Wang Fangfang, Mayca Pozo Franklin, Tian Danmei, Geng Xinran, Yao Xinsheng, Zhang Youwei, Tang Jinshan
Institute of Traditional Chinese Medicine and Natural Products, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drug Research, College of Pharmacy, Jinan University, Guangzhou, China.
International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, Guangzhou, China.
Front Pharmacol. 2020 Jun 9;11:861. doi: 10.3389/fphar.2020.00861. eCollection 2020.
Shikonin is a natural naphthoquinone compound and has demonstrated potent anti-cancer activities; however, the underlying molecular mechanisms remained elusive. Here we report that Shikonin inhibited the growth of a wide range of human cancer cell lines, illustrating a broad anticancer effect. Mechanistically, we show that Shikonin arrested the cell cycle at the G2/M phase, inhibited the ERK-dependent cell growth signal, and induced cell death in both P53 wild type and mutant cancer cells, which collectively contributed to the growth inhibitory effect of Shikonin. A pan-apoptosis inhibitor largely suppressed Shikonin-induced cell death, suggesting an important role of apoptosis in this process. Intriguingly, Shikonin also activated autophagy and inhibition of autophagy by depleting critical autophagic genes further increased Shikonin-induced cell death, indicating a protective role of autophagy. In uncovering the molecular mechanisms underlying these effects of Shikonin, we found that Shikonin induced a robust upregulation of P21 independent of the P53 status, upregulated autophagy genes, as well as inhibited expression of genes required for cell growth. Using mouse tumor models, we confirmed the strong anticancer effect of Shikonin . Together, our data reveal a broad range of pharmacological functions of Shikonin, involving simultaneous growth inhibition, cell cycle arrest, autophagy activation and apoptosis induction through regulating expression of critical genes involved in these pathways. Our study may facilitate the development of Shikonin in cancer therapy as a single agent or in combination with other anticancer therapies.
紫草素是一种天然萘醌化合物，已显示出强大的抗癌活性；然而，其潜在的分子机制仍不清楚。在此我们报告，紫草素抑制多种人类癌细胞系的生长，显示出广泛的抗癌作用。从机制上讲，我们表明紫草素使细胞周期停滞在G2/M期，抑制ERK依赖的细胞生长信号，并在P53野生型和突变型癌细胞中诱导细胞死亡，这些共同促成了紫草素的生长抑制作用。一种泛凋亡抑制剂在很大程度上抑制了紫草素诱导的细胞死亡，表明凋亡在这一过程中起重要作用。有趣的是，紫草素还激活自噬，通过消耗关键自噬基因抑制自噬进一步增加了紫草素诱导的细胞死亡，表明自噬具有保护作用。在揭示紫草素这些作用的分子机制时，我们发现紫草素诱导P21强烈上调，与P53状态无关，上调自噬基因，并抑制细胞生长所需基因的表达。使用小鼠肿瘤模型，我们证实了紫草素强大的抗癌作用。总之，我们的数据揭示了紫草素广泛的药理功能，包括通过调节参与这些途径的关键基因的表达同时抑制生长、使细胞周期停滞、激活自噬和诱导凋亡。我们的研究可能有助于将紫草素开发为癌症治疗的单一药物或与其他抗癌疗法联合使用。
