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Iranian Journal of Basic Medical Sciences، جلد ۲۵، شماره ۳، صفحات ۲۹۵-۳۰۱
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عنوان انگلیسی 1,3,5-triazines inhibit osteosarcoma and avert lung metastasis in a patient-derived orthotopic xenograft mouse model with favorable pharmacokinetics
چکیده انگلیسی مقاله Objective(s): Osteosarcoma is a major solid malignant tumor of bone, possessing significant burden on healthcare due to non-availability of specific anticancer agents. The current study was conducted to identify novel 1,3,5-triazine derivatives against osteosarcoma. Materials and Methods: The compounds were synthesized in a straight-forward two-step reaction and subsequently tested against PI3K and mTOR kinase and anticancer activity against osteosarcoma cells (MG-63, U2-OS, and Saos-2). The effect of the most potent compound was evaluated on apoptosis and cell phase of Saos-2 cells. The pharmacological activity was further established in the patient-derived orthotopic xenograft (PDOX) mouse model. Results: The developed compounds 8 (a-f) showed significant inhibitory activities against PI3K, mTOR, and OS cells. Among the tested series, compound 8a showed highly potent PI3K/mTOR inhibitory activity with significant anticancer activity against Saos-2 cells compared with Imatinib as standard. It also induces apoptosis and causes G2/M arrest in Saos-2 cells. Compound 8a significantly improved body weight, reduced tumor volume, and inhibited lung metastasis in athymic nude mice in a PDOX mouse model. It also showed optimal pharmacokinetic parameters in SD rats. Conclusion: In summary, 1,3,5-triazine analogs were identified as new PI3K/mTOR inhibitors against osteosarcoma.
کلیدواژه‌های انگلیسی مقاله 1,3,5-triazine, Apoptosis, mTOR, Osteosarcoma, PI3K
نویسندگان مقاله | Qing Su
Department of Orthopedic Oncology, Yantai Shan Hospital, Yantai, 264003, China


| Baolin Xu
Department of Orthopedics, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, 310006, China


| Zhoubin Tian
Departments of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China


| Ziling Gong
Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, 200233, China
نشانی اینترنتی https://ijbms.mums.ac.ir/article_19829.html
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نوع مقاله منتشر شده Original Article
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