Kakkadath Muhsina, Naidu Disha, Kanthlal S K, Sharun Khan
Department of Pharmacology, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, Kochi 682041, Kerala, India.
Graduate Institute of Medicine, Yuan Ze University, Taoyuan 32003, Taiwan.
Scientifica (Cairo). 2025 Apr 16;2025:8259470. doi: 10.1155/sci5/8259470. eCollection 2025.
Methotrexate (MTX), a potent analogue and antagonist of folic acid, is a first-line treatment for rheumatoid arthritis, IBD and cancer. The development of MTX resistance contributes to the reduced efficacy and development of adverse reactions, forcing clinicians to withdraw treatment early. This drawback requires combinational approaches to combat the resistance and enhance the efficacy and safety of MTX. To provide a brief overview of MTX resistance and strategies to mitigate its aftereffects in cancer therapy, a literature-based search was conducted using keywords such as cancer pathology, MTX mechanism and resistance, S100A4, folate uptake, folate efflux, P-glycoprotein, beta-catenin and anticancer properties of Vitamins A, D, E and K. Investigations encompassing in vitro studies, in vivo studies and clinical trials were reviewed to identify the mechanisms of resistance induced by MTX and the potential benefits of coadministering fat-soluble vitamins with existing anticancer drugs. Derivates of Vitamin A could target cancer stem cells and increase chemotherapy sensitivity in non-small cell lung cancer. Similarly, calcitriol and cytotoxic medications exhibit additive or synergistic effects. Existing research revealed that fat-soluble vitamins can inhibit drug transporters, such as P-glycoprotein, which inhibit drug efflux, improving chemotherapy efficacy in cancer. As personalised medicine continues to evolve, incorporating combination approaches with MTX and fat-soluble vitamins holds promise for enhancing treatment efficacy, which can counteract MTX resistance via multiple pathways and improve the safety profile.
甲氨蝶呤（MTX）是一种强效的叶酸类似物和拮抗剂，是类风湿性关节炎、炎症性肠病和癌症的一线治疗药物。MTX耐药性的产生导致疗效降低和不良反应的出现，迫使临床医生提前终止治疗。这一缺点需要采用联合方法来对抗耐药性，并提高MTX的疗效和安全性。为了简要概述MTX耐药性以及减轻其在癌症治疗中后遗症的策略，我们使用了癌症病理学、MTX作用机制和耐药性、S100A4、叶酸摄取、叶酸外排、P-糖蛋白、β-连环蛋白以及维生素A、D、E和K的抗癌特性等关键词进行了基于文献的检索。对包括体外研究、体内研究和临床试验在内的调查进行了综述，以确定MTX诱导的耐药机制以及将脂溶性维生素与现有抗癌药物联合使用的潜在益处。维生素A的衍生物可以靶向癌症干细胞并提高非小细胞肺癌的化疗敏感性。同样，骨化三醇和细胞毒性药物表现出相加或协同作用。现有研究表明，脂溶性维生素可以抑制药物转运蛋白，如P-糖蛋白，后者抑制药物外排，从而提高癌症化疗的疗效。随着个性化医疗的不断发展，将MTX与脂溶性维生素的联合方法纳入其中有望提高治疗效果，这可以通过多种途径对抗MTX耐药性并改善安全性。
