Ali 2019 MiPschool Coimbra

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Sameh Ali
Metabolic blackout in hepatocellular carcinoma cells by submicromolar iodoacetate-loaded galactosylated nanoparticles.

Link: MitoEAGLE

Ali SS, Abd-Rabou AA, Reda AM, Khalifa AM (2019)

Event: MiPschool Coimbra 2019


Targeting characteristic metabolic modes to drain bioenergetics in cancer cells has recently gained attention. To increase the potential of this strategy, drugs must be drastic inhibitors of all metabolic pathways in cancer cell subpopulations, and importantly, be targeting malignant cells selectively. We exploited enhanced expression of asialoglycoprotein receptors on human hepatocellular carcinoma HepG2 cell membrane for specific delivery of an effective metabolic inhibitor loaded in nanoparticles conjugated with galactosylated chains as recognition termini. Submicromoles of iodoacetate-loaded nanoparticles (NIA) were sufficient to completely disrupt glycolytic as well as mitochondrial metabolism, causing substantial cytotoxicity of HepG2 cells within 4 h. To identify the mechanism of cell death by NIA, we performed extensive metabolic investigations of mitochondria stress in intact-attached or permeabilized-suspended HepG2 cells as well as on isolated mitochondria. Metabolic, flow cytometric, and molecular studies provided converging evidence that NIA triggers complete cell death through mitochondrial ROS-mediated apoptosis induction concomitant with bioenergetic deprivation in HepG2 and HuH-7 but not in normal WI-38 cells. Imaging studies confirmed lower uptake of NIA by normal cells and their mitochondria relative to cancer cells which highlight the targetability of cancer cell mitochondria by the current combination. Overall, our results revealing the ability of relatively low NIA concentrations to completely disrupt various metabolic pathways that are crucial for proliferating as well as resilient cancer cells provide a new treatment approach via nanoparticle-assisted metabolic interventions.

Bioblast editor: Plangger M

Labels: MiParea: Pharmacology;toxicology  Pathology: Cancer 

Organism: Human  Tissue;cell: Liver 

Affiliations and support

Abd-Rabou AA(1), Reda AM(1), Khalifa AM(1), and Ali SS(1,2)
  1. Center Aging Associated Diseases, Helmy Inst Medical Sciences, Zewail City Science Technology, Giza
  2. 57357 Children's Cancer Hospital, Cairo; Egypt. - [email protected]