Digitoxin inhibits HeLa cell growth through the induction of G2/M cell cycle arrest and apoptosis in vitro and in vivo

Abstract

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 IC 50 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 G 2 /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.

RRM2 Mediates the Anti-Tumor Effect of the Natural Product Pectolinarigenin on Glioblastoma Through Promoting CDK1 Protein Degradation by Increasing Autophagic Flux

“…CDK1, an essential kinase regulating cell cycle progression, is upregulated in multiple cancers. CDK1 depletion promote cell-cycle arrest and ultimately inhibit tumor cell proliferation ( 42 – 44 ). Additionally, p62 is an adapter that is widely involved in protein interactions.…”

Digitoxin Affects Metabolism, ROS Production and Proliferation in Pancreatic Cancer Cells Differently Depending on the Cell Phenotype

“…An increase in the proportion of cells in the S/G2-phase might imply DNA damage. In a study on HeLa cells by Gan et al, 2020, they found digitoxin to cause cell arrest in G2 due to DNA double strand breaks [ 66 ].…”

Monovalent ions and stress-induced senescence in human mesenchymal endometrial stem/stromal cells

“…However, the high resistance of senescent hMESCs to ouabain is not consistent with proposed selective cytotoxic (senolytic) activity of cardiac glycosides in relation to senescence 14 , 15 . Note that there is a lot of data in the literature that cardiac glycosides also kill high proliferating cancer cells, but not cells that normally cycle 55 – 59 . The question arises as to what may underlie the selective toxic effect of cardiac glycosides on senescent or cancer cells, and whether disturbances in cell ion homeostasis (in particular, K + content) can be involved in the anti-aging or anticancer effects of these drugs.…”