Molecular pathways in the chemosensitization of cisplatin by quercetin in human head and neck cancer.
The aim of this study was to develop novel and less toxic therapy for human head and neck squamous cell carcinoma (HNSCCs) and to investigate the mechanism of quercetin-induced apoptosis in human laryngeal HeP2 cells and its effect on cisplatin induced apoptosis. Priming the cells with quercetin (40 microM) increased the apoptosis induced by cisplatin alone from 18.7% to 42.2% in HeP2 cells. Quercetin induced apoptosis via inhibition of Akt/PKB phosphorylation, an upstream kinase of pro-survival protein kinase cascade. Inhibition of Akt phosphorylation was coupled with a significant decrease of anti-apoptotic Bcl-2 and Bcl-XL. Quercetin caused a downregulation of Cu-Zn Superoxide Dismutase which perhaps led to an increase of reactive oxidative stress (ROS). The decrease of Bcl-2 and Bcl-XL along with this oxidative stress caused release of mitochondrial cytochrome c into the cytosol and subsequent induction of pro-caspase-9 processing. Inhibition of heat shock proteins may be another mechanism for the pro-apoptotic activity of quercetin. Cisplatin induced apoptosis appears to be partly due to induction of JNK activity which leads to the activation of endonucleases. Increased JNK activity led to increased phosphorylation of c-Fos. Cisplatin additionally appears to induce apoptosis by down-regulating the enzyme Nitric Oxide Synthase (NOS). Cisplatin also acts by increasing pro-apoptotic Bax concentration in the cells thereby leading to caspase-9 activation via the mitochondrial pathway. These results support the fact that quercetin and cisplatin act by separate pathways and demonstrate interactions between the pathways that result in synergistic actions. Possibly of greater potential value is the interaction of a conventional cytotoxic drug (cisplatin) and a nontoxic chemopreventive agent (quercetin) thereby allowing the use of less toxic doses of chemotherapy for treatment of HNSCCs.
Sharma
Himani
H
Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India.
Sen
Sudip
S
Singh
Neeta
N
D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D053453:Caspase 9; D020169:Caspases / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000737:chemistry; D004790:Enzyme Induction; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D008928:Mitochondria / Q000201:enzymology; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D011794:Quercetin / Q000378:metabolism / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000032:analysis / Q000235:genetics; D051020:bcl-X Protein / Q000032:analysis / Q000235:genetics
D016760:Proto-Oncogene Proteins c-fos; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D045304:Cytochromes c; D011794:Quercetin; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases; D002945:Cisplatin