Liu Xiaoyu,Yang Lin,Guan Kunping,Chen Zhen,Yang Hua
Purpose This study aims to investigate the increased toxicity of Cytarabine (Ara-c) by knockdown of chromosome segregation 1-like (CSE1L) in acute myeloid leukemia(AML) cells(Kasumi-1, U937, and THP-1 cells) and to explore its possible mechanisms. Methods Target gene silencing was achieved using the shRNA-mediated lentivirus method. Apoptosis was identified using the Annexin V PE/7-AAD double-staining assay. Cell viability was assessed with the Cell Counting Kit-8 (CCK-8) assay. Protein expression was detected by Western blotting. Results In vitro, knocking down CSE1L promoted caspase-3 and caspase-9 proteins expression and induced apoptosis in AML cells. Knockdown of CSE1L enhanced AML cells' sensitivity to Ara-c. knockdown of CSE1L reduced the expression levels of p-JKA2 and p-STAT3 proteins, while no significant difference was observed in the expression levels of total JAK2 and STAT3 proteins. Furthermore, JAK2 overexpression reversed the increase in Ara-c toxicity to AML cells caused by CSE1L knockdown. Conclusion In conclusion, our study reveals that CSE1L is a potential therapeutic target for overcoming Ara-c resistance in AML cells. Thus, we have gained new insights into the oncogenic process of CSE1L in AML cells and raised the prospect of knockdown of CSE1L in AML in combination with cytarabine-targeted therapy.
Cytarabine (Ara-C) is an essential medicine used in the clinical treatment of acute lymphoblastic leukemia. However, Ara-C suffers from high hydrophilicity, rapid plasma degradation and significant side effects. Thus, herein, to eliminate the limitations of Ara-C in the treatment of leukemia, Sgc8 aptamer targeting and glutathione (GSH)-responsive polymeric micelles (PCL-ss-Ara@Sgc8-BSA) were prepared. The prodrug was synthesized via covalent bond formation between acryloyl chloride-terminal PCL-ss-PCL and Ara-C, and surface decoration with Sgc8-bovine serum albumin (Sgc8-BSA). The obtained PCL-ss-Ara@Sgc8-BSA exhibited good GSH-responsive drug release behavior, obvious targetability and sufficient antitumor effect to acute lymphoblastic leukemia (ALL) cells (CCRF-CEM). A hemolysis test was further carried out to demonstrate that these polymeric micelles are safe to be administrated intravenously. Compared with free Ara-C, PCL-ss-Ara@Sgc8-BSA significantly enhanced tumor growth inhibition in mice bearing CCRF-CEM xenograft tumors, while causing little side effects, and improved the survival rate of CCRF-CEM tumor-bearing mice in vivo. Therefore, this new self-assembling small molecular prodrug equipped with Sgc8 targeting function is a potential treatment for the targeted therapy of acute lymphoblastic leukemia.
Background Currently, high doses of cytarabine arabinoside (Ara-C)-based combined chemotherapy are commonly used in acute myeloid leukemia (AML) therapy, but severe adverse effects and poor suppression effects in leukemia cells limit the clinical therapeutic efficiency of Ara-C-based chemotherapy due to a lack of targeting selectivity. To improve the therapeutic effect of Ara-C in AML, here, since we confirmed that transferrin receptor 1 (TFRC) expression in AML cells was constant, we generated Ara-C@HFn by encapsulating free Ara-C into self-assembled heavy ferritin chain (HFn, the ligand of TFRC) nanocages.Results The analysis of clinically relevant data suggested that the high expression levels of TFRC from AML cells would not decrease significantly after treatment with Ara-C. Ara-C@HFn can be efficiently internalized by leukemia cells, showing stronger cytotoxic effects in vitro and reducing the burden of leukemia in AML mice more effectively in vivo than free Ara-C. Ara-C@HFn treatment showed no acute toxicity in visceral organs of mice. Moreover, the analysis of clinically relevant data also suggested that there are several drugs (such as tamibarotene and ABT199) that would not cause significant expression down-regulation of TFRC in AML cells (after treatment).Conclusion The above results suggested that TFRC can be used as a constant and effective target for drug targeting delivery of AML cells. Thus Ara-C@HFn treatment can become a safe and efficient strategy for AML therapy by specifically delivering Ara-C to AML cells. Besides, the HFn nanocages are promising for improving antineoplastic effect of other AML-related therapy drugs that do not cause downregulated expression of TFRC in AML cells.Graphical Abstract
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