ABSTRACT
TRAP1 (Hsp75) is the mitochondrial paralog of the Hsp90 molecular chaperone family. Due to structural similarity among Hsp90 chaperones, a potential strategy to induce apoptosis through mitochondrial TRAP1 ATPase inhibition has been envisaged and a series of compounds has been developed by binding the simple pharmacophoric core of known Hsp90 inhibitors with various appendages bearing a permanent cationic head, or a basic group highly ionizable at physiologic pH. Cationic appendages were selected as vehicles to deliver drugs to mitochondria. Indeed, masses of new derivatives were evidenced to accumulate in the mitochondrial fraction from colon carcinoma cells and a compound in the series, with a guanidine appendage, demonstrated good activity in inhibiting recombinant TRAP1 ATPase and cell growth and in inducing apoptotic cell death in colon carcinoma cells.
Subject(s)
HSP90 Heat-Shock Proteins/antagonists & inhibitors , Isoxazoles/pharmacology , Mitochondria/metabolism , Adenosine Triphosphatases/antagonists & inhibitors , Apoptosis/drug effects , Cell Proliferation/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Guanidines/chemical synthesis , Guanidines/chemistry , Guanidines/pharmacology , HCT116 Cells , Humans , Isoxazoles/chemical synthesis , Isoxazoles/chemistry , Molecular Structure , Onium Compounds/chemical synthesis , Onium Compounds/chemistry , Onium Compounds/pharmacology , Organophosphorus Compounds/chemical synthesis , Organophosphorus Compounds/chemistry , Organophosphorus Compounds/pharmacology , Pyridinium Compounds/chemical synthesis , Pyridinium Compounds/chemistry , Pyridinium Compounds/pharmacologyABSTRACT
PURPOSE: We evaluated the role of quantitative assessment by maximum standardized uptake value (SUVmax) on F-18 fluorodeoxyglucose [F-18]FDG positron emission tomography/computed tomography (PET/CT) in stratifying colorectal cancer (CRC) patients with unexplained carcinoembryonic antigen (CEA) rise after surgical curative resection. MATERIAL AND METHODS: Forty asymptomatic patients (mean age, 64 ± 12 years) with previous CRC and current serum CEA levels >5 ng/ml underwent [F-18] FDG PET/CT 13 ± 3 months after complete surgical resection. The SUVmax was registered on anastomosis and peri-anastomotic tissue lesions, if present. The patients were followed for 24 ± 9 months thereafter. Re-intervention, evidence of newly discovered distant metastases, and death were recognized as main events and constituted surrogate end points. The receiver-operator-curve (ROC) analysis was performed to estimate the optimal SUVmax cut-off to predict patients at high risk of main events. PET/CT results were then related to disease outcome (overall survival; OS). RESULTS: The mean SUVmax at the anastomotic site was 6.2 ± 3 (range 2.6-15). At multivariate logistic regression analysis, the anastomotic SUVmax remained as the only significant contributor to the prediction of the events (p = 0.004; OR 1.97). The ROC analysis recognized that the optimal threshold of SUVmax to differentiate patients was 5.7. A worse OS was observed in patients presenting with a SUVmax greater than 5.7 as compared to those having lesser (median survival: 16 vs. 31 months; p = 0.002). CONCLUSIONS: The quantitative assessment by SUVmax on [F-18]FDG PET/CT may be helpful in patients presenting with unexplained CEA rise after curative resection of CRC, by identifying those at risk of main events.
