Inhibitors of Chemoresistance Pathways in Combination with Ara-C to Overcome Multidrug Resistance in AML. A Mini Review

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).

5-Demethylnobiletin Inhibits Cell Proliferation, Downregulates ID1 Expression, Modulates the NF-κB/TNF-α Pathway and Exerts Antileukemic Effects in AML Cells

“…Cytarabine (Ara-C) inhibits cellular proliferation and promotes cancer cell apoptosis in the treatment of patients with AML. However, chemoresistance to cytarabine remains a common and serious problem, and some elderly patients may not tolerate high doses of Ara-C due to high toxicity in AML therapy [61]. In clinical studies, it is likely that novel agents for molecular targets combined with traditional chemotherapy will achieve the highest response effects for cancer treatment.…”

Lysosome-mediated chemoresistance in acute myeloid leukemia

“…Primary and secondary chemoresistance have been widely explored using conventional approaches, searching for gene mutations, chromosomal aberrations, and dysregulated signaling pathways [5][6][7][8] . Changes in the multidrug resistance gene family affect the intracellular concentration of drugs by either reducing the active transport into the tumor cells or increasing the efflux out to the extracellular space.…”

“…Changes in the multidrug resistance gene family affect the intracellular concentration of drugs by either reducing the active transport into the tumor cells or increasing the efflux out to the extracellular space. Other mechanisms of action that affect the response to chemotherapy include: modifications in the chemotherapy molecular targets, preventing the pharmacologic action, increased ability to repair tumor DNA damage, defective response to proapoptotic stimuli, and changes in the tumor microenvironment [ 8 ] . Although several inhibitors targeting drug-resistance mechanisms have been reported, their clinical development is still under evaluation.…”

Transfer of IGF2BP3 Through Ara-C-Induced Apoptotic Bodies Promotes Survival of Recipient Cells

“…~60% of AML patients respond favorably to these treatments and undergo complete remission; however, a smaller proportion eventually relapse, develop refractory disease or chemoresistance, and survive for less than five years ( 4 ). The main obstacle to successful AML treatment is drug resistance that occurs initially in leukemic cells (primary resistance) or that develops during or after treatment (acquired resistance) ( 5 ). Genetic, molecular, and cellular mechanisms underlying acquired drug resistance have been described.…”