RESUMO
BACKGROUND: The identification of a novel and effective strategy for the clinical treatment of acute leukemia (AL) is a long-term goal. Minnelide, a water-soluble prodrug of triptolide, has recently been evaluated in phase I and II clinical trials in patients with multiple cancers and has shown promise as an antileukemic agent. However, the molecular mechanism underlying minnelide's antileukemic activity remains unclear. PURPOSE: To explore the molecular mechanisms by which minnelide exhibits antileukemic activity. METHODS: AL cells, primary human leukemia cells, and a xenograft mouse model were treated with triptolide and minnelide. The molecular mechanism was elucidated using western blotting, immunoprecipitation, flow cytometry, GSEA and liquid chromatography-mass spectrometry analysis. RESULTS: Minnelide was highly effective in inhibiting leukemogenesis and improving survival in two complementary AL mouse models. Triptolide, an active form of minnelide, causes cell cycle arrest in G1 phase and induces apoptosis in both human AL cell lines and primary AL cells. Mechanistically, we identified Ars2 as a new chemotherapeutic target of minnelide for AL treatment. We found that triptolide directly targeted Ars2, resulting in the downregulation of miR-190a-3p, which led to the disturbance of PTEN/Akt signaling and culminated in G1 cell cycle arrest and apoptosis. CONCLUSIONS: Our findings demonstrate that targeting Ars2/miR-190a-3p signaling using minnelide could represent a novel chemotherapeutic strategy for AL treatment and support the evaluation of minnelide for the treatment of AL in clinical trials.
Assuntos
Apoptose , Diterpenos , Compostos de Epóxi , MicroRNAs , Fenantrenos , Fenantrenos/farmacologia , Animais , Humanos , Diterpenos/farmacologia , Compostos de Epóxi/farmacologia , Linhagem Celular Tumoral , Camundongos , Apoptose/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Leucemia/tratamento farmacológico , Organofosfatos/farmacologia , Antineoplásicos Fitogênicos/farmacologiaRESUMO
Arsenic resistance protein 2 (Ars2) is a nuclear protein that plays a critical role in the regulation of microRNA (miRNA) biogenesis. Ars2 is required for cell proliferation and for the early stages of mammalian development through a possible effect on miRNA processing. Increasing evidence reveal that Ars2 is highly expressed in proliferating cancer cells, suggesting that Ars2 may be a potential therapeutic target for cancer. Therefore, development of the novel Ars2 inhibitors could represent the novel therapeutic strategies for treatment of cancer. In this review, we briefly discuss the mechanisms by which Ars2 regulates miRNA biogenesis and its impact on cell proliferation and cancer development. Particularly, we mainly discuss the role of Ars2 in the regulation of cancer development and highlight pharmacological targeting of Ars2 as a promising cancer therapeutic strategy.
Assuntos
Arsênio , MicroRNAs , Neoplasias , Animais , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas Nucleares/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Proliferação de Células , Mamíferos/genética , Mamíferos/metabolismoRESUMO
microRNAs (miRNAs) are non coding RNAs with different biological functions and pathological implications. Given their role as post-transcriptional gene expression regulators, they are involved in several important physiological processes like development, cell differentiation and cell signaling. miRNAs act as modulators of gene expression programs in different diseases, particularly in cancer, where they act through the repression of genes which are critical for carcinogenesis. The expression level of mature miRNAs is the result of a fine mechanism of biogenesis, carried out by different enzymatic complexes that exert their function at transcriptional and post-transcriptional levels. In this review, we will focus our discussion on the alterations in the miRNA biogenesis machinery, and its impact on the establishment and development of cancer programs.