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新型葡萄糖-甲氨蝶呤缀合物对急性淋巴细胞白血病和非霍奇金淋巴瘤细胞系的影响。

The Effect of a New Glucose-Methotrexate Conjugate on Acute Lymphoblastic Leukemia and Non-Hodgkin's Lymphoma Cell Lines.

机构信息

Department of Pathology, Wroclaw Medical University, 50-367 Wroclaw, Poland.

Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Faculty of Chemistry, Silesian University of Technology, 44-100 Gliwice, Poland.

出版信息

Molecules. 2021 Apr 27;26(9):2547. doi: 10.3390/molecules26092547.

DOI:10.3390/molecules26092547
PMID:33925555
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8123764/
Abstract

Patients with hematologic malignancies require intensive therapies, including high-dose chemotherapy. Antimetabolite-methotrexate (MTX) has been used for many years in the treatment of leukemia and in lymphoma patients. However, the lack of MTX specificity causes a significant risk of morbidity, mortality, and severe side effects that impairs the quality of patients' life. Therefore, novel targeted therapies based on the malignant cells' common traits have become an essential treatment strategy. Glucose transporters have been found to be overexpressed in neoplastic cells, including hematologic malignancies. In this study, we biologically evaluated a novel glucose-methotrexate conjugate (Glu-MTX) in comparison to a free MTX. The research aimed to assess the effectiveness of Glu-MTX on chosen human lymphoma and leukemia cell lines. Cell cytotoxicity was verified by MTT viability test and flow cytometry. Moreover, the cell cycle and cellular uptake of Glu-MTX were evaluated. Our study reveals that conjugation of methotrexate with glucose significantly increases drug uptake and results in similar cytotoxicity of the synthesized compound. Although the finding has been confined to in vitro studies, our observations shed light on a potential therapeutic approach that increases the selectivity of chemotherapeutics and can improve leukemia and lymphoma patients' outcomes.

摘要

血液病患者需要强化治疗，包括大剂量化疗。抗代谢物甲氨蝶呤（MTX）多年来一直用于白血病和淋巴瘤患者的治疗。然而，MTX 的非特异性导致发病率、死亡率和严重副作用的风险显著增加，从而损害了患者的生活质量。因此，基于恶性细胞共同特征的新型靶向治疗已成为一种重要的治疗策略。已经发现葡萄糖转运蛋白在包括血液恶性肿瘤在内的肿瘤细胞中过度表达。在这项研究中，我们对一种新型的葡萄糖-甲氨蝶呤缀合物（Glu-MTX）进行了生物学评估，并与游离 MTX 进行了比较。该研究旨在评估 Glu-MTX 对选定的人类淋巴瘤和白血病细胞系的疗效。通过 MTT 活力试验和流式细胞术验证细胞毒性。此外，还评估了 Glu-MTX 的细胞周期和细胞摄取。我们的研究表明，将甲氨蝶呤与葡萄糖偶联可显著增加药物摄取，并导致合成化合物具有相似的细胞毒性。尽管这一发现仅限于体外研究，但我们的观察结果为提高化疗药物选择性并改善白血病和淋巴瘤患者预后的潜在治疗方法提供了启示。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/77a4/8123764/954944942849/molecules-26-02547-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/77a4/8123764/240f5c51dbf9/molecules-26-02547-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/77a4/8123764/b87d121d940e/molecules-26-02547-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/77a4/8123764/a6cbe005f26c/molecules-26-02547-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/77a4/8123764/fca2e2258758/molecules-26-02547-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/77a4/8123764/f3dbb54f7884/molecules-26-02547-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/77a4/8123764/5494cf777563/molecules-26-02547-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/77a4/8123764/5e66a7820049/molecules-26-02547-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/77a4/8123764/954944942849/molecules-26-02547-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/77a4/8123764/240f5c51dbf9/molecules-26-02547-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/77a4/8123764/b87d121d940e/molecules-26-02547-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/77a4/8123764/a6cbe005f26c/molecules-26-02547-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/77a4/8123764/fca2e2258758/molecules-26-02547-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/77a4/8123764/f3dbb54f7884/molecules-26-02547-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/77a4/8123764/5494cf777563/molecules-26-02547-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/77a4/8123764/5e66a7820049/molecules-26-02547-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/77a4/8123764/954944942849/molecules-26-02547-g008.jpg

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Pharmaceuticals (Basel). 2020 Dec 24;14(1):13. doi: 10.3390/ph14010013.
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Glycoconjugates for glucose transporter-mediated cancer-specific targeting and treatment.
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