Woźniak Marta, Pastuch-Gawołek Gabriela, Makuch Sebastian, Wiśniewski Jerzy, Ziółkowski Piotr, Szeja Wiesław, Krawczyk Monika, Agrawal Siddarth
Department of Pathology, Wrocław Medical University, Marcinkowskiego 1, 50-368 Wrocław, Poland.
Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Faculty of Chemistry, Silesian University of Technology, Krzywoustego 4, 44-100 Gliwice, Poland.
Pharmaceuticals (Basel). 2020 Dec 24;14(1):13. doi: 10.3390/ph14010013.
The oxygen and nutrient-deprived tumor microenvironment is considered a key mechanism responsible for cancer resistance to chemotherapy. Methotrexate (MTX) is a widely incorporated chemotherapeutic agent employed in the treatment of several malignancies. However, drug resistance and systemic toxicity limit the curative effect in most cases. The present work aimed to design, synthesize, and biologically evaluate a novel glucose-methotrexate conjugate (Glu-MTX). Our study showed that Glu-MTX exerts an increased cytotoxic effect on cancer cells in comparison to MTX in hypoxia (1% O) and glucose starvation conditions. Furthermore, Glu-MTX was found to inhibit the proliferation and migration of cancer cells more effectively than MTX does. Our results demonstrate that the conjugation of MTX to glucose led to an increase in potency against malignant cells under oxygen and nutrient stress. The observations shed light on a potential therapeutic approach to overcome chemoresistance in cancer.
缺氧和营养匮乏的肿瘤微环境被认为是癌症对化疗产生抗性的关键机制。甲氨蝶呤（MTX）是一种广泛应用于多种恶性肿瘤治疗的化疗药物。然而，耐药性和全身毒性在大多数情况下限制了其治疗效果。目前的工作旨在设计、合成并对一种新型葡萄糖 - 甲氨蝶呤偶联物（Glu - MTX）进行生物学评估。我们的研究表明，在缺氧（1% O₂）和葡萄糖饥饿条件下，与MTX相比，Glu - MTX对癌细胞具有更强的细胞毒性作用。此外，发现Glu - MTX比MTX更有效地抑制癌细胞的增殖和迁移。我们的结果表明，MTX与葡萄糖偶联导致在氧气和营养应激条件下对恶性细胞的效力增加。这些观察结果为克服癌症化疗耐药性的潜在治疗方法提供了线索。
