Liqiong Wang , Xi Zhang , Shu Chen , Qiuhua Ye , Basappa Basappa , Tao Zhu , Peter E. Lobie , Vijay Pandey
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引用次数: 0
Abstract
Objective
Mitomycin C (MMC), a DNA-damaging chemotherapeutic, is commonly used clinically for recurrent cervical carcinoma (CC), either alone or in combination. MMC generates DNA damage resulting in CC cell death yet also induces increased AKT-BAD phosphorylation associated with drug resistance and reduced clinical benefit. The present study evaluates the efficacy of combined MMC and a BAD phosphorylation inhibitor in CC.
Methods
The association and function of phosphorylation of BAD on serine 99 (pBADS99) for cell survival of both MMC-resistant or sensitive-CC cells was explored. BAD was mutated to BADS99A to examine the requirement of BADS99 for CC cell survival and a novel small-molecule inhibitor of pBADS99 was utilized. Cell proliferation, survival, foci formation, and patient-derived organoids (PDOs) assays were utilized to determine efficacy, synergy and related mechanisms.
Results
MMC IC50 was positively correlated to the cell line pBADS99/BAD ratio. Increased BADS99 phosphorylation was observed in both MMC-sensitive or -resistant CC cells after MMC treatment. Inhibition of pBADS99 in CC cell lines produced synergistic apoptosis through BAD-mediated apoptotic pathways and enhanced DNA damage in response to MMC. The concurrent use of pharmacological inhibition of pBADS99 and MMC was synergistic, resulting in diminished cell viability and inducing apoptotic cell death in MMC-sensitive and -resistant CC cell lines or patient-derived organoids.
Conclusion
A combination of MMC with inhibition of BAD phosphorylation potentiated efficacy compared to single agent treatment. The potential further development of such strategies may provide outcome benefits to patients with CC.
目的：临床上通常单独或联合使用治疗复发性宫颈癌（CC）的脱氧核糖核酸损伤化疗药丝裂霉素 C（MMC）。MMC 会造成 DNA 损伤，导致 CC 细胞死亡，但也会诱导 AKT-BAD 磷酸化增加，从而产生耐药性，降低临床疗效。本研究评估了 MMC 和 BAD 磷酸化抑制剂联合治疗 CC 的疗效。方法探讨了 BAD 在丝氨酸 99 上的磷酸化（pBADS99）与 MMC 耐药或敏感 CC 细胞存活的关联和功能。研究人员将 BAD 突变为 BADS99A，以检测 BADS99 对 CC 细胞存活的要求，并使用了一种新型的 pBADS99 小分子抑制剂。利用细胞增殖、存活、病灶形成和患者衍生器官组织（PDOs）测定来确定疗效、协同作用和相关机制。经 MMC 处理后，在对 MMC 敏感或耐药的 CC 细胞中均观察到 BADS99 磷酸化增加。通过 BAD 介导的凋亡途径抑制 CC 细胞系中的 pBADS99，可产生协同凋亡，并增强对 MMC 的 DNA 损伤反应。在对 MMC 敏感和耐药的 CC 细胞系或患者衍生的器官组织中，同时使用 pBADS99 和 MMC 的药理抑制具有协同作用，可降低细胞活力并诱导细胞凋亡。这种策略的进一步发展可能会为CC患者带来疗效。
期刊介绍：
Translational Oncology publishes the results of novel research investigations which bridge the laboratory and clinical settings including risk assessment, cellular and molecular characterization, prevention, detection, diagnosis and treatment of human cancers with the overall goal of improving the clinical care of oncology patients. Translational Oncology will publish laboratory studies of novel therapeutic interventions as well as clinical trials which evaluate new treatment paradigms for cancer. Peer reviewed manuscript types include Original Reports, Reviews and Editorials.
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