1. Studies of Jatrogossone A as a Reactive Oxygen Species Inducer in Cancer Cellular Models
- Author
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Malia B. Potts, Taotao Ling, Jane E. Craig, Julie Maier, Travis D. Marsico, John C. Bollinger, Fatima Rivas, Joseph T. Opferman, Walter H. Lang, and Amit Budhraja
- Subjects
Mitochondrial ROS ,Programmed cell death ,Cell Survival ,Cell ,Poly (ADP-Ribose) Polymerase-1 ,Pharmaceutical Science ,Jatropha ,Mitochondrion ,Antioxidants ,Analytical Chemistry ,Cell Line, Tumor ,Neoplasms ,Drug Discovery ,Mitophagy ,medicine ,Humans ,Cell Proliferation ,Membrane Potential, Mitochondrial ,Pharmacology ,chemistry.chemical_classification ,Reactive oxygen species ,Dose-Response Relationship, Drug ,Organic Chemistry ,Cell Cycle Checkpoints ,Antineoplastic Agents, Phytogenic ,Acetylcysteine ,Cell biology ,medicine.anatomical_structure ,Complementary and alternative medicine ,chemistry ,Cancer cell ,Molecular Medicine ,Reactive Oxygen Species ,Intracellular - Abstract
Natural products continue to provide a platform to study biological systems. A bioguided study of cancer cell models led us to a new member of the jatrophane natural products from Jatropha gossypiifolia, which was independently identified and characterized as jatrogossone A (1). Purification and structure elucidation was performed by column chromatography and high-performance liquid chromatography-mass spectrometry and NMR techniques, and the structure was confirmed via X-ray crystallography. The unique molecular scaffold of jatrogossone A prompted an evaluation of its mode of action. Cytotoxicity assays demonstrated that jatrogossone A displays selective antiproliferative activity against cancer cell models in the low micromolar range with a therapeutic window. Jatrogossone A (1) affects mitochondrial membrane potential (ΔΨm) in a time- and dose-dependent manner. This natural product induces radical oxygen species (ROS) selectively in cancer cellular models, with minimal ROS induction in noncancerous cells. Compound 1 induces ROS in the mitochondria, as determined by colocalization studies, and it induces mitophagy. It promotes also in vitro cell death by causing cell arrest at the G2/M stage, caspase (3/7) activation, and PARP-1 cleavage. The combined findings provide a potential mechanism by which 1 relies on upregulation of mitochondrial ROS to potentiate cytotoxic effects through intracellular signaling.
- Published
- 2019