Reversal of inflammation‐associated dihydrodiol dehydrogenases (AKR1C1 and AKR1C2) overexpression and drug resistance in nonsmall cell lung cancer cells by wogonin and chrysin

• Published in: International journal of cancer Vol. 120; no. 9; pp. 2019 - 2027
• Main Authors: Wang, Hao‐Wei, Lin, Chin‐Ping, Chiu, Jen‐Hwey, Chow, Kuan‐Chih, Kuo, Kuang‐Tai, Lin, Chen‐Sung, Wang, Liang‐Shun
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.05.2007; Wiley-Liss
• Subjects: 20-Hydroxysteroid Dehydrogenases - antagonists & inhibitors; 20-Hydroxysteroid Dehydrogenases - physiology; aldo‐keto reductase (AKR); Antineoplastic agents; Apoptosis; Biological and medical sciences; carcinoma; Carcinoma, Non-Small-Cell Lung - drug therapy; Cell Cycle; Cell Line, Tumor; cytokines; dihydrodiol dehydrogenase; DNA Repair; Dose-Response Relationship, Drug; Doxorubicin - pharmacology; drug resistance; Drug Resistance, Neoplasm; Flavanones - pharmacology; Flavonoids - pharmacology; General aspects; Humans; Hydroxysteroid Dehydrogenases - antagonists & inhibitors; Hydroxysteroid Dehydrogenases - physiology; Interleukin-6 - pharmacology; Lung Neoplasms - drug therapy; Medical sciences; non‐small‐cell lung; Pharmacology. Drug treatments; Tumors; Antineoplastic agent; dihydrodiol dehydrogenase; Isozyme; Lung cancer; Gene overexpression; non-small cell lung carcinoma; Dehydrogenase; Doxorubicin; Medicinal plant; Isomerases; Cancerology; aldo- keto reductase (AKR); Folk medicine; Bronchus disease; Genetics; cytokines; Platinum II Complexes; Human; DNA topoisomerase (ATP-hydrolysing); Lung disease; Treatment resistance; Respiratory disease; Enzyme; Pharmacognosy; Cytokine; Enzyme inhibitor; Inflammation; Malignant tumor; Cisplatin; Alkylating agent; Wogonin; carcinoma; Reversibility; non-small-cell lung; Anthracyclins; Oxidoreductases; drug resistance
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.22402

Dihydrodiol dehydrogenase (DDH) is a member of the aldo‐keto reductases superfamily (AKR1C1–AKR1C4), which plays central roles in the metabolism of steroid hormone, prostaglandin and xenobiotics. We have previously detected overexpression of DDH as an indicator of poor prognosis and chemoresistance in human non‐small lung cancer (NSCLC). We also found DDH expression to be closely related to chronic inflammatory conditions. The aim of this study was to investigate the links between inflammation, DDH expression and drug resistance in NSCLC cells. We showed that pro‐inflammatory mediators including interleukin‐6 (IL‐6) could induce AKR1C1/1C2 expression in NSCLC cells and increase cellular resistance to cisplatin and adriamycin. This effect was nullified by Safingol, a protein kinase C inhibitor. Moreover, the expression of AKR1C1/1C2 was inversely correlated to NBS1 and apoptosis‐inducing factor (AIF). We also showed that IL‐6‐induced AKR1C1/1C2 expression and drug resistance were inhibited by wogonin and chrysin, which are major flavonoids in Scutellaria baicalensis, a widely used traditional Chinese and Japanese medicine. In conclusion, this study demonstrated novel links of pro‐inflammatory signals, AKR1C1/1C2 expression and drug resistance in NSCLC. The protein kinase C pathway may play an important role in this process. Overexpression of AKR1C1/1C2 may serve as a marker of chemoresistance. Further studies are warranted to evaluate wogonin and chrysin as a potential adjuvant therapy for drug‐resistant NSCLC, especially for those with AKR1C1/1C2 overexpression. © 2007 Wiley‐Liss, Inc.