RESUMO
Tcell acute lymphoblastic leukemia (TALL) is a common pediatric malignancy, characterized by the abnormal presence of immature Tcell progenitors. Conventional treatments for TALL fail to prevent or cure the disease, with a highrisk of recurrence after the first remission. Thus, medical options are in demand to develop novel therapies for patients suffering with TALL. Niclosamide, a traditional oral antihelminthic drug, has been reported to be a potential anticancer agent that regulates intracellular signaling pathways. Few studies have yet investigated the effects of niclosamide on the development of TALL. Here, the present study aimed to investigate the antileukemia effects of niclosamide on TALL. We first hypothesized that the suppressive effects of niclosamide on the tumor growth of TALL are exerted by regulating autophagy and apoptosis. Following niclosamide treatment, TALL cell viability was evaluated using MTT assay, and apoptosis with Annexin V/propidium iodide staining. In TALL cells treated with niclosamide, changes in apoptosis and autophagyrelated proteins were analyzed by western blotting. In addition, in an in vivo model, TALL xenograft mice were used to study the antileukemia effects of niclosamide. The results showed that niclosamide significantly reduced the viability of Jurkat and CCRFCEM TALL cells in both a dose and timedependent manner. Niclosamide significantly activated the early and late phases of apoptosis in Jurkat (at 2 µM) and CCRFCEM cells (at 1 µM). Furthermore, niclosamide upregulated protein expression of cleaved caspase3 and LC3B, while downregulated those of Bcl2 and p62, in a dosedependent manner in both Jurkat and CCRFCEM cells. The in vivo results showed that niclosamide treatment significantly suppressed tumor growth and the disease progression in TALL xenograft mice by activating cleaved caspase3 and LC3B. We conclude that niclosamide plays an antileukemia role, and that it represents a novel approach for the treatment of TALL.
Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Niclosamida/farmacologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , CamundongosRESUMO
The incidence of colon cancer continues to increase annually, and it is the leading cause of cancer-associated mortality worldwide. Altering cell metabolism and inducing autophagic cell death have recently emerged as novel strategies in preventing tumor growth. Autophagy plays an essential role in energy production by degrading damaged cellular components and is also associated with tumor proliferation suppression. Itraconazole is an FDA-approved drug used as an antifungal medication and has been reported to induce autophagic cell death in breast cancer. However, the effects of itraconazole on cell metabolism and induction of apoptosis in colon cancer remain unclear. The present study analyzed extensive data from patients diagnosed with colon cancer using itraconazole between January 2011 and December 2015, from the Taiwanese National Health Insurance Research Database. The underlying molecular mechanisms of itraconazole in autophagy-induced cell death were also investigated. The results demonstrated that the 5-year survival rate was significantly higher in patients with colon cancer who received itraconazole treatment. In addition, itraconazole decreased the viability and cell colony formation, and induced cleaved caspase-3 expression and G1 cell cycle arrest of COLO 205 and HCT 116 cells. Notably, itraconazole induced autophagy by enhancing LC3B and p62 expression. Following LC3 knockdown, the viability of itraconazole-treated COLO 205 and HCT 116 cells notably improved. Taken together, the results of the present study suggest that itraconazole may have a beneficial effect on patients with colon cancer, and its underlying molecular mechanisms may be associated with the induction of autophagic cell death.