title: Combined activity of oridonin and wogonin in advanced-stage ovarian cancer cells: sensitivity of ovarian cancer cells to phyto-active chemicals.
abstract: The initial response rates of advanced-stage epithelial ovarian cancer to the chemotherapeutic agents carboplatin and paclitaxel are high. However, once drug resistance develops, further chemotherapy is less effective. The objective of this study is to investigate the anti-proliferative activity of the phyto-active chemicals (PACs) oridonin and wogonin in chemo-resistant epithelial ovarian cancer cells. Primary cell cultures from the ascitic fluid of three patients at diagnosis, two patients chemo-resistant to carboplatin and paclitaxel, and one patient treated with letrozole for breast cancer were studied and compared to the ovarian cancer cell lines A2780 and PTX10, by cell viability assay (MTS). Effects on cell cycle modulation and apoptosis were examined by flow cytometry and Western blot analysis (WB). WB was further conducted to investigate protein expressions altered by PACs. The results show that IC(50) of the primary cultures ranged from 0.6 to 5.4 μg/ml for oridonin and 0.3-12.7 μg/ml for wogonin. The paclitaxel-resistant cell line PTX10 was more sensitive to each of the PACs than the chemo-sensitive cell line A2780. Of particular interest is that in combination, the two PACs were synergistic in their cytotoxicity to five of six of the primary cultures and to both the cell lines (combination indices of 0.39-0.95). The inhibition is attributable to apoptosis and cell cycle modulation induced by the PACs as demonstrated in A2780 and PTX10. Up-regulation of the functional p53 protein in A2780 and down-regulation of Akt protein in PTX10 have in part contributed to the apoptosis. These findings suggest that oridonin and wogonin may have activity in ovarian cancer following its development of resistance to carboplatin and paclitaxel.
authors.affiliation: Ovarian and Prostate Cancer Research Trust Laboratory, Guildford, Surrey GU2 7AF, UK. s.chen@opcart-lab.org
authors.forename: Sophie
authors.initials: S
authors.lastname: Chen
authors.forename: Matt
authors.initials: M
authors.lastname: Cooper
authors.forename: Matt
authors.initials: M
authors.lastname: Jones
authors.forename: Thumuluru Kavitha
authors.initials: TK
authors.lastname: Madhuri
authors.forename: Julie
authors.initials: J
authors.lastname: Wade
authors.forename: Ashleigh
authors.initials: A
authors.lastname: Bachelor
authors.forename: Simon
authors.initials: S
authors.lastname: Butler-Manuel
mesh_terms: D000368:Aged; D000951:Antigens, Neoplasm / Q000378:metabolism; D001201:Ascites / Q000150:complications / Q000473:pathology; D014408:Biomarkers, Tumor / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D045786:Diterpenes, Kaurane / Q000494:pharmacology / Q000627:therapeutic use*; D004354:Drug Screening Assays, Antitumor; D004359:Drug Therapy, Combination; D000071858:Epithelial Cell Adhesion Molecule; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D044950:Flavanones / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism; D009367:Neoplasm Staging; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D013194:Staining and Labeling
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; D045786:Diterpenes, Kaurane; D000071858:Epithelial Cell Adhesion Molecule; D044950:Flavanones; D009363:Neoplasm Proteins; C011959:oridonin; C085514:wogonin