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Luteolin sensitizes two oxaliplatin-resistant colorectal cancer cell lines to chemotherapeutic drugs via inhibition of the Nrf2 pathway
- Source :
- Asian Pacific journal of cancer prevention : APJCP. 15(6)
- Publication Year :
- 2014
-
Abstract
- Oxaliplatin is a first-line therapy for colorectal cancer, but cancer cell resistance to the drug compromises its efficacy. To explore mechanisms of drug resistance, we treated colorectal cancer cells (HCT116 and SW620) long-term with oxaliplatin and established stable oxaliplatin-resistant lines (HCT116-OX and SW620-OX). Compared with parental cell lines, IC50s for various chemotherapeutic agents (oxaliplatin, cisplatin and doxorubicin) were increased in oxaliplatin-resistant cell lines and this was accompanied by activation of nuclear factor erythroid-2 p45-related factor 2 (Nrf2) and NADPH quinone oxidoreductase 1 (NQO1). Furthermore, luteolin inhibited the Nrf2 pathway in oxaliplatin-resistant cell lines in a dose-dependent manner. Luteolin also inhibited Nrf2 target gene [NQO1, heme oxygenase-1 (HO-1) and GSTĪ±1/2] expression and decreased reduced glutathione in wild type mouse small intestinal cells. There was no apparent effect in Nrf2-/- mice. Luteolin combined with other chemotherapeutics had greater anti-cancer activity in resistant cell lines (combined index values below 1), indicating a synergistic effect. Therefore, adaptive activation of Nrf2 may contribute to the development of acquired drug-resistance and luteolin could restore sensitivity of oxaliplatin-resistant cell lines to chemotherapeutic drugs. Inhibition of the Nrf2 pathway may be the mechanism for this restored therapeutic response.
- Subjects :
- Male
Cancer Research
Organoplatinum Compounds
Epidemiology
Colorectal cancer
NF-E2-Related Factor 2
Blotting, Western
Antineoplastic Agents
Apoptosis
Pharmacology
Flow cytometry
chemistry.chemical_compound
Mice
NAD(P)H Dehydrogenase (Quinone)
Tumor Cells, Cultured
Medicine
Animals
Humans
Doxorubicin
Luteolin
Cell Proliferation
Cisplatin
Antibiotics, Antineoplastic
medicine.diagnostic_test
business.industry
Public Health, Environmental and Occupational Health
medicine.disease
Flow Cytometry
Xenograft Model Antitumor Assays
digestive system diseases
Oxaliplatin
Gene Expression Regulation, Neoplastic
Mice, Inbred C57BL
Oncology
chemistry
Cell culture
Drug Resistance, Neoplasm
Cancer cell
business
Colorectal Neoplasms
medicine.drug
Subjects
Details
- ISSN :
- 2476762X
- Volume :
- 15
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Asian Pacific journal of cancer prevention : APJCP
- Accession number :
- edsair.doi.dedup.....f9cf6237d01a3cfdaab8ae74b7546fb8