The Neem Limonoid Nimbolide Modulates Key Components of the DNA Damage Response Signalling in Cellular and Animal Models of Oral Squamous Cell Carcinoma.

IF 2.2 4区 医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY
Soundararajan Arvindh, Manashi Priyadarshini, Abdul Basit Baba, Veeran Veeravarmal, Rajakishore Mishra, Rupesh Dash, Siddavaram Nagini
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引用次数: 0

Abstract

Background: Deregulated DNA damage response (DDR) network is implicated in cancer progression and therapy resistance.

Objective: The present study was designed to investigate whether nimbolide, an anticancer neem limonoid, targets key components of the DDR signalling pathway in cellular and animal models of oral squamous cell carcinoma (OSCC).

Methods: OSCC cells (SCC-4 and SCC-9), 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinoma model, chemoresistant OSCC patient-derived xenograft (PDX) model established in athymic nude mice, and tissue sections from patients with oral premalignant/malignant disease were used for the study. Key molecules that orchestrate the DDR, including the MRN complex, ATM, DNA-PKcs, H2AX, and p53, were analysed by qRTPCR, immunoblotting, immunofluorescence, and immunohistochemistry. Cell proliferation and apoptosis indices were evaluated.

Results: Nimbolide significantly reduced 8-oxodG levels, expression of MRN, ATMS1891, and γ- H2AX, with an increase in p-p53S15 in OSCC cells as well as in the HBP model. Nimbolide potentiated the effect of KU-55933 in ATM inhibition. In the PDX model, nimbolide suppressed tumor formation, stimulated DDR and apoptosis, inhibited cell proliferation, and enhanced sensitivity to cisplatin. Analysis of p-ATM expression revealed a significant increase during the sequential progression of hamster and human OSCC.

Conclusion: This study provides compelling evidence that nimbolide functions as a DDR inhibitor in cellular and hamster OSCC models and as a DDR activator in the PDX model primarily by targeting ATM. Small molecules like nimbolide that modulate DDR are of immense benefit in cancer therapy. The study has also unveiled p-ATM as a promising biomarker of tumour progression in human OSCCs.

楝树类柠檬素 Nimbolide 在口腔鳞状细胞癌细胞模型和动物模型中调节 DNA 损伤应答信号的关键成分。
背景:DNA 损伤应答(DDR)网络失调与癌症进展和耐药性有关:DNA损伤应答(DDR)网络失调与癌症进展和耐药性有关:本研究旨在探讨印楝素(一种抗癌印楝素)是否能在口腔鳞状细胞癌(OSCC)的细胞和动物模型中靶向 DDR 信号通路的关键成分:研究使用了口腔鳞状细胞癌(OSCC)细胞(SCC-4 和 SCC-9)、7,12-二甲基苯并[a]蒽(DMBA)诱导的仓鼠颊囊癌(HBP)模型、在无胸腺裸鼠体内建立的化疗耐药 OSCC 患者异种移植(PDX)模型以及口腔恶性肿瘤前病变/恶性肿瘤患者的组织切片。通过 qRTPCR、免疫印迹、免疫荧光和免疫组化等方法分析了协调 DDR 的关键分子,包括 MRN 复合物、ATM、DNA-PKcs、H2AX 和 p53。对细胞增殖和凋亡指数进行了评估:结果:在 OSCC 细胞和 HBP 模型中,宁波利可明显降低 8-oxodG 水平、MRN、ATMS1891 和 g- H2AX 的表达,并增加 p-p53S15。Nimbolide 增强了 KU-55933 抑制 ATM 的效果。在 PDX 模型中,宁博利抑制了肿瘤的形成,刺激了 DDR 和细胞凋亡,抑制了细胞增殖,并提高了对顺铂的敏感性。对p-ATM表达的分析表明,在仓鼠和人类OSCC的连续进展过程中,p-ATM的表达显著增加:本研究提供了令人信服的证据,证明宁波利在细胞和仓鼠 OSCC 模型中作为 DDR 抑制剂,在 PDX 模型中作为 DDR 激活剂,主要是通过靶向 ATM 发挥作用。像宁博利这样能调节 DDR 的小分子药物对癌症治疗大有裨益。这项研究还揭示了 p-ATM 作为人类 OSCC 肿瘤进展生物标志物的前景。
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来源期刊
Current pharmaceutical biotechnology
Current pharmaceutical biotechnology 医学-生化与分子生物学
CiteScore
5.60
自引率
3.60%
发文量
203
审稿时长
6 months
期刊介绍: Current Pharmaceutical Biotechnology aims to cover all the latest and outstanding developments in Pharmaceutical Biotechnology. Each issue of the journal includes timely in-depth reviews, original research articles and letters written by leaders in the field, covering a range of current topics in scientific areas of Pharmaceutical Biotechnology. Invited and unsolicited review articles are welcome. The journal encourages contributions describing research at the interface of drug discovery and pharmacological applications, involving in vitro investigations and pre-clinical or clinical studies. Scientific areas within the scope of the journal include pharmaceutical chemistry, biochemistry and genetics, molecular and cellular biology, and polymer and materials sciences as they relate to pharmaceutical science and biotechnology. In addition, the journal also considers comprehensive studies and research advances pertaining food chemistry with pharmaceutical implication. Areas of interest include: DNA/protein engineering and processing Synthetic biotechnology Omics (genomics, proteomics, metabolomics and systems biology) Therapeutic biotechnology (gene therapy, peptide inhibitors, enzymes) Drug delivery and targeting Nanobiotechnology Molecular pharmaceutics and molecular pharmacology Analytical biotechnology (biosensing, advanced technology for detection of bioanalytes) Pharmacokinetics and pharmacodynamics Applied Microbiology Bioinformatics (computational biopharmaceutics and modeling) Environmental biotechnology Regenerative medicine (stem cells, tissue engineering and biomaterials) Translational immunology (cell therapies, antibody engineering, xenotransplantation) Industrial bioprocesses for drug production and development Biosafety Biotech ethics Special Issues devoted to crucial topics, providing the latest comprehensive information on cutting-edge areas of research and technological advances, are welcome. Current Pharmaceutical Biotechnology is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments.
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