丹参酮诱导凋亡抵抗的结肠癌细胞发生自噬性细胞死亡和非 p53 依赖的细胞毒性。
Sensitivity of apoptosis-resistant colon cancer cells to tanshinones is mediated by autophagic cell death and p53-independent cytotoxicity.
机构信息
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
出版信息
Phytomedicine. 2015 May 15;22(5):536-44. doi: 10.1016/j.phymed.2015.03.010. Epub 2015 Mar 27.
BACKGROUND
Multidrug resistance (MDR) develops in nearly all patients with colon cancer. The reversal of MDR plays an important role in the success of colon cancer chemotherapy. One of the commonest mechanisms conferring MDR is the suppression of apoptosis in cancer cells.
PURPOSE
This study investigated the sensitivity of cryptotanshinone (CTS) and dihydrotanshinone (DTS), two lipophilic tanshinones from a traditional Chinese medicine Salvia miltiorrhiza, in apoptosis-resistant colon cancer cells.
METHODS
Cell viability was measured by MTT assay. Cell cycle distribution and apoptosis were determined by flow cytometry. Protein levels were analyzed by western blot analysis. The formation of acidic vesicular organelles was visualized by acridine orange staining.
RESULTS
Experimental results showed that multidrug-resistant colon cancer cells SW620 Ad300 were sensitive to both CTS and DTS in terms of cell death, but with less induction of apoptosis when compared with the parental cells SW620, suggesting that other types of cell death such as autophagy could occur. Indeed, the two tanshinones induced more LC3B-II accumulation in SW620 Ad300 cells with increased autophagic flux. More importantly, cell viability was increased after autophagy inhibition, indicating that autophagy induced by the two tanshinones was pro-cell death. Besides, the cytotoxic actions of the two tanshinones were p53-independent, which could be useful in inhibiting the growth of apoptosis-resistant cancer cells with p53 defects.
CONCLUSION
The current findings strongly indicate that both CTS and DTS could inhibit the growth of apoptosis-resistant colon cancer cells through induction of autophagic cell death and p53-independent cytotoxicity. They are promising candidates to be further developed as therapeutic agents in the adjuvant therapy for colon cancer, especially for the apoptosis-resistant cancer types.
背景
几乎所有结肠癌患者都会产生多药耐药性（MDR）。MDR 的逆转在结肠癌化疗的成功中起着重要作用。赋予 MDR 的最常见机制之一是抑制癌细胞凋亡。
目的
本研究调查了脂溶性丹参酮（CTS）和二氢丹参酮（DTS）这两种来自传统中药丹参的化合物在凋亡抵抗的结肠癌细胞中的敏感性。
方法
通过 MTT 测定法测量细胞活力。通过流式细胞术测定细胞周期分布和细胞凋亡。通过 Western blot 分析分析蛋白水平。通过吖啶橙染色可视化酸性囊泡细胞器的形成。
结果
实验结果表明，多药耐药性结肠癌细胞 SW620 Ad300 对 CTS 和 DTS 均敏感，在细胞死亡方面，但与亲本细胞 SW620 相比，诱导凋亡的程度较低，表明可能发生其他类型的细胞死亡，如自噬。事实上，两种丹参酮在 SW620 Ad300 细胞中诱导更多的 LC3B-II 积累，并增加自噬通量。更重要的是，自噬抑制后细胞活力增加，表明两种丹参酮诱导的自噬是促进细胞死亡的。此外，两种丹参酮的细胞毒性作用与 p53 无关，这在抑制具有 p53 缺陷的凋亡抵抗癌细胞的生长方面可能很有用。
结论
目前的研究结果强烈表明，CTS 和 DTS 均可通过诱导自噬性细胞死亡和 p53 非依赖性细胞毒性来抑制凋亡抵抗的结肠癌细胞的生长。它们是有希望的候选药物，可以进一步开发为结肠癌辅助治疗的治疗剂，特别是对于凋亡抵抗的癌症类型。
Zotero 插件