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Targeting SAMHD1: To overcome multiple anti-cancer drugs resistance in hematological malignancies

Genes & Diseases 2023年第3期10卷 891-900页

作者： Tao Wang Ping Liu Jianmin Yang Department of Hematology Institute of HematologyChanghai HospitalNaval Medical UniversityShanghai 200433China

Sterile α motif and histidine/aspartic acid domain containing protein 1 (SAMHD1) is a deoxynucleoside triphosphate (dNTPs) triphosphohydrolase that can hydrolyze dNTPs into deoxynucleosides and triphosphates to keep the balance of the intracellular dNTPs pool. Moreover, it has been reported that SAMHD1 plays a role in regulating cell proliferation and the cell cycle, maintaining genome stability and inhibiting innate immune responses. SAMHD1 activity is regulated by phosphorylation, oxidation, SUMOylation, and O-GlcNAcylation. SAMHD1 mutations have been reported to cause diseases, including chronic lymphocytic leukemia and mantle cell lymphoma. SAMHD1 expression in acute myeloid leukemia predicts inferior prognosis. Recently, it has been revealed that SAMHD1 mediates the resistance to anti-cancer drugs. This review will focus on SAMHD1 function and regulation, the association between SAMHD1 and hematological malignancies and will provide updated information on SAMHD1 mediating resistance to nucleoside analogue antimetabolites, topoisomerase inhibitors, platinum-derived agents and DNA hypomethylating agents. Furthermore, histone deacetylase inhibitors and tyrosine kinase inhibitors indirectly increase anti-cancer drug resistance by increasing SAMDH1 activity. We herein highlight the importance of the development of novel agents targeting SAMHD1 to overcome treatment resistance of hematological malignancies, which would be an opportunity to improve the outcome of patients with refractory hematological malignancies.

关键词： anti-cancer drugs Hematological malignancies Resistance mechani sm SAMHD1 Regulation

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Control the Silver Content in the Preparation Process of Platinum Group anti-cancer drugs

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贵金属 2012年第A1期33卷 243-245页

作者： HE Jian ZHU Zhebin LI Xuejie LUAN Chunfang PENG Juan WANG Qinkun PU Shaopin Kunming Guiyan Pharmaceutical Co. Ltd.Kunming 650106China

In order to control the silver content in the preparation process of platinum group anti-cancer drugs, we put two kinds of color reagent to color in the production process of the platinum anti-cancer drugs by UV spectra measurement to control drugs production of platinum anticancer, thus we could control the silver content in the drugs so that it meets the pharmacopoeia standards of US and

关键词： silver platinum anti-cancer drugs

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Cellular irinotecan resistance in colorectal cancer and overcoming irinotecan refractoriness through various combination trials including DNA methyltransferase inhibitors: a review

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cancer Drug Resistance 2021年第4期4卷 946-964页

作者： Shogo Ozawa Toshitaka Miura Jun Terashima Wataru Habano Division of Pharmacodynamics and Molecular Genetics School of PharmacyIwate Medical UniversityYahabaIwate 0283694Japan

Treatment with pharmacological drugs for colorectal cancer(CRC)remains unsatisfactory.A major cause of failure in pharmacotherapy is the resistance of colon cancer cells to the drugs,creating an urgent issue.In this review,we summarize previous studies on the resistance of CRC cells to irinotecan and discuss possible reasons for refractoriness.Our review presents the following five major causes of irinotecan resistance in human CRC:(1)cellular irinotecan resistance is induced mainly through the increased expression of the drug efflux transporter,ABCG2;(2)cellular irinotecan resistance is also induced in association with a nuclear receptor,pregnane/steroid X receptor(PXR/SXR),which is enriched in the CYP3A4 gene enhancer region in CRC cells by exposing the cells to SN-38;(3)irinotecan-resistant cells possess either reduced DNA topoisomerase I(Top1)expression at both the mRNA and protein levels or Top1 missense mutations;(4)alterations in the tumor microenvironment lead to drug resistance through intercellular vesicle-mediated transmission of miRNAs;and(5)CRC stem cells are the most difficult targets to successfully treat CRC.In the clinical setting,CRC gradually develops resistance to initially effective irinotecan-based therapy.To solve this problem,several clinical trials,such as irinotecan plus cetuximab vs.cetuximab monotherapy,have been conducted.Another clinical trial on irinotecan plus guadecitabine,a DNA-methyltransferase inhibitor,has also been conducted.

关键词： Drug resistance colorectal cancer anti-cancer drugs irinotecan ABCG2 DNA topoisomerase I cancer stem cells epigenetics

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Research on the effect of Oleanolic Acid Derivatives and related mechanisms in breast cancer

Research on the effect of Oleanolic Acid Derivatives and rel...

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2021年中国肿瘤标志物学术大会暨第十五届肿瘤标志物青...

作者： Jun Yang Shisheng Wang Xiaorui Li Yiwen Ma Tao Sun Department of Breast Medicine Cancer Hospital of China Medical University College of Pharmaceutical Science and Technology Dalian University of Technology Key Laboratory of Liaoning Breast cancer Research

Background: In recent years, much attention has been paid to the application of oleanolic acid and its derivatives as anti-cancer drugs to limit the development of cancer. Studies have shown that oleanolic acid and synthetic derivatives have obvious anti-tumor effects. In this study, in order to solve the problems of poor bioavailability and severe adverse events of oleanolic acid and its derivatives, we developed a new compound（ZQL-3 d） introducing chemical groups of Mannich base derivatives and Michael receptor derivatives, and evaluated the anti-tumor effect and related mechanism of ZQL-3 d in breast cancer cells.Methods: cck8, clone formation, scratch wound healing, and transwell assay were used to verify the biological function of ZQL-3 d in breast cancer cells, and the cell cycle and apoptosis were analyzed by flow cytometry. The expression levels of cell cycle and apoptosis-related pathways were detected by molecular biotechnology including qPCR and Western Blot.Results: We found that ZQL-3 d had significant anti-cancer activity in three different molecular types of breast cancer cells（MCF-7, MDA-MB-231, SKBR3）. In breast cancer cells incubated with ZQL-3 d,the proportion of early apoptosis and the proportion of cells in G0/G1 phase increased in a dosedependent manner, suggesting that ZQL-3 d induced early apoptosis in breast cancer cells and blocked the cell cycle in G0/G1 phase. In the exploration of related pathway, we have proved that ZQL-3 d promotes the expression of cell cycle-related protein（ P21, P27） in MDA-MB-231 cells, while inhibits the expression of STAT3.Conclusion: ZQL-3 d shows great anti-tumor activity in breast cancer cells, which may be related to apoptosis, cell cycle and JAK-STAT signal pathway. The novel oleanolic acid derivative（ZQL-3 d）developed in this study may become an effective anti-cancer drug and provide a new idea for the clinical treatment of breast cancer.

关键词： Oleanolic acid derivatives Apoptosis Breast cancer cells anti-cancer drugs

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