RESUMEN
Acute lymphoblastic leukemia (ALL) is an aggressive malignant disorder of lymphoid progenitor cells that affects children and adults. Despite the high cure rates, drug resistance still remains a significant clinical problem, which stimulates the development of new therapeutic strategies and drugs to improve the disease outcome. Antipsychotic phenothiazines have emerged as potential candidates to be repositioned as antitumor drugs. It was previously shown that the anti-histaminic phenothiazine derivative promethazine induced autophagy-associated cell death in chronic myeloid leukemia cells, although autophagy can act as a "double-edged sword" contributing to cell survival or cell death. Here we evaluated the role of autophagy in thioridazine (TR)-induced cell death in the human ALL model. TR induced apoptosis in ALL Jurkat cells and it was not cytotoxic to normal peripheral mononuclear blood cells. TR promoted the activation of caspase-8 and -3, which was associated with increased NOXA/MCL-1 ratio and autophagy triggering. AMPK/PI3K/AKT/mTOR and MAPK/ERK pathways are involved in TR-induced cell death. The inhibition of the autophagic process enhanced the cytotoxicity of TR in Jurkat cells, highlighting autophagy as a targetable process for drug development purposes in ALL.
RESUMEN
Relapse and drug resistance is still major challenges in the treatment of leukemia. Promethazine, an antihistaminic phenothiazine derivative, has been used to prevent chemotherapy-induced emesis, although there is no report about its antitumor potential. Thus, we evaluated the promethazine cytotoxicity against several leukemia cells and the underlying mechanisms were investigated. Promethazine exhibited potent and selective cytotoxicity against all leukemia cell types in vitro at clinically relevant concentrations. Philadelphia positive chronic myeloid leukemia (CML) K562â¯cells were the most sensitive cell line. The cytotoxicity of promethazine in these cells was triggered by the activation of AMPK and inhibition of PI3K/AKT/mTOR pathway. The subsequent downstream effects were NOXA increase, MCL-1 decrease, and Beclin-1 activation, resulting in autophagy-associated apoptosis. These data highlight targeting autophagy may represent an interesting strategy in CML therapy, and also the antitumor potential of promethazine by acting in AMPK and PI3K/AKT/mTOR signaling pathways. Since this drug is currently used with relative low side effects, its repurposing may represent a new therapeutic opportunity for leukemia treatment.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Beclina-1/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Fosforilación/efectos de los fármacos , Prometazina/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Antineoplásicos/farmacología , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Humanos , Células Jurkat , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Melanoma is a malignant proliferative disease originated from melanocyte transformations, which are characterized by a high metastatic rate and mortality. Advances in Nanotechnology have provided useful new approaches and tools for antitumor chemotherapy. The aim of this study was to investigate the molecular mechanisms underlying chitosan nanoparticles containing S-nitrosomercaptosuccinic acid ( S-nitroso-MSA-CS) induced cytotoxicity in melanoma cells. S-Nitroso-MSA-CS induced concentration-dependent cell death against B16-F10 tumor cells, whereas non-nitroso nanoparticles (CS or MSA-CS) did not induce significant cytotoxicity. Additionally, melanoma cells were more sensitive to cell death than normal melanocytes. S-Nitroso-MSA-CS-induced cytotoxicity exhibited features of caspase-dependent apoptosis, and it was associated with oxidative stress, characterized by increased mitochondrial superoxide production and oxidation of protein thiol groups. In addition, tyrosine nitration and cysteine S-nitrosylation of amino acid residues in cellular proteins were observed. The potential use of these nanoparticles in antitumor chemotherapy of melanoma is discussed.