Cardiac glycoside cerberin exerts anticancer activity through PI3K/AKT/mTOR signal transduction inhibition

Md Shahadat Hossan, Zi Yang Chan, Hilary M. Collins, Fiona N. Shipton, Mark S. Butler, Mohammed Rahmatullah, Jong Bong Lee, Pavel Gershkovich, Leonid Kagan, Teng Jin Khoo, Christophe Wiart, Tracey D. Bradshaw

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Natural products possess a significant role in anticancer therapy and many currently-used anticancer drugs are of natural origin. Cerberin (CR), a cardenolide isolated from the fruit kernel of Cerbera odollam, was found to potently inhibit cancer cell growth (GI 50 values < 90 nM), colony formation and migration. Significant G2/M cell cycle arrest preceded time- and dose-dependent apoptosis-induction in human cancer cell lines corroborated by dose-and time-dependent PARP cleavage and caspase 3/7 activation, in addition to reduced Bcl-2 and Mcl-1 expression. CR potently inhibited PI3K/AKT/mTOR signalling depleting polo-like kinase 1 (PLK-1), c-Myc and STAT-3 expression. Additionally, CR significantly increased the generation of reactive oxygen species (ROS) producing DNA double strand breaks. Preliminary in silico biopharmaceutical assessment of CR predicted >60% bioavailability and rapid absorption; doses of 1–10 mg/kg CR were predicted to maintain efficacious unbound plasma concentrations (>GI 50 value). CR's potent and selective anti-tumour activity, and its targeting of key signalling mechanisms pertinent to tumourigenesis support further preclinical evaluation of this cardiac glycoside.

Original languageEnglish (US)
Pages (from-to)57-73
Number of pages17
JournalCancer Letters
Volume453
DOIs
StatePublished - Jul 1 2019

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Keywords

  • Apoptosis
  • Cardenolide
  • Cerbera odollam
  • DNA damage
  • Reactive oxygen species

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    Hossan, M. S., Chan, Z. Y., Collins, H. M., Shipton, F. N., Butler, M. S., Rahmatullah, M., Lee, J. B., Gershkovich, P., Kagan, L., Khoo, T. J., Wiart, C., & Bradshaw, T. D. (2019). Cardiac glycoside cerberin exerts anticancer activity through PI3K/AKT/mTOR signal transduction inhibition. Cancer Letters, 453, 57-73. https://doi.org/10.1016/j.canlet.2019.03.034