Amorfrutin C induces apoptosis and inhibits proliferation in colon cancer cells through targeting mitochondria

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Item Type:	Article
Title:	Amorfrutin C induces apoptosis and inhibits proliferation in colon cancer cells through targeting mitochondria
Creators Name:	Weidner, C., Rousseau, M., Micikas, R.J., Fischer, C., Plauth, A., Wowro, S.J., Siems, K., Hetterling, G., Kliem, M., Schroeder, F.C. and Sauer, S.
Abstract:	A known (1) and a structurally related new natural product (2), both belonging to the amorfrutin benzoic acid class, were isolated from the roots of Glycyrrhiza foetida. Compound 1 (amorfrutin B) is an efficient agonist of the nuclear peroxisome proliferator activated receptor (PPAR) gamma and of other PPAR subtypes. Compound 2 (amorfrutin C) showed comparably lower PPAR activation potential. Amorfrutin C exhibited striking antiproliferative effects for human colorectal cancer cells (HT-29 and T84), prostate cancer (PC-3), and breast cancer (MCF7) cells (IC50 values ranging from 8 to 16 μM in these cancer cell lines). Notably, amorfrutin C (2) showed less potent antiproliferative effects in primary colon cells. For HT-29 cells, compound 2 induced G0/G1 cell cycle arrest and modulated protein expression of key cell cycle modulators. Amorfrutin C further induced apoptotic events in HT-29 cells, including caspase activation, DNA fragmentation, PARP cleavage, phosphatidylserine externalization, and formation of reactive oxygen species. Mechanistic studies revealed that 2 disrupts the mitochondrial integrity by depolarization of the mitochondrial membrane (IC50 0.6 μM) and permanent opening of the mitochondrial permeability transition pore, leading to increased mitochondrial oxygen consumption and extracellular acidification. Structure-activity-relationship experiments revealed the carboxylic acid and the hydroxy group residues of 2 as fundamental structural requirements for inducing these apoptotic effects. Synergy analyses demonstrated stimulation of the death receptor signaling pathway. Taken together, amorfrutin C (2) represents a promising lead for the development of anticancer drugs.
Keywords:	Antitumor Drug Screening Assays, Apoptosis, Caspases, Cell Cycle Checkpoints, Cell Proliferation, Colonic Neoplasms, G1 Phase Cell Cycle Checkpoints, Glycyrrhiza, HT29 Cells, Inhibitory Concentration 50, Mitochondria, Mitochondrial Membrane Potential, Molecular Structure, Morocco, Peroxisome Proliferator-Activated Receptors, Phytogenic Antineoplastic Agents, Plant Roots, Reactive Oxygen Species, Salicylates, Structure-Activity Relationship, bcl-2-Associated X Protein
Source:	Journal of Natural Products
ISSN:	1520-6025
Publisher:	American Chemical Society / American Society of Pharmacognosy
Volume:	79
Number:	1
Page Range:	2-12
Date:	22 January 2016
Official Publication:	https://doi.org/10.1021/acs.jnatprod.5b00072
PubMed:	View item in PubMed

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