RESUMEN
Patients with myelodysplastic syndromes (MDS) who resist or fail to respond to hypomethylating agents (HMAs) show very poor outcomes and have no effective treatment strategies. Therefore, new therapeutic approaches are urgently needed for MDS patients harboring adverse prognostic factors. Repurposing disulfiram (DSF), an alcohol-abuse drug, with or without Copper (Cu) has attracted considerable attentions as a candidate anti-tumor therapy in diverse malignancies. However, the effect of DSF in the presence or absence of Cu on MDS has not been reported yet. In this study, we found that monotherapy with DSF showed mild cytotoxic effects on MDS preclinical models. However, the anti-tumor activity of DSF was significantly enhanced in the presence of Cu in MDS in vitro and in vivo with minimal safety profiles. DSF/Cu combination blocked MDS cell cycle progression at the G0/G1 phase, accompanied by reduction of the S phase. Accordingly, co-treatment with DSF and Cu downregulated the expression of Cyclin D1 and Cyclin A2, whereas this combination upregulated the level of P21 and P27. Mechanistically, the anti-MDS effectiveness of DSF/Cu was potentially associated with activation of the ER stress-related Bip pathway and inactivation of the Akt pathway. In addition, inhibition of autophagy process also contributed to the cytotoxicity of DSF/Cu in MDS cells. In conclusion, these findings provide impressive evidence that the DSF/Cu complex shows potent anti-tumor efficacies on MDS preclinical models, representing a potential alternative therapy for MDS patients and warranting further investigation in clinical contexts.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Cobre/farmacología , Disulfiram/farmacología , Proteínas de Choque Térmico/metabolismo , Síndromes Mielodisplásicos/tratamiento farmacológico , Animales , Antineoplásicos/uso terapéutico , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cobre/uso terapéutico , Disulfiram/uso terapéutico , Chaperón BiP del Retículo Endoplásmico , Estrés del Retículo Endoplásmico/efectos de los fármacos , Femenino , Humanos , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , Mitocondrias/efectos de los fármacos , Síndromes Mielodisplásicos/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Acute myeloid leukemia (AML) is a heterogeneous myeloid neoplasm with poor clinical outcome, despite the great progress in treatment in recent years. The selective Bcl-2 inhibitor venetoclax (ABT-199) in combination therapy has been approved for the treatment of newly diagnosed AML patients who are ineligible for intensive chemotherapy, but resistance can be acquired through the upregulation of alternative antiapoptotic proteins. Here, we reported that a newly emerged histone deacetylase inhibitor, chidamide (CS055), at low-cytotoxicity dose enhanced the anti-AML activity of ABT-199, while sparing normal hematopoietic progenitor cells. Moreover, we also found that chidamide showed a superior resensitization effect than romidepsin in potentiation of ABT-199 lethality. Inhibition of multiple HDACs rather than some single component might be required. The combination therapy was also effective in primary AML blasts and stem/progenitor cells regardless of disease status and genetic aberrance, as well as in a patient-derived xenograft model carrying FLT3-ITD mutation. Mechanistically, CS055 promoted leukemia suppression through DNA double-strand break and altered unbalance of anti- and pro-apoptotic proteins (e.g., Mcl-1 and Bcl-xL downregulation, and Bim upregulation). Taken together, these results show the high therapeutic potential of ABT-199/CS055 combination in AML treatment, representing a potent and alternative salvage therapy for the treatment of relapsed and refractory patients with AML.
Asunto(s)
Aminopiridinas/farmacología , Benzamidas/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Proliferación Celular/efectos de los fármacos , Leucemia Mieloide Aguda/tratamiento farmacológico , Sulfonamidas/farmacología , Antineoplásicos/farmacología , Proteínas Reguladoras de la Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/metabolismo , Compuestos de Bifenilo/farmacología , Humanos , Leucemia Mieloide Aguda/inducido químicamente , Leucemia Mieloide Aguda/metabolismoRESUMEN
Leukemia stem cells (LSCs) are deemed to the mainspring for treatment failure in acute myeloid leukemia (AML). Conventional chemotherapeutic drugs fail to eradicate leukemia stem cells, which becomes the root of drug resistance and disease recurrence. Hence, new therapeutic strategies targeting LSCs are supposed to be critical for patients with AML. Here we report that combination of Bcl-2 inhibitor AT-101 and chemotherapeutic drug idarubicin (IDA) results in synergistic lethality in CD34+CD38- leukemia stem-like cells sorted from KG-1α and Kasumi-1 AML cell lines and primary CD34+ AML cells in vitro while sparing the normal counterparts. In addition, combinatorial treatment also significantly inhibits the growth of patient-derived xenograft (PDX) mouse models generated from FLT3-ITDmut AML patient in vivo. Mechanistically, the synergistic effects of AT-101 with IDA to induce cell death are closely associated with blockage of DNA damage repair and thus activates the intrinsic apoptotic pathway. In summary, these findings suggest that combinatorial therapy with AT-101 and IDA selectively eliminates leukemia stem-like cells both in vitro and in vivo, representing a potent and alternative salvage therapy for the treatment of relapsed and refractory patients with AML.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Mutaciones Letales Sintéticas/efectos de los fármacos , Adolescente , Adulto , Anciano , Animales , Biomarcadores de Tumor/genética , Estudios de Casos y Controles , Proliferación Celular/efectos de los fármacos , Reparación del ADN/genética , Sinergismo Farmacológico , Femenino , Estudios de Seguimiento , Gosipol/administración & dosificación , Gosipol/análogos & derivados , Humanos , Idarrubicina/administración & dosificación , Leucemia Mieloide Aguda/genética , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Pronóstico , Proteína 1 Compañera de Translocación de RUNX1/antagonistas & inhibidores , Proteína 1 Compañera de Translocación de RUNX1/genética , Tasa de Supervivencia , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto , Adulto Joven , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
Acute myeloid leukemia (AML) is a heterogeneous malignancy of hematopoietic stem cells with poor clinical outcome despite recent improvements in chemotherapy and stem cell transplantation regimens. Thus, new therapeutic agents are urgently needed in order to prolong the disease-free survival of AML patients in clinic. Here, we report that BBI608 is highly active against diverse AML cell lines in vitro and primary samples obtained from patients with AML ex vivo, as well as effective in vivo in AML xenograft models. Meanwhile, the anti-AML property of BBI608 is closely associated with the inhibition of Stat3 pathway and induction of DNA damage. Of note, BBI608 combined with Bcl-2 inhibitor (i.e., ABT-199) exerts a significantly enhanced anti-leukemia effect in BBI608-resistant cell line Kasumi-1. Together, the present findings suggest that BBI608 might represent a potential candidate agent for AML treatment.