Role of SIRT1 in Chemoresistant Leukemia.

Leukemias of the AML, CML, and CLL types are the most common blood cancers worldwide, making them a major global public health problem. Furthermore, less than 24% of patients treated with conventional chemotherapy (low-risk patients) and 10-15% of patients ineligible for conventional chemotherapy (high-risk patients) survive five years. The low levels of survival are mainly due to toxicity and resistance to chemotherapy or other medication, the latter leading to relapse of the disease, which is the main obstacle to the treatment of leukemia. Drug resistance may include different molecular mechanisms, among which epigenetic regulators are involved. Silent information regulator 2 homolog 1 (SIRT1) is an epigenetic factor belonging to the sirtuin (SIRT) family known to regulate aspects of chromatin biology, genome stability, and metabolism, both in homeostasis processes and in different diseases, including cancer. The regulatory functions of SIRT1 in different biological processes and molecular pathways are dependent on the type and stage of the neoplasia; thus, it may act as both an oncogenic and tumor suppressor factor and may also participate in drug resistance. In this review, we explore the role of SIRT1 in drug-resistant leukemia and its potential as a therapeutic target.

Mesenchymal Stem/Stromal Cells Derived from Cervical Cancer Promote M2 Macrophage Polarization.

Macrophages with the M2 phenotype promote tumor development through the immunosuppression of antitumor immunity. We previously demonstrated the presence of mesenchymal stem/stromal cells (MSCs) in cervical cancer (CeCa-MSCs), suggesting an immune protective capacity in tumors, but to date, their effect in modulating macrophage polarization remains unknown. In this study, we compared the capacities of MSCs from normal cervix (NCx) and CeCa to promote M2 macrophage polarization in a coculture system. Our results demonstrated that CeCa-MSCs, in contrast to NCx-MSCs, significantly decreased M1 macrophage cell surface marker expression (HLA-DR, CD80, CD86) and increased M2 macrophage expression (CD14, CD163, CD206, Arg1) in cytokine-induced CD14+ monocytes toward M1- or M2-polarized macrophages. Interestingly, compared with NCx-MSCs, in M2 macrophages generated from CeCa-MSC cocultures, we observed an increase in the percentage of phagocytic cells, in the intracellular production of IL-10 and IDO, the capacity to decrease T cell proliferation and for the generation of CD4+CD25+FoxP3+ Tregs. Importantly, this capacity to promote M2 macrophage polarization was correlated with the intracellular expression of macrophage colony-stimulating factor (M-CSF) and upregulation of IL-10 in CeCa-MSCs. Furthermore, the presence of M2 macrophages was correlated with the increased production of IL-10 and IL-1RA anti-inflammatory molecules. Our in vitro results indicate that CeCa-MSCs, in contrast to NCx-MSCs, display an increased M2-macrophage polarization potential and suggest a role of CeCa-MSCs in antitumor immunity.

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

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).

Improved Survival of Leukemic Mice Treated with Sodium Caseinate in Combination with Daunorubicin without Toxicity.

In recent years, low doses of chemotherapy have been resumed and explored for the treatment of acute myeloid leukemia. Thus, CPX-351, a dual-drug liposomal encapsulation of cytarabine and daunorubicin, was approved by the US Food and Drug Administration, to deliver a synergistic 5 : 1 molar drug ratio into leukemia cells to a greater extent than normal bone marrow cells and significantly enhance survival compared with conventional treatment in older and newly diagnosed AML patients, but overall survival rate remains low; therefore, the need for new therapeutic options continues. Sodium caseinate (SC), a salt of casein, the main milk protein, has cytotoxic effect in leukemia cell lines, but promotes proliferation of hematopoietic normal cells, while its administration in leukemic mice promotes survival for more than 40 days, but bone marrow surviving mice still harbour leukemic cells, but it is not known whether the combination with cytarabine or daunorubicin can improve survival without damaging normal hematopoietic cells. Here, it is shown that, in vitro, the combination of the IC25 of SC-cytarabine or SC-daunorubicin synergizes in the elimination of leukemic cells, with evident induction of apoptosis, while the proliferation of mononuclear cells of bone marrow is not affected. In leukemic mice, the combined administration of SC-daunorubicin or SC-cytarabine promotes the highest survival rate at 40 days; in addition, no autoproliferating cells were detected in the bone marrow of survivors of more than 60 days, evidence of eradication of leukemic cells, but only the bone marrow of mice treated with the SC-daunorubicin combination proliferated in the presence of interleukin-3, which shows that this combination is not toxic to normal bone marrow cells, thus emerging as a possible antileukemic agent.