Hematopoiesis and Leukemia Laboratory, Research Unit on Cell Differentiation and Cancer, FES Zaragoza, National Autonomous University of Mexico, 09230 Mexico City, Mexico.
Department of Biomedical Sciences, School of Medicine, Faculty of High Studies Zaragoza, National Autonomous University of Mexico, 09230 Mexico City, Mexico.
Int J Mol Sci. 2021 May 7;22(9):4955. doi: 10.3390/ijms22094955.
Acute myeloid leukemia (AML), the most common type of leukemia in older adults, is a heterogeneous disease that originates from the clonal expansion of undifferentiated hematopoietic progenitor cells. These cells present a remarkable variety of genes and proteins with altered expression and function. Despite significant advances in understanding the molecular panorama of AML and the development of therapies that target mutations, survival has not improved significantly, and the therapy standard is still based on highly toxic chemotherapy, which includes cytarabine (Ara-C) and allogeneic hematopoietic cell transplantation. Approximately 60% of AML patients respond favorably to these treatments and go into complete remission; however, most eventually relapse, develop refractory disease or chemoresistance, and do not survive for more than five years. Therefore, drug resistance that initially occurs in leukemic cells (primary resistance) or that develops during or after treatment (acquired resistance) has become the main obstacle to AML treatment. In this work, the main molecules responsible for generating chemoresistance to Ara-C in AML are discussed, as well as some of the newer strategies to overcome it, such as the inclusion of molecules that can induce synergistic cytotoxicity with Ara-C (MNKI-8e, emodin, metformin and niclosamide), subtoxic concentrations of chemotherapy (PD0332991), and potently antineoplastic treatments that do not damage nonmalignant cells (heteronemin or hydroxyurea + azidothymidine).
急性髓细胞白血病（AML）是老年人中最常见的白血病类型，是一种起源于未分化造血祖细胞克隆性扩增的异质性疾病。这些细胞具有显著的多种基因和蛋白，其表达和功能发生改变。尽管在理解 AML 的分子全景和开发针对突变的治疗方法方面取得了重大进展，但生存率并没有显著提高，治疗标准仍然基于高度毒性的化疗，包括阿糖胞苷（Ara-C）和异基因造血细胞移植。大约 60%的 AML 患者对这些治疗方法反应良好并进入完全缓解；然而，大多数最终会复发、出现难治性疾病或化疗耐药，并且五年生存率不超过 5 年。因此，最初在白血病细胞中发生的耐药性（原发性耐药性）或在治疗期间或之后发展的耐药性（获得性耐药性）已成为 AML 治疗的主要障碍。在这项工作中，讨论了 AML 中导致对 Ara-C 产生化疗耐药性的主要分子，以及一些克服这种耐药性的新策略，例如包括能够与 Ara-C 诱导协同细胞毒性的分子（MNKI-8e、大黄素、二甲双胍和尼氯硝唑）、亚毒性化疗浓度（PD0332991），以及不会损伤非恶性细胞的强效抗肿瘤治疗（heteronemin 或羟基脲+叠氮胸苷）。
