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

Md Shahadat Hossan1, Zi-Yang Chan2, Hilary M Collins3

  • 1School of Pharmacy, Centre for Biomolecular Sciences, The University of Nottingham, University Park, Nottingham, NG7 2RD, UK; School of Pharmacy, University of Nottingham Malaysia Campus, Jalan Broga, Semenyih, 43500, Selangor, Malaysia.

Cancer Letters
|April 2, 2019
PubMed

Insights

Cerberin, a natural product, effectively inhibits cancer cell growth and migration by inducing cell cycle arrest and apoptosis. This cardiac glycoside shows promise for preclinical anticancer therapy due to its potent activity and favorable bioavailability.

Area of Science:

  • Natural product chemistry
  • Pharmacology
  • Cancer biology

Background:

  • Natural products are a vital source of anticancer drugs.
  • Many established chemotherapeutics originate from natural sources.
  • Identifying novel natural compounds with anticancer potential is crucial.

Purpose of the Study:

  • To investigate the anticancer properties of Cerberin (CR), a cardenolide from Cerbera odollam.
  • To elucidate the mechanisms underlying CR's anti-tumour effects.
  • To assess the preliminary biopharmaceutical profile of CR for therapeutic potential.

Main Methods:

  • In vitro assays to evaluate cancer cell growth inhibition, colony formation, and migration.
  • Cell cycle analysis and apoptosis assays (PARP cleavage, caspase activation, Bcl-2/Mcl-1 expression).
  • Western blotting to assess signaling pathway modulation (PI3K/AKT/mTOR, PLK-1, c-Myc, STAT-3) and reactive oxygen species (ROS) generation.
  • In silico prediction of pharmacokinetic properties (bioavailability, absorption).

Main Results:

  • CR potently inhibited cancer cell growth (GI50 < 90 nM), colony formation, and migration.
  • CR induced G2/M cell cycle arrest and apoptosis, evidenced by PARP cleavage and caspase activation, with decreased Bcl-2 and Mcl-1.
  • CR suppressed PI3K/AKT/mTOR signaling, reduced PLK-1, c-Myc, and STAT-3, and increased ROS leading to DNA damage.
  • In silico analysis predicted >60% bioavailability and rapid absorption for CR.

Conclusions:

  • Cerberin exhibits potent and selective anticancer activity against human cancer cell lines.
  • CR targets key tumorigenesis pathways, including PI3K/AKT/mTOR, and induces apoptosis.
  • The favorable in silico pharmacokinetic profile suggests CR warrants further preclinical investigation as an anticancer agent.
Keywords:
ApoptosisCardenolideCerbera odollamDNA damageReactive oxygen species

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