title: Isorhamnetin augments the anti-tumor effect of capecitabine through the negative regulation of NF-κB signaling cascade in gastric cancer.
abstract: Development of drug resistance to standard chemotherapy is a common phenomenon that leads to poor prognosis in patients. Thus, novel agents that can attenuate chemoresistance are urgently needed. Therefore, we analyzed whether isorhamnetin (IH), a 3'-O-methylated metabolite of quercetin, can enhance the potential efficacy of capecitabine in gastric cancer. The potential effect of IH on viability was analyzed by MTT assay, apoptosis by flow cytometric analysis, and NF-κB activation by DNA binding as well as Western blot assays. The in vivo effect of IH was also examined on the growth of subcutaneously implanted tumors in nude mice. IH inhibited the viability, potentiated the apoptotic effects of capecitabine, abrogated NF-κB activation, and suppressed the expression of various NF-κB regulated gene products in tumor cells. In a gastric cancer xenograft model, administration of IH alone (1 mg/kg body weight, i.p.) significantly suppressed the tumor growth alone as well as in combination with capecitabine. IH further reduced NF-κB activation and the expression of various proliferative and oncogenic biomarkers in tumor tissues. Overall, our results demonstrate that IH can significantly enhance the anti-tumor effects of capecitabine through the negative regulation of NF-κB regulated oncogenic genes.
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.
authors.forename: Kanjoormana A
authors.initials: KA
authors.lastname: Manu
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.
authors.forename: Muthu K
authors.initials: MK
authors.lastname: Shanmugam
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.
authors.forename: Lalitha
authors.initials: L
authors.lastname: Ramachandran
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.
authors.forename: Kodappully Sivaraman
authors.initials: KS
authors.lastname: Siveen
authors.affiliation: Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia.
authors.forename: Arunachalam
authors.initials: A
authors.lastname: Chinnathambi
authors.affiliation: Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia.
authors.forename: M E
authors.initials: ME
authors.lastname: Zayed
authors.affiliation: Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia.
authors.forename: Sulaiman Ali
authors.initials: SA
authors.lastname: Alharbi
authors.affiliation: Curtin Health Innovation Research Institute, Biosciences Research Precinct, School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, Perth, WA 6845, Australia.
authors.forename: Frank
authors.initials: F
authors.lastname: Arfuso
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597; Curtin Health Innovation Research Institute, Biosciences Research Precinct, School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, Perth, WA 6845, Australia; Cancer Science Institute of Singapore, Centre for Translational Medicine, 14 Medical Drive, #11-01M, Singapore 117599; Department of Biological Sciences, University of North Texas, Denton, TX 76203, USA.
authors.forename: Alan Prem
authors.initials: AP
authors.lastname: Kumar
authors.affiliation: College of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, Seoul 130-701, Republic of Korea.
authors.forename: Kwang Seok
authors.initials: KS
authors.lastname: Ahn
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597; Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia; Curtin Health Innovation Research Institute, Biosciences Research Precinct, School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, Perth, WA 6845, Australia. Electronic address: phcgs@nus.edu.sg.
authors.forename: Gautam
authors.initials: G
authors.lastname: Sethi
mesh_terms: D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D000069287:Capecitabine; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D011794:Quercetin / Q000008:administration & dosage / Q000031:analogs & derivatives; D015398:Signal Transduction / Q000187:drug effects*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D042501:Angiogenic Proteins; D016328:NF-kappa B; C047368:3-methylquercetin; D003841:Deoxycytidine; D000069287:Capecitabine; D004247:DNA; D011794:Quercetin; D005472:Fluorouracil
keywords: Capecitabine; Gastric cancer; Isorhamnetin; NF-κB