(+)-Strebloside-Induced Cytotoxicity in Ovarian Cancer Cells Is Mediated through Cardiac Glycoside Signaling Networks

Chen, Wei Lun; Ren, Yulin; Ren, Jinhong; Erxleben, Christian; Johnson, Michael E.; Gentile, Sandro; Kinghorn, A. Douglas; Swanson, Steven M.; Burdette, Joanna E.

doi:10.1021/acs.jnatprod.6b01150

Cited by 34 publications

(63 citation statements)

References 38 publications

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“…Dg, deHyr, and Cy have also docked as Ob to the CG binding site in NKA with the same orientation of the steroid skeleton as Ob in the aforementioned NKA crystal structure [ 45 ]. The same orientation of the steroid skeleton was also observed in the crystal structure of NKA with digoxin [ 46 ] and strebloside, which is a structural analog of Cy [ 47 ]. However, deHyr and Cy showed higher binding energies compared to Ob caused by a lower number of interactions with NKA, which is due to the lower number of substituents on the steroid skeleton.…”

Section: Resultsmentioning

confidence: 53%

Steroid Glycosides Hyrcanoside and Deglucohyrcanoside: On Isolation, Structural Identification, and Anticancer Activity

Rimpelová

Zimmermann

Drašar

et al. 2021

Foods

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Cardiac glycosides (CGs) represent a group of sundry compounds of natural origin. Most CGs are potent inhibitors of Na+/K+-ATPase, and some are routinely utilized in the treatment of various cardiac conditions. Biological activities of other lesser known CGs have not been fully explored yet. Interestingly, the anticancer potential of some CGs was revealed and thereby, some of these compounds are now being evaluated for drug repositioning. However, high systemic toxicity and low cancer cell selectivity of the clinically used CGs have severely limited their utilization in cancer treatment so far. Therefore, in this study, we have focused on two poorly described CGs: hyrcanoside and deglucohyrcanoside. We elaborated on their isolation, structural identification, and cytotoxicity evaluation in a panel of cancerous and noncancerous cell lines, and on their potential to induce cell cycle arrest in the G2/M phase. The activity of hyrcanoside and deglucohyrcanoside was compared to three other CGs: ouabain, digitoxin, and cymarin. Furthermore, by in silico modeling, interaction of these CGs with Na+/K+-ATPase was also studied. Hopefully, these compounds could serve not only as a research tool for Na+/K+-ATPase inhibition, but also as novel cancer therapeutics.

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Section: Resultsmentioning

confidence: 53%

Steroid Glycosides Hyrcanoside and Deglucohyrcanoside: On Isolation, Structural Identification, and Anticancer Activity

Rimpelová

Zimmermann

Drašar

et al. 2021

Foods

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“…The best small-molecule agents that can inhibit NKA activity are the cardiac glycosides that are composed of a sterol moiety linked to a glucoside 14,24 . Plumbagin and atovaquone do not share structural similarities with the known cardiac glycoside inhibitors of NKA [23][24][25][26][27] . Therefore, it is unlikely that plumbagin and atovaquone can serve as direct inhibitors of NKA.…”

Section: Discussionmentioning

confidence: 91%

Oxidative stress induced by the anti-cancer agents, plumbagin, and atovaquone, inhibits ion transport through Na+/K+-ATPase

Alharbi

Kapur

Felder

et al. 2020

Sci Rep

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Oxidative stress inhibits Na+/K+-ATPase (NKA), the ion channel that maintains membrane potential. Here, we investigate the role of oxidative stress-mediated by plumbagin and atovaquone in the inhibition of NKA activity. We confirm that plumbagin and atovaquone inhibit the proliferation of three human (OVCAR-3, SKOV-3, and TYKNu) and one mouse (ID8) ovarian cancer cell lines. The oxygen radical scavenger, N-acetylcysteine (NAC), attenuates the chemotoxicity of plumbagin and atovaquone. Whole-cell patch clamping demonstrates that plumbagin and atovaquone inhibit outward and the inward current flowing through NKA in SKOV-3 and OVCAR-3. Although both drugs decrease cellular ATP; providing exogenous ATP (5 mM) in the pipet solution used during patch clamping did not recover NKA activity in the plumbagin or atovaquone treated SKOV-3 and OVCAR-3 cells. However, pretreatment of the cells with NAC completely abrogated the NKA inhibitory activity of plumbagin and atovaquone. Exposure of the SKOV-3 cells to either drug significantly decreases the expression of NKA. We conclude that oxidative stress caused by plumbagin and atovaquone degrades NKA, resulting in the inability to maintain ion transport. Therefore, when evaluating compounds that induce oxidative stress, it is important to consider the contribution of NKA inhibition to their cytotoxic effects on tumor cells.

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“…Our results first demonstrated that digoxin treatment led to cell cycle arrest at the G0/G1 phase in SKOV-3 cells. It has been reported that CGs arrest the cell cycle in many cancers including glioblastoma, 35 breast, 22 ovarian, 28 and bladder cancers. 36 Digoxin treatment causes cell cycle arrest at the G0/G1 and G2/M phase for Raji and NAMALWA cells, and Burkitt’s lymphoma cell lines, respectively.…”

Section: Discussionmentioning

confidence: 99%

“… 37 In ovarian cancer cells, it has been reported that bufalin and digitoxin arrest cell cycle at the G0/G1 and G2/M phases, respectively. 28 , 38 Recently, it has been shown that digoxin and digitoxin create anti-cancer effects on hepatocellular carcinoma by inhibiting the cell viability and migration. 39 It is apparent that not only reproduction-related cancers, but also the cancers of other systems are affected by digoxin and digitoxin.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Effects of Digoxin and Digitoxin on Cell Growth in Human Ovarian Cancer Cell Line SKOV-3

Chou

Chen

et al. 2021

Integr Cancer Ther

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Background: Cardiac glycosides (CGs) possess a chemical structure similar to steroids, and are inhibitors of the sodium potassium pump. An anti-tumor effect of CGs in breast and prostate cancers has been reported, but the effect of CGs on ovarian cancer is still unclear. Aims: In this study, the effects of CGs on proliferation, cytotoxicity and cell cycle of ovarian cancer cell line (SKOV-3) have been investigated. Procedure: The cell proliferation and cytotoxicity were detected by MTT assay and LDH activity assay, respectively. CGs, at concentrations higher than IC50, decreased cell proliferation and showed increased cytotoxicity toward SKOV-3 cells. The colony-formation ability was reduced after treatment with digoxin and digitoxin for 10 days. Furthermore, we explored the effect of digoxin and digitoxin on the distribution of cell cycle by flow cytometry. Results: Results revealed that both digoxin and digitoxin led to cell cycle arrest in G0/G1 phase with 24 or 48 hours, but the arrest of G0/G1 phase was not observed at 72 hours. We evaluated the percentage of hypodiploid cell population as an index of the cellular fragments through flow cytometry. The data indicated that cellular fragments were significantly increased by treating with digitoxin at the concentrations of IC50 and 10−6 M for 72 hours. Conclusion: Taken together, these data suggest that CGs decreased cell proliferation and increased cytotoxicity through cell cycle arrest at the G0/G1 phase. CGs have anti-tumor effect in SKOV-3 cells and might be a potential therapeutic drug for ovarian cancer. Since this study is a preliminary investigation of CGs on SKOV-3 cells, more experiments might be performed in the future. Furthermore, more ovarian cancer cell lines might also be employed in the future studies to confirm the effect of CGs in ovarian cancer.

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(+)-Strebloside-Induced Cytotoxicity in Ovarian Cancer Cells Is Mediated through Cardiac Glycoside Signaling Networks

Cited by 34 publications

References 38 publications

Steroid Glycosides Hyrcanoside and Deglucohyrcanoside: On Isolation, Structural Identification, and Anticancer Activity

Steroid Glycosides Hyrcanoside and Deglucohyrcanoside: On Isolation, Structural Identification, and Anticancer Activity

Oxidative stress induced by the anti-cancer agents, plumbagin, and atovaquone, inhibits ion transport through Na+/K+-ATPase

Inhibitory Effects of Digoxin and Digitoxin on Cell Growth in Human Ovarian Cancer Cell Line SKOV-3

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