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LTe2通过抑制AKT在苏氨酸308和丝氨酸473位点的磷酸化来诱导多发性骨髓瘤细胞凋亡。

LTe2 induces cell apoptosis in multiple myeloma by suppressing AKT phosphorylation at Thr308 and Ser473.

作者信息

Zhang Yuanjiao, Qian Jiacheng, Jiang Mingmei, Yang Shu, Zhou Lianxin, Zhang Qin, Lin Liping, Yang Ye

机构信息

Nanjing Hospital of Chinese Medicine and School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China.

State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, China.

出版信息

Front Oncol. 2023 Sep 14;13:1269670. doi: 10.3389/fonc.2023.1269670. eCollection 2023.

Abstract

Multiple myeloma (MM) is a highly heterogeneous hematological malignancy originating from B lymphocytes, with a high recurrence rate primarily due to drug resistance. 2-((1H-indol-3-yl)methyl)-3-((3-((1H-indol-3-yl)methyl)-1H-indol-2-yl)methyl)-1H-indole (LTe2), a tetrameric indole oligomer, possesses a wide range of anticancer activities through various mechanisms. Here, we aim to explore the anti-tumor efficiency and potential downstream targets of LTe2 in MM. Its bioactivity was assessed by employing MTT assays, flow cytometry, and the 5TMM3VT mouse model. Additionally, transcriptomic RNA-seq analysis and molecular dynamics (MD) experiments were conducted to elucidate the mechanism underlying LTe2 induced MM cell apoptosis. The results demonstrated that LTe2 significantly inhibited MM cell proliferation both and , and revealed that LTe2 exerts its effect by inhibiting the phosphorylation of AKT at the Thr308 and Ser473 sites. In summary, our findings highlight the potential of LTe2 as a novel candidate drug for MM treatment and provided a solid foundation for future clinical trials involving LTe2.

摘要

多发性骨髓瘤(MM)是一种起源于B淋巴细胞的高度异质性血液系统恶性肿瘤,复发率高,主要原因是耐药性。2 - ((1H - 吲哚 - 3 - 基)甲基) - 3 - ((3 - ((1H - 吲哚 - 3 - 基)甲基) - 1H - 吲哚 - 2 - 基)甲基) - 1H - 吲哚(LTe2),一种四聚体吲哚低聚物,通过多种机制具有广泛的抗癌活性。在此,我们旨在探索LTe2在MM中的抗肿瘤效率和潜在的下游靶点。通过MTT试验、流式细胞术和5TMM3VT小鼠模型评估其生物活性。此外,进行了转录组RNA测序分析和分子动力学(MD)实验,以阐明LTe2诱导MM细胞凋亡的机制。结果表明,LTe2在体内和体外均显著抑制MM细胞增殖,并表明LTe2通过抑制AKT在Thr308和Ser473位点的磷酸化发挥作用。总之,我们的研究结果突出了LTe2作为MM治疗新候选药物的潜力,并为未来涉及LTe2的临床试验提供了坚实的基础。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d173/10539572/d42050cc5b90/fonc-13-1269670-g001.jpg

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