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

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

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.

Citation

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

• Journal Article Type: Article
• Acceptance Date: Mar 20, 2019
• Online Publication Date: Mar 28, 2019
• Publication Date: Jul 1, 2019
• Deposit Date: Nov 27, 2019
• Publicly Available Date: Mar 29, 2020
• Journal: Cancer Letters
• Print ISSN: 0304-3835
• Electronic ISSN: 1872-7980
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 453
• Pages: 57-73
• DOI: https://doi.org/10.1016/j.canlet.2019.03.034
• Keywords: Cardenolide; DNA damage; Apoptosis; Reactive oxygen species; Cerbera odollam
• Public URL: https://nottingham-repository.worktribe.com/output/3357803
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0304383519301909
• Additional Information: This article is maintained by: Elsevier; Article Title: Cardiac glycoside cerberin exerts anticancer activity through PI3K/AKT/mTOR signal transduction inhibition; Journal Title: Cancer Letters; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.canlet.2019.03.034
• Contract Date: Nov 27, 2019