title: Synthesis of a dual functional anti-MDR tumor agent PH II-7 with elucidations of anti-tumor effects and mechanisms.
abstract: Multidrug resistance mediated by P-glycoprotein in cancer cells has been a major issue that cripples the efficacy of chemotherapy agents. Aimed for improved efficacy against resistant cancer cells, we designed and synthesized 25 oxindole derivatives based on indirubin by structure-activity relationship analysis. The most potent one was named PH II-7, which was effective against 18 cancer cell lines and 5 resistant cell lines in MTT assay. It also significantly inhibited the resistant xenograft tumor growth in mouse model. In cell cycle assay and apoptosis assay conducted with flow cytometry, PH II-7 induced S phase cell cycle arrest and apoptosis even in resistant cells. Consistently revealed by real-time PCR, it modulates the expression of genes related to the cell cycle and apoptosis in these cells, which may contributes to its efficacy against them. By side-chain modification and FITC-labeling of PH II-7, we were able to show with confocal microscopy that not only it was not pumped by P-glycoprotein, it also attenuated the efflux of Adriamycin by P-glycoprotein in MDR tumor cells. Real-time PCR and western blot analysis showed that PH II-7 down-regulated MDR1 gene via protein kinase C alpha (PKCA) pathway, with c-FOS and c-JUN as possible mediators. Taken together, PH II-7 is a dual-functional compound that features both the cytotoxicity against cancer cells and the inhibitory effect on P-gp mediated drug efflux.
authors.affiliation: State Key Laboratory of Experimental Hematology, Department of Pharmacy, Institute of Hematology & Hospital of Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, People's Republic of China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Su
authors.forename: Xin
authors.initials: X
authors.lastname: Cheng
authors.forename: Yaohong
authors.initials: Y
authors.lastname: Tan
authors.forename: Yunhui
authors.initials: Y
authors.lastname: Hu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Juanni
authors.initials: J
authors.lastname: Liu
authors.forename: Yuanfu
authors.initials: Y
authors.lastname: Xu
authors.forename: Yinliang
authors.initials: Y
authors.lastname: Xie
authors.forename: Caiyun
authors.initials: C
authors.lastname: Wang
authors.forename: Yingdai
authors.initials: Y
authors.lastname: Gao
authors.forename: Jianxiang
authors.initials: J
authors.lastname: Wang
authors.forename: Tao
authors.initials: T
authors.lastname: Cheng
authors.forename: Chunzheng
authors.initials: C
authors.lastname: Yang
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Xiong
authors.forename: Hua
authors.initials: H
authors.lastname: Miao
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000378:metabolism; D015195:Drug Design; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D005260:Female; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D057054:Molecular Imaging; D000078183:Oxindoles; D051571:Protein Kinase C-alpha / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D059467:Transcriptome / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D007211:Indoles; D000078183:Oxindoles; D012333:RNA, Messenger; C022960:2-oxindole; D004317:Doxorubicin; C496628:PRKCA protein, human; D051571:Protein Kinase C-alpha