cells. In conclusion, for the first time, our study reveals that HuaChanSu interferes with PPP via suppression of G6PD expression and enzyme activity to restrain growth of tumor cells, and these results provide a novel insight for the anti-hepatoma mechanisms of HuaChanSu and promote the innovation of the research model of TCM. Moreover, the development of drugs targeting abnormal tumor metabolism is currently a hot topic, our works provide theoretical support for further drug development from HuaChanSu, meanwhile, the revelation of the new molecular mechanism also provides a new perspective for the study of the pathogenesis of liver cancer.
研究领域:
肿瘤学
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药理学
·
分子生物学
·
癌症代谢
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
·
2023
·Vol. 14
·期 10
·1-17
·
IF 9
Deng Huan,Chen Yamei,Wang Li,Zhang Yibi,Hang Qingqing,Li Peijing,Zhang Peng,Ji Jing,Song Hai,Chen Ming,Jin Ying
Our previous study revealed that PI3K/AKT/mTOR signaling was associated with SCLC radioresistance. SBC2 cells were used as primary radioresistance models, while H446 cells were continuously exposed to ionizing radiation (IR) to develop acquired radioresistance. Cell viability and apoptosis assays were used to investigate synergistic effects of BEZ235/GSK2126458 and IR in vitro, while immunoblotting, metabolite quantitative analysis and bioinformatic analyses were utilized to explore the underlying mechanism. Both genetically engineered mouse models (GEMM) and subcutaneous tumor models were used to confirm the synergistic effect in vivo. Key molecules of PI3K/AKT/mTOR signaling were upregulated after IR, which was correlated with primary radioresistance, and they were more expressed in acquired radioresistant cells. BEZ235/GSK2126458 effectively enhanced the cytotoxic effects of IR. BEZ235/GSK2126458 plus IR elevated γ-H2AX and p-Nrf2 expression, suggesting DNA and oxidative stress damage were intensified. Mechanistically, BEZ235/GSK2126458 plus IR significantly reduced the expression of G6PD protein, the rate-limiting enzyme of the pentose phosphate pathway (PPP). In detail, PI3K/mTOR inhibitors reinforced interaction between G6PD and HSPA8/HSC70, and G6PD was degraded by chaperone-mediated autophagy processes. Their metabolites (NADPH and R-5P) were decreased, and ROS levels were indirectly elevated, both of which exacerbated cell death. PI3K/AKT/mTOR signaling activator, insulin, enhanced SCLC radioresistance, while the synergistic effect of BEZ235/GSK2126458 and IR can be attenuated by N-acetylcysteine, and enhanced by 6-amino niacinamide. GEMM and allograft transplantation assays further confirmed their synergistic effect in vivo. This study provided insights into the connection between PI3K/AKT/mTOR signaling and the PPP underlying radioresistance and provided evidence of mechanisms supporting PI3K/mTOR inhibitors as possible therapeutic strategies to abrogate SCLC radioresistance.
研究领域:
肿瘤学
·
药理学
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细胞生物学
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分子生物学
·
放射生物学
✓ 已验证
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Ying Huang,Huisi Zhao,Yu Zhang,Chuanqi Zhao,Jinsong Ren,Xiaogang Qu
The nanozyme with NADPH oxidase (NOX)-like activity can promote the consumption of NADPH and the generation of free radicals. In consideration of that the upregulation of glucose-6-phosphate dehydrogenase (G6PD) would accelerate the compensation production of NADPH, for inhibition of G6PD activity, our designed bioorthogonal nanozyme can in situ catalyze pro-DHEA to produce G6PD inhibitor and dehydroepiandrosterone (DHEA) drugs to inhibit G6PD activity. Therefore, the well-defined platform can disrupt NADPH homeostasis, leading to the collapse of the antioxidant defense system in the tumor cells. The enzyme-like activity of PdCuFe is further enhanced when irradiated by NIR-II light. The destruction of NADPH homeostasis can promote ferroptosis and, in turn, facilitate mild photothermal therapy. Our design can realize NADPH depletion and greatly improve the therapeutic effect through metabolic regulation, which may provide inspiration for the design of bioorthogonal catalysis
研究领域:
癌症治疗
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生物医学工程
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纳米技术
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生物化学
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诊疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
TOXICOLOGY
·
2016
·
IF 3.817
Xu Wang,Yijie Bai,Guyue Cheng,Awais Ihsan,Feng Zhu,Yulian Wang,Yanfei Tao,Dongmei Chen,Menghong Dai,Zhengli Liu,Zonghui Yuan
Quinoxaline 1,4-dioxides (QdNOs) are widely used as a kind of antibacterial growth promoter in animal husbandry. The adrenal cortex was found to be one of the main toxic targets of QdNOs, accompanied by a decreased aldosterone level. However, the way in which QdNOs decrease production of the hormone aldosterone is far from clear. To illustrate the mechanism by which QdNOs damage the adrenal cortex and decrease aldosterone hormone levels, the QdNOs were screened to choose the drug with most toxic effects on aldosterone production, and then to reveal the mechanism between the gene and protein profiles in human adrenocortical cells (NCI-H295R cells). The results found that quinocetone (QCT) showed the highest adrenal toxic effect among QdNOs. After exposing H295R cells to 10 and 20 μM QCT for 24 h, compared with blank cells, the gene and protein expression profiles obtained were analyzed by microarray and MALDI TOF/TOF mass spectrometry, respectively. The results of microarray analysis suggested that ABCG1 and SREBF1, which were involved in the cholesterol biosynthetic and metabolic processes, and CYP17A1, NR4A2 and G6PD, which were related to aldosterone biosynthesis, were important molecular targets. It has been speculated that PKC and ERK pathways might be involved in the reduction of aldosterone production caused by QCT, through enhanced mRNA expression of CYP17A1. Additionally, JNK and p38MAPK signal transduction pathways might participate in apoptosis induced by QCT. Twenty-nine and 32 protein spots were successfully identified when cells were treated with 10 and 20 μM QCT, respectively. These identified proteins mainly included material synthesis and energy metabolism-related proteins, transcription/translation processing-related proteins, signal transduction proteins, cytoskeletal proteins, molecular chaperones, proteins related to response to stress, and transport proteins. Further investigations suggested that oxidative stress caused by QCT was exacerbated through disruption of the Keap1/Nrf2/ARE anti-oxidative stress pathway. Taken together, the data demonstrated for the first time that the Keap1/Nrf2/ARE pathway plays a crucial role in adrenal toxicity, and that CYP17A1 was the key switch to reduce the aldosterone production induced by QCT. Furthermore, large numbers of genes and proteins and entry points for research in the inhibition of aldosterone synthesis induced by QCT were offered, which will provide new insight into the adrenal toxicity of QdNOs and help to provide a theoretical foundation for the formulation of safety controls for products obtained from animals and to design new QdNOs with less harmful effects.
研究领域:
毒理学
·
药理学
·
内分泌学
·
分子生物学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2024
·
IF 6.1
Mingye Li,Yuyu Dong,Zheng Wang,Yanjun Zhao,Yujie Dai,Baoxin Zhang
Glucose-6-phosphate dehydrogenase (G6PD) is a promising target in cancer therapy. However, poor cellular uptake and off-target toxicity impeded the clinical translation of a canonical G6PD inhibitor (6-aminonicotinamide/6AN). Here, we report a prodrug strategy to address this issue. The tailored 6AN prodrug contains an azo-bearing protection moiety. The hydrophobic prodrug showed increased cellular uptake than 6AN and is vulnerable to hypoxia, resulting in NAD(P)H quinone dehydrogenase 1 (NQO1)-triggered cleavage of azo bonds. Intriguingly, the prodrug shows configuration-dependent anti-cancer potency. Despite the lower thermodynamic stability, the cis isomer showed enhanced cellular uptake compared to the trans counterpart due to the increased aqueous solubility. Moreover, the boosted potency of cis isomer compared to the trans isomer resulted from the enhancement of NOQ1-catalyzed 6AN release under hypoxia, a hallmark of solid tumors. The discovery of hypoxia-responsive 6AN prodrugs in the current work opens new avenues of G6PD-targeting cancer medicines via redox manipulation.
研究领域:
药学
·
癌症研究
·
药物递送系统
·
氧化还原生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2021
·
IF 7.376
Yue Zhang,Shibo Sun,Weiping Xu,Rui Yang,Yijia Yang,Jianli Guo,Kun Ma,Jianqiang Xu
Shikonin , a naturally occurring naphthoquinone with potent anti-tumor activity, has been reported to induce cancer cell death via targeting selenoenzyme thioredoxin reductase 1 (TrxR1; TXNRD1). However, the interaction between shikonin and TrxR1 remains unclear, and the roles of the cellular antioxidant system in shikonin induced cell death are obscure. Here, we found that shikonin modified the Sec 498 residue of TrxR1 to fully inhibit its antioxidant activity , however, the shikonin-modified TrxR1 still remained intrinsic NADPH oxidase activity, which promotes superoxide anions production. Besides, TrxR1 efficiently reduced shikonin in both selenocysteine dependent and selenocysteine independent manners, and the oxygen-coupled redox cycling of shikonin also generates excessive superoxide anions. The inhibitory effects and the redox cycling of shikonin towards TrxR1 caused cancer cell ROS-dependent necroptosis. Interestingly, as we evaluated, some cancer cell lines were insensitive to shikonin, especially kelch-like ECH associated protein 1 (KEAP1)-mutant non-small cell lung cancer (NSCLC) cells, which harbor constitutive activation of the nuclear factor-erythroid 2-related factor 2 (NRF2). NADPH bankruptcy caused by glucose starvation or glucose limitation (inhibiting glucose transporter 1 by BAY-876) could efficiently overcome the resistance of KEAP1-mutant NSCLC cells to shikonin. Glucose-6-phosphate dehydrogenase (G6PD), was known as a rate-limiting enzyme in the pentose phosphate pathway , however, the pharmacological inhibition of G6PD by 6-aminonicotinamide (6-AN), enhanced the shikonin-induced cytotoxicity but has no selectivity on KEAP1-mutant NSCLC cells. This study will be helpful in applying shikonin for potential chemotherapy, and in combinational treatment of KEAP1-mutant NSCLC.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2023
·
IF 15.1
Qing Yao,Jinyao Ye,Yahui Chen,Lihui Huang,Lining Sun,Zhinan He,Jianing Wu,Yingyi Zhao,Xinyu Zhao,Aimin Cai,Xiandan Chen,Hailun Zheng,Aliaksei Sysa,Congying Xie,Ruijie Chen,Longfa Kou
The clinical presentation of triple-negative breast cancer signifies a pathophysiological trajectory characterized by an aggressive nature. To satisfy the rapid tumor cell proliferation, glycolysis emerges as the primary modality for energy production, consequently engendering the copious generation of lactic acid. This, in turn, fosters an acidic microenvironment within the tumor milieu, which facilitates angiogenesis, tumor metastasis, extracellular matrix remodeling, and immune evasion. If the glycolytic flux was attenuated, a heightened influx of glucose-6-phosphate (G6P) towards the pentose phosphate pathway (PPP) ensues, promoting the synthesis of nicotinamide adenine dinucleotide phosphate (NADPH) and reduced glutathione (GSH). This orchestrated metabolic cascade gives rise to reductive equivalents and biosynthetic substrates, emblematic of a salient hallmark in the landscape of cancer cell metabolism. To surmount the quandary presented by aberrant tumor metabolism, we developed macrophage-membrane-coated metal–organic framework nanoparticles (AP@ZIF-Mem) to deliver atorvastatin (an inhibitor of MCT4, a lactic acid transporter within glycolysis) and polydatin (an inhibitor of G6PD, the rate-limiting enzyme of PPP) to interfere the glucose metabolism for sensitizing triple-negative breast cancer treatment. After i.v. injection, AP@ZIF-Mem could be accumulated into the tumor site via macrophage-biomimetic behavior. Through orchestrated intervention, these nanoparticles could provoke the accumulation of lactic acid within tumor cells, thereby precipitating a pronounced intratumoral acidosis; In parallel, the abrogation of G6PD function occasioned a surge in intracellular reactive oxygen species (ROS), consequentially culminating in diminished ribulose-5-phosphate and NADPH production. This dual-pronged intervention not only disrupted the tumor's energy provisioning framework but also perturbed the aberrant redox state of the tumor milieu, thereby sensitizing tumor treatment and impeding the metastatic trajectory. This study provided a paradigm of treatment/adjuvant treatment via the manipulation of glucose metabolism for triple-negative breast cancer.
研究领域:
肿瘤学
·
药学
·
纳米技术
·
癌症代谢
·
药物递送系统
✓ 已验证
产品关联
DOI
高影响因子
PHARMACOLOGICAL RESEARCH
·
2019
·
IF 5.574
Rinkiko Suguro,Xiao-cong Pang,Zhong-wen Yuan,Si-yao Chen,Yi-Zhun Zhu,Ying Xie
Silybin (SB) is widely used to treat chronic liver diseases , especially this compound is much efficient for the treatments of alcoholic and non-alcoholic steatohepatitis (NASH). However, low bioavailability seriously limits wide-application of SB in biomedical niche. Prior to this study, we found that tangeretin (TG) could remarkably increase the bioavailability of SB by the inhibition of efflux transporters, which encourges us to therapeutical discovery of SB and TG combitional use against NASH. Here, we revealed that TG is capable of improving hepatic-protective activity of SB in mice with NASH by interfering liver oxidative stress, inflammation, and lipid accumulation. In addition, TG was observed to enhance the exposural level of SB in the plasma and liver of mice. Our metabolome assay confirmed that amino acid metabolism and lipid biosynthesis mostly accounted for combitional use of SB and TG to teat NASH in mice, basically biosynthesis of unsaturated fatty acids was mostly affected. Notably, significant inhibitions in fatty acid generating and transporting proteins such as G6PD, FABP4, LPL and CD36/FAT, and cholesterol metabolism enzyme CYP27A1 as well as nuclear transcription factors FXR , PPAR-γ, and LXR were illustrated to decipher therapeutic mechanisms of SB and TG against experimental NASH . Taken together, the strategy based combitional use of SB and TG has a potential-capacity to treat NASH.
研究领域:
肝病学
·
药理学
·
代谢组学
✓ 已验证
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2019
·
IF 3.775
Jiankang Wang,Yutong He,Deqing Yu,Liang Jin,Xiaobao Gong,Baoshun Zhang
Perilla oil (PerO), a natural oil with a high unsaturated fatty acid content derived from the mature seeds of Perilla frutescens , is a homology of medicine and food . The type 2 diabetes mellitus (T2DM) model was successfully established using a high-fat and high-sugar diet combined with a single low-dose of streptozocin (STZ). PerO intervention reduced the levels of fasting blood glucose and the level, size and accumulation of lipid droplets , increased the insulin level and diminished the body weight loss. PerO pretreatment markedly promoted the serum levels of alanine transaminase (ALT) and aspartate transaminase alanine (AST) and inhibited the levels of glucose (GLU), glucose-6-phosphate dehydrogenase (G6PD), triglycerides (TGs) and total cholesterol (TC). Moreover, PerO treatment enhanced the expression of phosphoinositide-3 kinase (PI3K)/protein kinase B (AKT) and activated the expression of glucose transporter 4 (Glut4) and phospho-AKT serine/threonine kinase (p-AS160) in the liver. Additionally, PerO treatment distinctly decreased the abundance of Aerococcus and facilitated the richness of Alloprevotella in the intestine, as well as accelerated the restoration of the gut microflora diversity. Thus, PerO regulates intestinal microbiota and alleviates insulin resistance through the PI3K/AKT signaling pathway in type-2 diabetic KKAy mice and may be a potential functional food for diabetic treatment.
研究领域:
营养学
·
糖尿病
·
分子生物学
·
微生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）