Formula‑pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. China.
Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University, Guangzhou, Guangdong 510632, P.R. China.
Int J Oncol. 2020 Aug;57(2):562-573. doi: 10.3892/ijo.2020.5070. Epub 2020 May 25.
Cervical cancer is the fourth most common gynecological malignancy affecting the health of women worldwide and the second most common cause of cancer‑related mortality among women in developing regions. Thus, the development of effective chemotherapeutic drugs for the treatment of cervical cancer has become an important issue in the medical field. The application of natural products for the prevention and treatment of various diseases, particularly cancer, has always attracted widespread attention. In the present study, a library of natural products composed of 78 single compounds was screened and it was found that digitoxin exhibited the highest cytotoxicity against HeLa cervical cancer cells with an IC50 value of 28 nM at 48 h. Furthermore, digitoxin exhibited extensive antitumor activities in a variety of malignant cell lines, including the lung cancer cell line, A549, the hepatoma cell line, MHCC97H, and the colon cancer cell line, HCT116. Mechanistically, digitoxin caused DNA double‑stranded breaks (DSBs), inhibited the cell cycle at the G2/M phase via the ataxia telangiectasia mutated serine/threonine kinase (ATM)/ATM and Rad3‑related serine/threonine kinase (ATR)‑checkpoint kinase (CHK1)/checkpoint kinase 2 (CHK2)‑Cdc25C pathway and ultimately triggered mitochondrial apoptosis, which was characterized by the disruption of Bax/Bcl‑2, the release of cytochrome c and the sequential activation of caspases and poly(ADP‑ribose) polymerase (PARP). In addition, the in vivo anticancer effect of digitoxin was confirmed in HeLa cell xenotransplantation models. On the whole, the findings of the present study demonstrate the efficacy of digitoxin against cervical cancer in vivo and elucidate its molecular mechanisms, including DSBs, cell cycle arrest and mitochondrial apoptosis. These results will contribute to the development of digitoxin as a chemotherapeutic agent in the treatment of cervical cancer.
宫颈癌是影响全球女性健康的第四大常见妇科恶性肿瘤，也是发展中地区女性癌症相关死亡的第二大主要原因。因此，开发有效的宫颈癌化疗药物已成为医学领域的重要问题。天然产物在预防和治疗各种疾病，特别是癌症方面的应用一直受到广泛关注。在本研究中，筛选了一个由 78 个单一化合物组成的天然产物文库，发现洋地黄毒苷对 HeLa 宫颈癌细胞具有最高的细胞毒性，在 48 小时时的 IC50 值为 28 nM。此外，洋地黄毒苷在多种恶性细胞系中表现出广泛的抗肿瘤活性，包括肺癌细胞系 A549、肝癌细胞系 MHCC97H 和结肠癌细胞系 HCT116。在机制上，洋地黄毒苷引起 DNA 双链断裂 (DSBs)，通过共济失调毛细血管扩张症突变丝氨酸/苏氨酸激酶 (ATM)/ATM 和 Rad3 相关丝氨酸/苏氨酸激酶 (ATR)-检查点激酶 (CHK1)/检查点激酶 2 (CHK2)-Cdc25C 途径抑制细胞周期在 G2/M 期，并最终触发线粒体凋亡，其特征是 Bax/Bcl-2 的破坏、细胞色素 c 的释放以及 caspase 和多聚（ADP-核糖）聚合酶 (PARP) 的顺序激活。此外，在 HeLa 细胞异种移植模型中证实了洋地黄毒苷的体内抗癌作用。总的来说，本研究的结果表明洋地黄毒苷在体内对宫颈癌的疗效，并阐明了其分子机制，包括 DSBs、细胞周期停滞和线粒体凋亡。这些结果将有助于将洋地黄毒苷开发为治疗宫颈癌的化疗药物。
