Tryptanthrin inhibits MDR1 and reverses doxorubicin resistance in breast cancer cells.
Development of agents to overcome multidrug resistance (MDR) is important in cancer chemotherapy. Up to date, few chemicals have been reported to down-regulate MDR1 gene expression. We evaluated the effect of tryptanthrin on P-glycoprotein (P-gp)-mediated MDR in a breast cancer cell line MCF-7. Tryptanthrin could depress overexpression of MDR1 gene. We observed reduction of P-gp protein in parallel with decreases in mRNA in MCF-7/adr cells treated with tryptanthrin. Tryptanthrin suppressed the activity of MDR1 gene promoter. Tryptanthrin also enhanced interaction of the nuclear proteins with the negatively regulatory CAAT region of MDR1 gene promoter in MCF-7/adr. It might result in suppression of MDR1 gene. In addition, tryptanthrin decreased the amount of mutant p53 protein with decreasing mutant p53 protein stability. It might contribute to negative regulation of MDR1 gene. In conclusion, tryptanthrin exhibited MDR reversing effect by down-regulation of MDR1 gene and might be a new adjuvant agent for chemotherapy.
Yu
Sung-Tsai
ST
Graduate Institute of Pharmaceutical Sciences, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
Chen
Tzer-Ming
TM
Tseng
Shih-Yun
SY
Chen
Yen-Hui
YH
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009154:Mutation; D011401:Promoter Regions, Genetic; D011799:Quinazolines / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D011799:Quinazolines; D016159:Tumor Suppressor Protein p53; C046243:tryptanthrine; D004317:Doxorubicin