SPECTROCHIMICA ACTA PART A-MOLECULAR AND BIOMOLECULAR SPECTROSCOPY
·
2016
·
IF 2.653
Li-Na Wen,Meng-Xia Xie
KRAS promoter can form G-quadruplex structure and regulate gene transcription. The drugs which can bind with G-quadruplex of KRAS promoter may be potential remedy for treatment of cancers associated with KRAS mutation. The interaction mechanism between the G-quadruplex of KRAS promoter and three isoquinoline alkaloids (jatrorrhizine, berberine and sanguinarine) has been investigated by UV-visible, fluorescence and circular dichroism spectroscopic methods. The results showed that the three alkaloids can form complexes with G-quadruplex KRAS promoter with the molecular ratio of 1:1, and the binding constants were (0.90 ± 0.16) × 10 6 L mol − 1 , (0.93 ± 0.21) × 10 6 L mol − 1 and (1.16 ± 0.45) × 10 6 L mol − 1 for jatrorrhizine , berberine and sanguinarine . The absorption spectra, KI quenching and fluorescence anisotropy and polarization studies suggested jatrorrhizine and berberine interacted with G-quadruplex by not only end-stacking binding mode but also grooves or loops binding mode, while sanguinarine by end-stacking binding mode. Sanguinarine was more beneficial to maintain the stability and parallel conformation of KRAS promoter G-quadruplex. MTT assay was performed to evaluate antiproliferation effects of the three isoquinoline alkaloids on SW620 cells, and the antiproliferation effects of the three alkaloids were sanguinarine > berberine > jatrorrhizine. All the three alkaloids can bind with KRAS promoter G-quadruplex, and sanguinarine had the better binding property and antiproliferation effects on SW620 cells. The results obtained are meaningful to explore potential reagents targeting the parallel G-quadruplex structure of KRAS promoter for gene theraphy of colorectal carcinomas.
研究领域:
分子生物学
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癌症研究
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药理学
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生物化学
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Qinglian Hu,Jiayu Feng,Lulu Qi,Yuanxiang Jin
Pancreatic ductal adenocarcinoma (PDAC) is a clinically challenging cancer and is often characterized with rich stroma and mutated KRAS, which determines the tumor microenvironment (TME) and therapy response. Turning immunologically “cold” PDAC into “hot” is an unmet need to improve the therapeutic outcome. Herein, we propose a programmable strategy by sequential delivery of pirfenidone (PFD) and nanoengineered KRAS specific inhibitor (AMG510) and gemcitabine (GEM) liposomes. PFD could achieve precise reduction of the extracellular matrix (ECM) by reprogramming pancreatic stellate cells (PSCs). Subsequently, targeting the KRAS-directed oncogenic signaling pathway effectively inhibited tumor proliferation and migration, which sensitized a chemotherapeutic drug and promoted immunogenic cell death (ICD). In preclinical mouse models of PDAC, PFD mediated stromal modulation enhanced the deep penetration of nanoparticles and improved their subsequent performance in tumor growth inhibition. The molecular mechanisms elucidated that the stroma intervention and KRAS signal pathway regulation reshaped the immunosuppression of PDAC and optimized cytotoxic T-cell-mediated antitumor immunity with sustained antitumor memory. Overall, our study provides a practical strategy with clinical translational promise for immunologically cold tumor PDAC treatment.
研究领域:
肿瘤学
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免疫学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2025
·
IF 10.2
Yurong Xiang,Qiang Liu,Kang Liu,Liuxian Chen,Fengjiao Chen,Tao Li,Siqi Li,Qiang Yu,Quan Lv,Zheng Xiang
Multi-drug combination therapy is one of the most effective strategies for the treatment of drug-resistant and advanced tumors. Modern nanodrug delivery systems are crucial for multi-drug combination therapy and gene therapy. However, research on direct injection of RNAi has not yielded significant results. Artificial vectors are emerging as promising delivery systemts for RNA for gene therapy. In this study, a multi-drug therapy system was built based on a biodegradable exosome nano-platform exploiting the protective and low immunogenic properties of exosomes for RNA. This work aimed to accomplish the co-delivery of siRNA and 3-Bromopyruvic acid (3BP) on an exosome nanoplatform, enhancing targeting by coupling cetuximab (CTX) to exosome membranes, resulting in a new nanomedicine Exo@siRNA/3BP-CTX (ERBC) engineered exosomes. The synthesis conditions were optimized to obtain stable, safe, and effective nanomedicines. Successful targeting of tumors with CTX inhibited KRAS oncogene expression and significantly reduced glucose uptake by cancer cells. This enhanced the starvation therapy effect of the energy deprivation agent 3BP, thus promoting excessive autophagy activation in cells and doubling apoptosis. However, ERBC combined with CTX therapy restored cellular chemosensitivity to CTX. These findings indicate that engineered exosomes with dual therapeutic activities is a promising approach for treating refractory KRAS-mutant cancers.
研究领域:
肿瘤学
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基因治疗
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纳米医学
✓ 已验证
DOI
PubMed
高影响因子
ACS Nano
·
2019
·
IF 13.903
Chao Kong,Yang Li,Zhengsheng Liu,Junxiao Ye,Zhaohui Wang,Ling Zhang,Weijian Kong,Huiqin Liu,Chun Liu,Huanhuan Pang,Zeping Hu,Jinming Gao,Feng Qian
Survival of KRAS mutant pancreatic cancer is critically dependent on reprogrammed metabolism including elevated macropinocytosis, autophagy, and lysosomal degradation of proteins. Lysosomal acidification is indispensable to protein catabolism, which makes it an exploitable metabolic target for KRAS mutant pancreatic cancer. Herein we investigated ultra-pH-sensitive micelles (UPSM) with pH-specific buffering of organelle pH and rapid drug release as a promising therapy against pancreatic cancer. UPSM undergo micelle–unimer phase transition at their apparent pKa, with dramatically increased buffer capacity in a narrow pH range (<0.3 pH). Cell studies including amino acid profiling showed that UPSM inhibited lysosomal catabolism more efficiently than conventional lysosomotropic agents (e.g., chloroquine) and induced cell apoptosis under starved condition. Moreover, pH-triggered rapid drug release from triptolide prodrug-loaded UPSM (T-UPSM) significantly enhanced cytotoxicity over non-pH-sensitive micelles (T-NPSM). Importantly, T-UPSM demonstrated superior safety and antitumor efficacy over triptolide and T-NPSM in KRAS mutant pancreatic cancer mouse models. Our findings suggest that the ultra-pH-sensitive nanoparticles are a promising therapeutic platform to treat KRAS mutant pancreatic cancer through simultaneous lysosomal pH buffering and rapid drug release.
研究领域:
肿瘤学
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药学
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癌症生物学
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纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PeerJ
·
2020
·
IF 2.379
Xiaoyan Li,Yiyan Lu,Xiaojun Ou,Sijing Zeng,Ying Wang,Xiaoxiao Qi,Lijun Zhu,Zhongqiu Liu
Background This study aimed to systematically profile the alterations and sex- and age-related differences in the drug metabolizing enzymes (DMEs) in a KRAS-mutant mouse model of lung cancer (KRAS mice). Methodology In this study, the LC-MS/MS approach and a probe substrate method were used to detect the alterations in 21 isoforms of DMEs, as well as the enzymatic activities of five isoforms, respectively. Western blotting was applied to study the protein expression of four related receptors. Results The proteins contents of CYP2C29 and CYP3A11, were significantly downregulated in the livers of male KRAS mice at 26 weeks (3.7- and 4.4-fold, respectively, p < 0.05). SULT1A1 and SULT1D1 were upregulated by 1.8- to 7.0- fold at 20 ( p = 0.015 and 0.017, respectively) and 26 weeks ( p = 0.055 and 0.031, respectively). There were positive correlations between protein expression and enzyme activity for CYP2E1, UGT1A9, SULT1A1 and SULT1D1 ( r 2 ≥ 0.5, p < 0.001). Western blotting analysis revealed the downregulation of AHR, FXR and PPARα protein expression in male KRAS mice at 26 weeks. For sex-related differences, CYP2E1 was male-predominant and UGT1A2 was female-predominant in the kidney. UGT1A1 and UGT1A5 expression was female-predominant, whereas UGT2B1 exhibited male-predominant expression in liver tissue. For the tissue distribution of DMEs, 21 subtypes of DMEs were all expressed in liver tissue. In the intestine, the expression levels of CYP2C29, CYP27A1, UGT1A2, 1A5, 1A6a, 1A9, 2B1, 2B5 and 2B36 were under the limitation of quantification. The subtypes of CYP7A1, 1B1, 2E1 and UGT1A1, 2A3, 2B34 were detected in kidney tissue. Conclusions This study, for the first time, unveils the variations and sex- and age-related differences in DMEs in C57 BL/6 (WT) mice and KRAS mice.
研究领域:
药理学
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肿瘤学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
SENSORS AND ACTUATORS B-CHEMICAL
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2022
·
IF 9.221
Peilin Wang,Zizhun Wang,Zhenrun Li,Yuan Wang,Qiang Ma
In this work, a novel electrochemiluminescence (ECL) biosensor was fabricated to detect the mutant KRAS gene in the tumor tissues. Firstly, a new kind of chitosan-based dots was prepared and regulated by phenylboronic acid (PBA) as ECL nanoprobe. Furthermore, the electrochemically deposited Ag structures with controllable morphology have been developed on the electrode. The detailed electrochemical deposition condition of Ag structure has been investigated deeply. Due to the synergistic effect of the large active surface area and the high conductivity , the layered Ag flower-like structure with branches can significantly enhance the ECL intensity of CS-PBA dots by 12.1 times. Finally, the toehold mediated strand displacement strategy was employed in the ECL biosensor to quantitatively detect mutant KRAS gene with the range of 0.01 pM to 10 nM. The limit of detection was 3.3 fM. This biosensor has been used successfully to analyze the target DNA in the tumor tissues of actual cancer patients . The results showed the novel sensing platform possessed great potential for clinical analysis.
研究领域:
生物医学工程
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分析化学
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分子生物学
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癌症研究
✓ 已验证
产品关联
DOI
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2022
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IF 7.088
Zhendong Song,Linlin Lou,Guangjin Fan,Lu Liu,Yang Ge,He Liu,Albert S.C. Chan,Xiaolei Zhang,Xiao-Feng Xiong
Oncogene KRAS plays predominant roles in human cancers by regulating cell proliferation , differentiation, and migration. Recent progress revealed that directly target KRAS G12C with allosteric inhibitors that covalently bind to the switch Ⅱ pocket is feasible. Herein, series of pyrrolo[2,3- d ]pyrimidine derivatives were designed and synthesized through systematic structural optimization, leading to the discovery of compound 2-(( S )-1-acryloyl-4-(2-((( 2R , 7aS )-2-fluorohexahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-7-methyl-6-(8-methylnaphthalen-1-yl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)piperazin-2-yl)acetonitrile ( 50 ) with high KRAS/SOS1 inhibitory potency (IC 50 = 0.21 μM) and strong anti-proliferation activities on cancer cells harboring KRAS p.G12C . Compound 50 also exhibited satisfactory selectivity , moderate pharmacokinetic characters, and good anticancer effects in vivo . Meaningfully, the identification of these compounds highlights the necessity of an appropriate conformational constraint for acquiring the applicable binding pose in the cryptic pocket of KRAS, and the results support efforts toward design of KRAS inhibitors with novel skeleton and binding mechanism could be beneficial for targeting the acquired drug resistance.
研究领域:
肿瘤学
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药理学
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药物化学
✓ 已验证
DOI
PubMed
高影响因子
ANALYTICAL SCIENCES
·
2020
·Vol. 36
·期 12
·1529-1533
·
IF 2.049
Zeng Ni,Guo Yaxin,Xiang Juan
Monitoring the changes in the level of KRAS point mutation (the concentration fraction of the KRAS point mutated DNA to the total DNA) in clinical treatment progress can guide and greatly improve the personalized therapy and therapeutic evaluation of patients with cancer. In this work, based on FRET fluorescence quenching and apyrimidinic site-induced guanine/pterin specific binding, we developed a pterin-FAM-TAMRA tri-color fluorescence sensing system to assess the level of KRAS point mutation in one step. The responses from TAMRA displayed good and similar linear correlations in the range from 60 nM to 2 µM for all four types of DNA, resulting in a common linear equation related to the T-DNA concentration ( N aftAMRA = 2.908 c T-DNA + 0.364). Meanwhile, the responses from pterin showed excellent selectivity to W-DNA and an excellent linear correlation to the W-DNA in the concentration range from 60 nM to 1 µM ( N ΔFpterin =–0.364 c gDNA-G + 0.034). This biosensor has an effective concentration range for detecting KRAS point mutations. Especially, because the apyrimidinic site-induced guanine/pterin binding is selective for the detection of wild-type DNA, the sensing system can be applied for clinical mutation level detection of all kinds of KRAS point mutations (G → A, G → C and G → T) in blood samples, which is crucial for the personalized therapy and therapeutic evaluation of patients with most KRAS-related cancer types.
研究领域:
分子生物学
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癌症研究
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生物医学工程
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遗传学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Nano Materials
·
2024
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IF 5.3
Ailing Su,Yuan Liu,Weihan Sun,Chongyang Liang,Weiqing Xu,Alison Rodger,James Piper,Yuling Wang,Shuping Xu
Specifically identifying one-base mismatched gene sequences is of significance for early diagnosis, prognosis, treatment, and evaluation. However, traditional polymerase chain reaction and next-generation sequencing methods require relatively long, carefully implemented analytical procedures. Here, we report a nanoconjugate that can synchronously discriminate two types of KRAS gene mutation due to the dual-recognition mechanism of the CRISPR/dCas system with the surface-enhanced Raman scattering (SERS) response output. This method applied two sets of CRISPR/dCas9 units to collect all KRAS genes via a magnetic force and the specific mutant sequence labeled through SERS nanotags, forming a dual-clamping architecture. This sensing conjugate was sufficient to quantify the amount of the two different mutations simultaneously with a low cross-reactivity. Consequently, we deem that this sensing assay satisfies the great characteristics of a genetic analytical tool with high specificity, accuracy, and simplicity, highlighting its potential as an alternative for screening multigene events and relevant genetic biomarkers.
研究领域:
分子生物学
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纳米技术
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基因工程
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生物医学工程
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癌症研究
✓ 已验证
产品关联
DOI
高影响因子
MOLECULES
·
2025
·Vol. 30
·期 16
·3436
·
IF 4.6
Junsong Qin,Zhepeng Chen,Chuangyan Wang,Lin Mai,Xian Wang,Junfeng Li,Hui Liu,Yun Song
This study systematically explored the interaction mechanisms between two KRAS G12C inhibitors (Sotorasib and Adagrasib) and human serum albumin (HSA) via UV-vis spectroscopy, fluorescence spectroscopy, three-dimensional fluorescence spectroscopy, and molecular docking methods. The experimental findings demonstrated that both drugs caused static quenching of HSA fluorescence, with binding constants of 13.64 × 103M−1(Sotorasib) and 63.67 × 103M−1(Adagrasib), demonstrating significant selectivity differences in their binding affinities. UV spectral analysis demonstrated distinct microenvironmental perturbations: Sotorasib and Adagrasib induced a shift (∆λ = 7 nm and ∆λ = 8 nm, respectively) at 211 nm, consistent with altered polarity in HSA’s binding pockets. Fluorescence spectroscopy confirmed a 1:1 binding stoichiometry, with Stern-Volmer analysis validating static quenching as the dominant mechanism. Three-dimensional fluorescence spectra further highlighted Adagrasib’s stronger conformational impact, reducing tyrosine and tryptophan residue fluorescence intensities by 16% (Peak 1) and 10% (Peak 2), respectively, compared to Sotorasib. Molecular docking revealed divergent binding modes: Sotorasib occupied Sudlow Site I via three hydrogen bonds and hydrophobic interactions (∆G = −24.60 kJ·mol−1), whereas Adagrasib bound through one hydrogen bond and hydrophobic forces (∆G = −30.92 kJ·mol−1), with stability differences attributed to structural characteristics. This study uses multispectral technology and molecular docking to reveal the binding mechanism of Sotorasib and Adagrasib with HSA, providing a theoretical basis for designing highly targeted albumin nanocarriers. The strong binding properties of Adagrasib and HSA may reduce the toxicity of free drugs, providing direction for the development of long-acting formulations.
研究领域:
药理学
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生物化学
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分子生物学
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结构生物学
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药物递送系统
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癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
TALANTA
·
2019
·
IF 4.916
Ni Zeng,Juan Xiang
KRAS G12D point mutation plays an important role in the incidence of non-small-cell lung cancer (NSCLC) as well as colorectal cancer, pancreatic cancer and breast cancer. Here, we developed a novel anchor-like DNA (alDNA) electrochemical sensor for the detection of KRAS point mutation level (the concentration ratio of the specific KRAS point mutant DNA (M-DNA) to the total DNA (t-DNA) of both mutant and wild-type DNAs carrying the same allele). Compared to those conventional ligation-based DNA sensors, the proposed alDNA sensor achieved the one-step capture of both wild-type and mutant DNA, and the subsequent detection on one chip, which effectively decreased systematic errors from the uncertain differences on the interfacial structural and microenvironmental changes, improved the detection accuracy. Also, with the usage of formamide-NaCl solution, the whole detection process including the denaturation of double-stranded DNA was performed under mild temperature conditions (~40 °C). It greatly decreased the cost and improved the reproducibility and feasibility of the method. Based on it, the linear correlations with the logarithm of concentration in wide range from 0.1 pM to 10 nM for t-DNA and from 100 pM to 10 nM for M-DNA were achieved, respectively. The analysis of t-DNA- and M-DNA-spiked human serum samples revealed the high accuracy of the method. This alDNA sensor is convenient, low-cost and time-saving, with broad dynamic range, high sensitivity and selectivity . It can meet the demands of the clinical detection on the KRAS point mutation level in blood samples, which means significant for the earlier NSCLC diagnosis, individualized treatment, and therapeutic efficacy evaluation.
研究领域:
癌症生物学
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分子诊断学
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电化学
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临床化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2023
·
IF 17.1
Yukun Huang,Yu Chen,Songlei Zhou,Laozhi Xie,Kaifan Liang,Jianpei Xu,Qian Zhang,Huan Chen,Dayuan Wang,Qingxiang Song,Gan Jiang,Ni Mei,Fenfen Ma,Huiping Lu,Xiaoling Gao,Jun Chen
Metabolic therapy targeting the metabolic addictions driven by gain-of-function mutations in KRAS is promising in fighting cancer through selective killing of malignant cells without hurting healthy cells. However, metabolic compensation and heterogeneity make current metabolic therapies ineffective. Here, we proposed a biomimetic “Nutri-hijacker” with “Trojan horse” design to induce synthetic lethality in KRAS-mutated (mtKRAS) malignant cells by hitchhiking and reprogramming the metabolic addictions. Nutri-hijacker consisted of the biguanide-modified nanoparticulate albumin that impaired glycolysis and a flavonoid that restrained glutaminolysis after the macropinocytosis of Nutri-hijacker by mtKRAS malignant cells. Nutri-hijacker suppressed the proliferation and spread of mtKRAS malignant cells while lowering tumor fibrosis and immunosuppression. Nutri-hijacker significantly extended the lifespan of pancreatic ductal adenocarcinoma (PDAC)-bearing mice when combined with the hydroxychloroquine-based therapies that failed in clinical trials. Collectively, our findings demonstrated that Nutri-hijacker is a strong KRAS mutation-customized inhibitor and the synthetic lethality based on mtKRAS-driven metabolic addictions might be a promising strategy against PDAC.
研究领域:
肿瘤学
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分子生物学
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癌症治疗
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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）