Combined activity of oridonin and wogonin in advanced-stage ovarian cancer cells

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.

Wogonin reverses multi-drug resistance of human myelogenous leukemia K562/A02 cells via downregulation of MRP1 expression by inhibiting Nrf2/ARE signaling pathway

“…The findings suggested that the combination of Wogonin and magnetic nanoparticles provided a promising strategy for lymphoma therapy [39]. It was reported that Wogonin could increase drug sensitivity in ovarian and NSCLC cells [9,40,41]. Previous studies including ours suggested that Wogonin enhanced the antitumor action of low dose 5-fluorouracil against gastric cancer through induced-apoptosis by downregulation of NF-kB and modulation of its metabolism [42].…”

Selection for High Oridonin Yield in the Chinese Medicinal Plant Isodon (Lamiaceae) Using a Combined Phylogenetics and Population Genetics Approach

“…1). Several studies have shown that oridonin has potent in vitro and in vivo activity against human cancer cells [1]–[3], including ovarian [4], breast [5], colorectal [6], laryngeal [7], leukemia [8], liver [9], and prostate [10] cancers. Oridonin was first isolated from the plant Isodon japonicus (Burm.…”

Targeting Apoptosis Pathways in Cancer and Perspectives with Natural Compounds from Mother Nature

“…Oridonin induced upregulation of the functional p53 protein in A2780 (33). Oridonin increased p53 and its target Bax and p21waf1 in prostate cancer LNCaP and NCI-H520 cells with wild-type p53 gene (33,34).…”

“…Oridonin induced upregulation of the functional p53 protein in A2780 (33). Oridonin increased p53 and its target Bax and p21waf1 in prostate cancer LNCaP and NCI-H520 cells with wild-type p53 gene (33,34). Oridonin also stabilizes p53 protein and sensitizes TRAIL (TNF receptor apoptosisinducing ligand)-induced apoptosis, and prevents or delays chemotherapy resistance in A2780 cells (35).…”