Calotropin and corotoxigenin 3-O-glucopyranoside from the desert milkweed Asclepias subulata inhibit the Na+/K+-ATPase activity

Salvador E. Meneses-Sagrero, Luisa A. Rascón-Valenzuela, Juan C. García-Ramos, Wagner Vilegas, Aldo A. Arvizu-Flores, Rogerio R. Sotelo-Mundo*, Ramon E. Robles-Zepeda

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Na+/K+-ATPase is an essential transmembrane enzyme found in all mammalian cells with critical functions for cell ion homeostasis. The inhibition of this enzyme by several cardiotonic steroids (CTS) has been associated with the cytotoxic effect on cancer cell lines of phytochemicals such as ouabain and digitoxin. This study evaluated the inhibitory capacity of cardenolides calotropin and corotoxigenin 3-O-glucopyranoside (C3OG) from Asclepias subulata over the Na+/K+-ATPase activity in vitro and silico. The inhibitory assays showed that calotropin and C3OG decreased the Na+/K+-ATPase activity with IC50 values of 0.27 and 0.87 mM, respectively. Furthermore, the molecules presented an uncompetitive inhibition on Na+/K+-ATPase activity, with Ki values of 0.2 mM to calotropin and 0.5 mM to C3OG. Furthermore, the molecular modeling indicated that calotropin and C3OG might interact with the Thr797 and Gln111 residues, considered essential to the interaction with the Na+/K+-ATPase. Besides, these cardenolides can interact with amino acid residues such as Phe783, Leu125, and Ala323, to establish hydrophobic interactions on the binding site. Considering the results, these provide novel evidence about the mechanism of action of cardenolides from A. subulata, proposing that C3OG is a novel cardenolide that deserves further consideration for in vitro cellular antiproliferative assays and in vivo studies as an anticancer molecule.

Original languageEnglish
Article numbere13524
JournalPeerJ
Volume10
DOIs
StatePublished - Jun 2022
Externally publishedYes

Bibliographical note

Funding Information:
The authors thank Dr. Aldo Arvizu-Flores for his support during the realization of the molecular models and appreciate the help of Beatriz Salcido Gonzalez during the development of this article. This work was supported by the Consejo Nacional de Ciencia y Tecnología (CONACYT, 83462) and the scholarship for SE Meneses Sagrero (grant 492204). There was no additional external funding received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Funding Information:
This work was supported by the Consejo Nacional de Ciencia y Tecnología (CONACYT, 83462) and the scholarship for SE Meneses Sagrero (grant 492204). There was no additional external funding received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Funding Information:
The following grant information was disclosed by the authors: Consejo Nacional de Ciencia y Tecnología (CONACYT): 83462 and 492204.

Publisher Copyright:
Copyright 2022 Meneses-Sagrero et al.

Keywords

  • Asclepias subulata
  • ATPase activity
  • Cardenolides
  • Uncompetitive inhibition

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