Abstract
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).
Highlights
Acute myeloid leukemia (AML) is a hematological disease characterized by the clonal expansion of immature myeloid hematopoietic cells, which accumulate in the bone marrow (BM) and blood and can infiltrate tissues such as the spleen, liver, skin, gums, and central nervous system
A greater understanding of the molecular biology of leukemia has allowed the development of therapies directed towards mutated genes and molecular targets; the new treatments approved by the US Food and Drug Administration (FDA) are only effective in some patients, and the survival period that is achieved does not differ from that obtained with standard therapy
The main molecules related to the induction of drug resistance and the different therapeutic strategies that seek to stop this condition are addressed, those that favor the sensitization of leukemic cells to Ara-C, the main drug used in the standard treatment of AML
Summary
Acute myeloid leukemia (AML) is a hematological disease characterized by the clonal expansion of immature myeloid hematopoietic cells (myeloblasts), which accumulate in the bone marrow (BM) and blood (more than 20% of myeloblasts) and can infiltrate tissues such as the spleen, liver, skin, gums, and central nervous system. For the past 50 years, the standard of care in AML has been the combination of cytarabine (Ara-C) and anthracyclines, resulting in complete remission of no more than 45% of patients regardless of age group [4]; most of them do not survive long-term (more than five years), largely due to treatment-related mortality and the appearance of relapse associated with chemoresistance [2,5,6] In this sense, drug resistance that initially occurs in leukemic cells or that develops during or after treatment is one of the most difficult challenges in AML therapy. Considering the large impact that the development of chemoresistance has on the development of relapse and refractory disease, it is reasonable that it is considered in the classification of AML [9,10]
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