ABSTRACT
Multidrug resistance (MDR) in cancer represents a variety of strategies employed by tumor cells to evade the beneficial cytotoxic effects of structurally different anticancer drugs and thus confers impediments to the successful treatment of cancers. Efflux of drugs by MDR protein-1, functional P-glycoprotein and elevated level of reduced glutathione confer resistance to cell death or apoptosis and thus provide a possible therapeutic target for overcoming MDR in cancer. Previously, we reported that a Schiff base ligand, potassium-N-(2-hydroxy 3-methoxy-benzaldehyde)-alaninate (PHMBA) overcomes MDR in both in vivo and in vitro by targeting intrinsic apoptotic/necrotic pathway through induction of reactive oxygen species (ROS). The present study describes the synthesis and spectroscopic characterization of a copper chelate of Schiff base, viz., copper (II)-N-(2-hydroxy-3-methoxy-benzaldehyde)-alaninate (CuPHMBA) and the underlying mechanism of cell death induced by CuPHMBA in vitro. CuPHMBA kills both the drug-resistant and sensitive cell types irrespective of their drug resistance phenotype. The cell death induced by CuPHMBA follows apoptotic pathway and moreover, the cell death is associated with intrinsic mitochondrial and extrinsic receptor-mediated pathways. Oxidative stress plays a pivotal role in the process as proved by the fact that antioxidant enzyme; polyethylene glycol conjugated-catalase completely blocked CuPHMBA-induced ROS generation and abrogated cell death. To summarize, the present work provides a compelling rationale for the future clinical use of CuPHMBA, a redox active copper chelate in the treatment of cancer patients, irrespective of their drug-resistance status.
Subject(s)
Antineoplastic Agents/pharmacology , Chelating Agents/pharmacology , Coordination Complexes/pharmacology , Copper/chemistry , Reactive Oxygen Species/agonists , Schiff Bases/pharmacology , Alanine/analogs & derivatives , Animals , Antineoplastic Agents/chemical synthesis , Apoptosis/drug effects , Benzaldehydes/chemistry , Carcinoma, Ehrlich Tumor/metabolism , Carcinoma, Ehrlich Tumor/pathology , Catalase/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Chelating Agents/chemical synthesis , Coordination Complexes/antagonists & inhibitors , Coordination Complexes/chemical synthesis , Drug Resistance, Multiple/drug effects , Drug Resistance, Neoplasm/drug effects , Humans , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Mice , Oxidation-Reduction , Polyethylene Glycols/chemistry , Primary Cell Culture , Reactive Oxygen Species/metabolism , Schiff Bases/antagonists & inhibitors , Schiff Bases/chemical synthesisABSTRACT
The efficiency of a newly introduced 'hemoglobin A1 aldimine eliminator' in minimizing the effect of recent fluxes of glucose on the determination of total glycosylated hemoglobin (HbA1) was evaluated by comparing HbA1 values measured during morning fast and again 6 h postprandially in 26 insulin-dependent diabetic subjects by Isolab's Fast Hemoglobin Test System employing dialyzed and aldimine eliminator-added non-dialyzed hemolysate. The HbA1 values determined by this microcolumn procedure were also compared with those of the conventional macrocolumn method of Trivelli. HbA1 measured by the microcolumn procedure and aldimine eliminator using non-dialyzed hemolysates did not differ from the HbA1 values based on dialyzed hemolysates, and a good correlation was found between the macrocolumn method and the Isolab's Fast Hemoglobin Test System employing both aldimine eliminator added non-dialyzed hemolysate (r = 0.88, p less than 0.001) and dialyzed hemolysate (r = 0.97, p less than 0.001). When 6 h changes were assessed, the mean blood glucose had increased from 11.7 to 15.5 mmol/l (p less than 0.001), and no significant increase in HbA1 occurred when HbA1 was assayed in aldimine eliminator-added non-dialyzed hemolysates (mean fast HbA1: 11.7% and mean postprandial HbA1: 11.8%). Therefore, the use of the HbA1 aldimine eliminator appears to be valuable, practical and time-saving.
