A modified natural small molecule inhibits triple-negative breast cancer growth by interacting with Tubb3,Phytomedicine

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A modified natural small molecule inhibits triple-negative breast cancer growth by interacting with Tubb3
Phytomedicine ( IF 6.7 ) Pub Date : 2023-05-19 , DOI: 10.1016/j.phymed.2023.154894
Hongwei Han ₁ , Minkai Yang ₁ , Zhongling Wen ₁ , Xuan Wang ₁ , Xiaohui Lai ₂ , Yahan Zhang ₃ , Rongjun Fang ₃ , Tongming Yin ₄ , Xiaorong Yang ₂ , Xiaoming Wang ₃ , Quan Zhao ₃ , Jinliang Qi ₁ , Hongyuan Chen ₅ , Hongyan Lin ₁ , Yonghua Yang ₆

Affiliation

State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing, 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, MOE Key Laboratory of Forest Genetics and Biotechnology, Nanjing Forestry University, Nanjing, 210037, China.
State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing, 210023, China; School of Biology and Geography Science, Yili Normal University, Yining, 835000, China; State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China.
State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing, 210023, China.
Co-Innovation Center for Sustainable Forestry in Southern China, MOE Key Laboratory of Forest Genetics and Biotechnology, Nanjing Forestry University, Nanjing, 210037, China.
State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China.
State Key Laboratory of Pharmaceutical Biotechnology, Institute of Plant Molecular Biology, School of Life Sciences, Nanjing University, Nanjing, 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, MOE Key Laboratory of Forest Genetics and Biotechnology, Nanjing Forestry University, Nanjing, 210037, China; State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China.

Background

Triple-negative breast cancer (TNBC) is a malignant tumor without specific therapeutic targets and a poor prognosis. Chemotherapy is currently the first-line therapeutic option for TNBC. However, due to the heterogeneity of TNBC, not all of TNBC patients are responsive to chemotherapeutic agents. Therefore, the demand for new targeted agents is critical. β-tubulin isotype III (Tubb3) is a prognostic factor associated with cancer progression, including breast cancer, and targeting Tubb3 may lead to improve TNBC disease control. Shikonin, the active compound in the roots of Lithospermun erythrorhizon suppresses the growth of various types of tumors, and its efficacy can be improved by altering its chemical structure.

Purpose

In this work, the anti-TNBC effect of a shikonin derivative (PMMB276) was investigated, and its mechanism was also investigated.

Study Design/Methods

This study combines flow cytometry, immunofluorescence staining, immunoblotting, immunoprecipitation, siRNA silencing, and the iTRAQ proteomics assay to analyze the inhibition potential of PMMB276 on TNBC. In vivo study was performed, Balb/c female murine models with or without the small molecule treatments.

Results

Herein, we screened 300 in-house synthesized analogs of shikonin against TNBC and identified a novel small molecule, PMMB276; it suppressed cell proliferation, induced apoptosis, and arrested the cell cycle at the G2/M phase, suggesting that it could have a tumor suppressive role in TNBC. Tubb3 was identified as the target of PMMB276 using proteomic and biological activity analyses. Meanwhile, PMMB276 regulated microtubule dynamics in vitro by inducing microtubule depolymerization and it could act as a tubulin stabilizer by a different process than that of paclitaxel. Moreover, suppressing or inhibiting Tubb3 with PMMB276 reduced the growth of breast cancer in an experimental mouse model, indicating that Tubb3 plays a significant role in TNBC progression.

Conclusion

The findings support the therapeutic potential of PMMB276, a Tubb3 inhibitor, as a treatment for TNBC. Our findings might serve as a foundation for the utilization of shikonin and its derivatives in the development of anti-TNBC.

中文翻译：

修饰的天然小分子通过与 Tubb3 相互作用抑制三阴性乳腺癌生长

背景

三阴性乳腺癌（TNBC）是一种无特异性治疗靶点、预后不良的恶性肿瘤。化疗是目前TNBC的一线治疗选择。然而，由于TNBC的异质性，并非所有TNBC患者都对化疗药物有反应。因此，对新靶向药物的需求至关重要。 β-微管蛋白同种型 III (Tubb3) 是与癌症进展（包括乳腺癌）相关的预后因素，靶向 Tubb3 可能会改善 TNBC 疾病控制。紫草根中的活性化合物紫草素可以抑制多种肿瘤的生长，通过改变其化学结构可以提高其疗效。

目的

在这项工作中，研究了紫草素衍生物（PMMB276）的抗TNBC作用，并对其机制进行了研究。

研究设计/方法

本研究结合流式细胞术、免疫荧光染色、免疫印迹、免疫沉淀、siRNA 沉默和 iTRAQ 蛋白质组学测定来分析 PMMB276 对 TNBC 的抑制潜力。进行了体内研究，Balb/c 雌性小鼠模型有或没有小分子治疗。

结果

在此，我们针对 TNBC 筛选了 300 种内部合成的紫草素类似物，并鉴定了一种新型小分子 PMMB276；它抑制细胞增殖，诱导细胞凋亡，并将细胞周期阻滞在 G2/M 期，表明它可能在 TNBC 中发挥肿瘤抑制作用。通过蛋白质组学和生物活性分析，Tubb3 被确定为 PMMB276 的靶标。同时，PMMB276通过诱导微管解聚来调节体外微管动力学，并且它可以通过与紫杉醇不同的过程充当微管蛋白稳定剂。此外，在实验小鼠模型中，用 PMMB276 抑制或抑制 Tubb3 可以减少乳腺癌的生长，表明 Tubb3 在 TNBC 进展中发挥重要作用。