植物来源的倍半萜内酯脱氧土大黄素与顺铂联用具有协同作用，可降低肾毒性，抑制小鼠 B16 黑色素瘤肺转移。

Phyto-sesquiterpene lactone deoxyelephantopin and cisplatin synergistically suppress lung metastasis of B16 melanoma in mice with reduced nephrotoxicity.

机构信息

Department of Nutrition and Health Sciences, Kainan University, Taoyuan 338, Taiwan.

Agricultural Biotechnology Research Center, Academia Sinica, Taipei 115, Taiwan.

出版信息

Phytomedicine. 2019 Mar 15;56:194-206. doi: 10.1016/j.phymed.2018.11.005. Epub 2018 Nov 6.

DOI:10.1016/j.phymed.2018.11.005

PMID:30668340

Abstract

BACKGROUND

Cisplatin (CP) is a chemotherapeutic drug for treating melanoma that also causes adverse side effects in cancer patients.

PURPOSE

This study investigated the bioefficacy of a phytoagent deoxyelephantopin (DET) in inhibiting B16 melanoma cell activity, its synergism with CP against metastatic melanoma, and its capability to attenuate CP side effects in animals.

METHODS

DET and CP bioactivities were assessed by MTT assay, isobologram analysis, time-lapse microscopy, migration and invasion assays, flow cytometry and western blotting. In vivo bioluminescence imaging was used to detect lung metastasis of B16 cells carrying COX-2 reporter gene in syngeneic mice. H&E staining and immunohistochemistry were used to evaluate the compound/drug efficacy and CP side effects. Nephrotoxicity caused by CP treatment in mice was evaluated by UPLC/ESI-QTOF MS - based metabolomics and haematometry.

RESULT

DET, alone or in combination with cisplatin, inhibited B16 cell proliferation, migration, and invasion, and induced cell-cycle arrested at the G/M phase and de-regulated cell-cycle mediators in cancer cells. In a murine B16 metastatic allograft model, CP2 (2  mg/kg) treatment inhibited B16 lung metastasis accompanied by severe body weight loss, renal damage and inflammation, and haematological toxicity. DET10 and CP cotreatment (DET10 + CP1) or sequential treatment (CP2→DET10) significantly inhibited formation of pulmonary melanoma foci and reduced renal damage. DET pretreatment (Pre-DET10) or CP2→DET10 treatment had the longest survival (52  vs. 37 days for tumor control mice). CP treatment caused abnormally accumulated urea cycle metabolites and serotonin metabolite hippuric acid in renal tissues that were not seen with DET alone or in combination with CP.

CONCLUSION

The CP and DET combination may be an effective intervention for melanoma with reduced side effects.

摘要

背景

顺铂（CP）是一种用于治疗黑色素瘤的化疗药物，但也会给癌症患者带来不良反应。

目的

本研究旨在探讨植物源药物去氧鬼臼毒素（DET）抑制 B16 黑色素瘤细胞活性的生物功效，其与 CP 联合抑制转移性黑色素瘤的协同作用，以及减轻 CP 在动物中的副作用的能力。

方法

通过 MTT 检测、棋盘式实验分析、延时显微镜观察、迁移和侵袭实验、流式细胞术和 Western blot 分析评估 DET 和 CP 的生物活性。在荷 COX-2 报告基因的 B16 细胞的同基因小鼠中，使用生物发光成像检测肺部转移。通过 H&E 染色和免疫组化评估化合物/药物的疗效和 CP 的副作用。通过基于 UPLC/ESI-QTOF MS 的代谢组学和血液学评估 CP 治疗引起的小鼠肾毒性。

结果

DET 单独或联合 CP 抑制 B16 细胞增殖、迁移和侵袭，并诱导细胞周期停滞在 G2/M 期，调节癌细胞中的细胞周期调节剂。在小鼠 B16 转移性同种异体移植模型中，CP2（2 mg/kg）治疗抑制了 B16 肺部转移，同时伴有严重的体重减轻、肾脏损伤和炎症以及血液学毒性。DET10 和 CP 联合治疗（DET10+CP1）或序贯治疗（CP2→DET10）显著抑制了肺黑色素瘤病灶的形成，减轻了肾脏损伤。DET 预处理（Pre-DET10）或 CP2→DET10 治疗的生存时间最长（肿瘤对照小鼠为 52 天 vs. 37 天）。CP 治疗导致肾脏组织中尿素循环代谢物和 5-羟色胺代谢物 hippuric acid 异常积累，而单独使用 DET 或与 CP 联合使用时则不会出现这种情况。