博安霉素通过诱导多发性骨髓瘤中的DNA损伤和内质网功能障碍来克服硼替佐米耐药性。
Boanmycin overcomes bortezomib resistance by inducing DNA damage and endoplasmic reticulum functional impairment in multiple myeloma.
作者信息
Wang Jin-Xing, Zhang Ling, Zhang Peng-Wei, Yuan Luo-Wei, Jiang Jian, Cheng Xiao-Hui, Zhu Wei, Lei Yong, Tian Fa-Qing
机构信息
Department of Hematology, The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen & Longgang District People's Hospital of Shenzhen, Shenzhen, 518172, China.
Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, National- Regional Key Technology Engineering Laboratory for Medical Ultrasound, Shenzhen University Medical School, Shenzhen, 518060, China.
出版信息
Biol Direct. 2025 Jan 6;20(1):1. doi: 10.1186/s13062-024-00590-y.
BACKGROUND
Multiple myeloma (MM) is a hematological malignancy characterized by uncontrolled proliferation of plasma cells and is currently incurable. Despite advancements in therapeutic strategies, resistance to proteasome inhibitors, particularly bortezomib (BTZ), poses a substantial challenge to disease management. This study aimed to explore the efficacy of boanmycin, a novel antitumor antibiotic, in overcoming resistance to BTZ in MM.
METHODS
BTZ-resistant cells were generated over a period of at least 6 months by gradually increasing the concentration of BTZ. The viability of MM cell lines and patient bone marrow mononuclear cells (BMMCs) was measured via the CCK8 reagent. The protein levels of cleaved caspase 3, cleaved caspase 7, cleaved PARP, PARP, p-JNK, JNK, and γ-H2AX were analyzed through Western blot. Cellular morphology was observed via transmission electron microscopy. Colony formation ability was evaluated, and cell apoptosis and the cell cycle were detected through flow cytometry. Xenograft experiments were conducted to evaluate the growth of MM cells in vivo.
RESULTS
Our results demonstrated that boanmycin effectively inhibited cell proliferation and colony formation, and triggered apoptosis in both BTZ-sensitive and BTZ-resistant MM cells. The combination of boanmycin with BTZ had greater inhibitory effects than either drug alone. Furthermore, boanmycin significantly suppressed MM cell growth in immunodeficient mouse xenograft models without inducing distinct toxic side effects. Notably, boanmycin markedly killed patient-derived MM cells ex vivo. Mechanistically, boanmycin not only disrupts the cell cycle and causes DNA damage but also exerts its antitumor effects by inducing endoplasmic reticulum (ER) functional impairment.
CONCLUSIONS
Our findings highlight the potential of boanmycin as a promising novel therapeutic option for treating MM, particularly in patients with BTZ resistance.
背景
多发性骨髓瘤（MM）是一种血液系统恶性肿瘤，其特征为浆细胞不受控制地增殖，目前无法治愈。尽管治疗策略有所进展，但对蛋白酶体抑制剂，尤其是硼替佐米（BTZ）的耐药性，给疾病管理带来了巨大挑战。本研究旨在探索新型抗肿瘤抗生素博安霉素在克服MM对BTZ耐药方面的疗效。
方法
通过逐渐增加BTZ浓度，在至少6个月的时间内产生BTZ耐药细胞。使用CCK8试剂测量MM细胞系和患者骨髓单个核细胞（BMMCs）的活力。通过蛋白质免疫印迹分析裂解的半胱天冬酶3、裂解的半胱天冬酶7、裂解的聚（ADP-核糖）聚合酶（PARP）、PARP、磷酸化应激活化蛋白激酶（p-JNK）、应激活化蛋白激酶（JNK）和γ-H2AX的蛋白质水平。通过透射电子显微镜观察细胞形态。评估集落形成能力，并通过流式细胞术检测细胞凋亡和细胞周期。进行异种移植实验以评估MM细胞在体内的生长情况。
结果
我们的结果表明，博安霉素有效抑制细胞增殖和集落形成，并在BTZ敏感和BTZ耐药的MM细胞中引发凋亡。博安霉素与BTZ联合使用比单独使用任何一种药物具有更强的抑制作用。此外，博安霉素在免疫缺陷小鼠异种移植模型中显著抑制MM细胞生长，且未诱导明显的毒副作用。值得注意的是，博安霉素在体外能显著杀死患者来源的MM细胞。从机制上讲，博安霉素不仅破坏细胞周期并导致DNA损伤，还通过诱导内质网（ER）功能障碍发挥其抗肿瘤作用。
结论
我们的研究结果凸显了博安霉素作为一种有前景的新型治疗选择用于治疗MM的潜力，尤其是对BTZ耐药的患者。
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