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

Authors: Hossan MS, Chan ZY, Collins HM, Shipton FN, Butler MS, Rahmatullah M, Lee JB, Gershkovich P, Kagan L, Khoo TJ, Wiart C, Bradshaw TD
Publication: Cancer Lett
Keywords: apoptosis, cardenolide, cerbera odollam, DNA damage, machine learning, PBPK modeling, reactive oxygen species
Software: ADMET Predictor®, GastroPlus®

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 (GI50 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 (>GI50 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.