千里光碱通过触发持续的 DNA 损伤抑制去势抵抗性前列腺癌细胞的迁移和增殖。
Piperlongumine inhibits migration and proliferation of castration-resistant prostate cancer cells via triggering persistent DNA damage.
机构信息
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, People's Republic of China.
The Fifth Affiliated Hospital of Wenzhou Medical University, Affiliated Lishui Hospital of Zhejiang University, The Central Hospital of Zhejiang Lishui, Lishui, 323000, Zhejiang, People's Republic of China.
出版信息
BMC Complement Med Ther. 2021 Jul 6;21(1):195. doi: 10.1186/s12906-021-03369-0.
BACKGROUND
Metastatic castration-resistant prostate cancer (CRPC) is the leading cause of death among men diagnosed with prostate cancer. Piperlongumine (PL) is a novel potential anticancer agent that has been demonstrated to exhibit anticancer efficacy against prostate cancer cells. However, the effects of PL on DNA damage and repair against CRPC have remained unclear. The aim of this study was to further explore the anticancer activity and mechanisms of action of PL against CRPC in terms of DNA damage and repair processes.
METHODS
The effect of PL on CRPC was evaluated by MTT assay, long-term cell proliferation, reactive oxygen species assay, western blot assay, flow cytometry assay (annexin V/PI staining), β-gal staining assay and DAPI staining assay. The capacity of PL to inhibit the invasion and migration of CRPC cells was assessed by scratch-wound assay, cell adhesion assay, transwell assay and immunofluorescence (IF) assay. The effect of PL on DNA damage and repair was determined via IF assay and comet assay.
RESULTS
The results showed that PL exhibited stronger anticancer activity against CRPC compared to that of taxol, cisplatin (DDP), doxorubicin (Dox), or 5-Fluorouracil (5-FU), with fewer side effects in normal cells. Importantly, PL treatment significantly decreased cell adhesion to the extracellular matrix and inhibited the migration of CRPC cells through affecting the expression and distribution of focal adhesion kinase (FAK), leading to concentration-dependent inhibition of CRPC cell proliferation and concomitantly increased cell death. Moreover, PL treatment triggered persistent DNA damage and provoked strong DNA damage responses in CRPC cells.
CONCLUSION
Collectively, our findings demonstrate that PL potently inhibited proliferation, migration, and invasion of CRPC cells and that these potent anticancer effects were potentially achieved via triggering persistent DNA damage in CRPC cells.
背景
转移性去势抵抗性前列腺癌（CRPC）是前列腺癌患者死亡的主要原因。胡椒碱（PL）是一种新型的潜在抗癌药物，已被证明对前列腺癌细胞具有抗癌功效。然而，PL 对 CRPC 细胞的 DNA 损伤和修复的影响仍不清楚。本研究旨在进一步探讨 PL 对 CRPC 的抗癌活性和作用机制，从 DNA 损伤和修复过程方面进行研究。
方法
通过 MTT 测定法、长期细胞增殖测定法、活性氧测定法、western blot 测定法、流式细胞术测定法（Annexin V/PI 染色）、β-gal 染色测定法和 DAPI 染色测定法评估 PL 对 CRPC 的影响。通过划痕愈合试验、细胞黏附试验、Transwell 试验和免疫荧光（IF）试验评估 PL 抑制 CRPC 细胞侵袭和迁移的能力。通过 IF 测定法和彗星试验测定 PL 对 DNA 损伤和修复的影响。
结果
结果表明，与紫杉醇、顺铂（DDP）、多柔比星（Dox）或 5-氟尿嘧啶（5-FU）相比，PL 对 CRPC 表现出更强的抗癌活性，且对正常细胞的副作用更小。重要的是，PL 处理显著降低了细胞对细胞外基质的黏附，并通过影响粘着斑激酶（FAK）的表达和分布抑制了 CRPC 细胞的迁移，导致 CRPC 细胞增殖呈浓度依赖性抑制，同时细胞死亡增加。此外，PL 处理引发持续的 DNA 损伤，并在 CRPC 细胞中引发强烈的 DNA 损伤反应。
结论
总之，我们的研究结果表明，PL 可有效抑制 CRPC 细胞的增殖、迁移和侵袭，其潜在的抗癌作用可能是通过在 CRPC 细胞中引发持续的 DNA 损伤而实现的。
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