Mechanistic evaluation of a novel small molecule targeting mitochondria in pancreatic cancer cells

• Published in: PloS one Vol. 8; no. 1; p. e54346
• Main Authors: Shabaik, Yumna H, Millard, Melissa, Neamati, Nouri
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 21.01.2013; Public Library of Science (PLoS)
• Subjects: Anticancer properties; Apoptosis; Apoptosis - drug effects; Autophagy; Autophagy - drug effects; Biology; Cancer; Cancer cells; Cancer therapies; Cancer treatment; Caspase; Cell death; Cell Line, Tumor; Cell migration; Cell Survival - drug effects; Coumarins - administration & dosage; Cytotoxicity; Drug Discovery; Fluorescence; Health aspects; Humans; Inhibition; Inhibitory Concentration 50; Kinases; Medicine; Metabolism; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Molecular modelling; Organophosphorus Compounds - administration & dosage; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Phagocytosis; Pharmaceutical sciences; Pharmacology; Pharmacy; Phase transitions; Phosphorylation; Phosphotransferases; Poly(ADP-ribose) polymerase; Proteins; Respiration; Salts; Signal Transduction - drug effects; Signaling; Tumor cell lines; Los Angeles California; United States > US; California
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0054346

Pancreatic cancer is one of the deadliest cancers with a 5-year survival rate of 6%. Therapeutic options are very limited and there is an unmet medical need for safe and efficacious treatments. Cancer cell metabolism and mitochondria provide unexplored targets for this disease. We recently identified a novel class of triphenylphosphonium salts, TP compounds, with broad- spectrum anticancer properties. We examined the ability of our prototypical compound TP421- chosen for its fluorescent properties - to inhibit the growth of pancreatic cancer cells and further investigated the molecular mechanisms by which it exerts its anticancer effects. TP421 exhibited sub-micromolar IC(50) values in all the pancreatic cancer cell lines tested using MTT and colony formation assays. TP421 localized predominantly to mitochondria and induced G(0)/G(1) arrest, ROS accumulation, and activation of several stress-regulated kinases. Caspase and PARP-1 cleavage were observed indicating an apoptotic response while LC3B-II and p62 were accumulated indicating inhibition of autophagy. Furthermore, TP421 induced de-phosphorylation of key signaling molecules involved in FAK mediated adhesion that correlated with inhibition of cell migration. TP421 is a representative compound of a new promising class of mitochondrial-targeted agents useful for pancreatic cancer treatment. Because of their unique mechanism of action and efficacy further development is warranted.