Synergistic effects of the sesquiterpene lactone, EPD, with cisplatin and paclitaxel in ovarian cancer cells

Abstract

BackgroundOvarian cancer remains still the leading cause of death of gynecological malignancy, in spite of first-line chemotherapy with cisplatin and paclitaxel. Although initial response is favorably, relapses are common and prognosis for women with advanced disease stays poor. Therefore efficacious approaches are needed.MethodsPreviously, an anti-cancer agent, EPD exhibited potent cytotoxic effects towards ovarian cancer and not towards normal cells. Cell viability and cell cycle analysis studies were performed with EPD, in combination with cisplatin and/or paclitaxel, using the ovarian carcinoma cell lines: SK-OV-3, OVCAR-3, JC, JC-pl and normal fibroblasts. Cell viability was measured using Presto Blue and cell cycle analysis using a flow cytometer. Apoptosis was measured in JC and JC-pl , using the caspase 3 assay kit.ResultsIn JC-pl, SK-OV-3 and JC, synergistic interactions between either EPD and cisplatin or EPD and paclitaxel were observed. For the first time the effects of EPD on the cell cycle of ovarian cancer cells and normal cells was studied. EPD and combinations of EPD with cisplatin and/ or paclitaxel showed cell cycle arrest in the G2/M phase. The combination of EPD and cisplatin showed a significant synergistic effect in cell line JC-pl, while EPD with paclitaxel showed synergistic interaction in JC. Additionally, synergistic drug combinations showed increased apoptosis.ConclusionsOur results showed a synergistic effect of EPD and cisplatin in an ovarian drug resistant cell line as well as a synergistic effect of EPD and paclitaxel in two other ovarian cell lines. These results might enhance clinical efficacy, compared to the existing regimen of paclitaxel and cisplatin.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-015-0157-2) contains supplementary material, which is available to authorized users.

Anticancer activity of a trans-platinum(II) complex of 3-aminoflavone to ovarian cancer cells

“…Therefore, it is very important to get to know the mechanisms that determine drug resistance. However, it is cisplatin that, despite the numerous side effects, is the most often used chemotherapeutic agent [33]. Ineffective apoptosis can be the cause of chemoresistance of cancer cells [34].…”

Chemosensitivity of BRCA1-Mutated Ovarian Cancer Cells and Established Cytotoxic Agents

“…4B); for these drug interactions, a simplified Bliss independence model was used, 22 and the results described were similar to other low passage ovarian cancer cell lines. 21 Stordal et al 5 studied cytotoxicity of olaparib in 20 ovarian cell lines and concluded that further research is needed to determine which patients who are BRCA1/2 wild type will benefit from treatment with PARP inhibitors. After a successful cytoreductive operation in 2013, patient OVCA-TR3 was treated with a combination of platinum/paclitaxel.…”

“…However, when the observed viability after combination treatment is lower than the expected viability, synergistic drug interaction is found (Bliss independence model). 21,22 Hardly any effects were noted for OVCA-TR3.2 with cisplatin alone, but clear synergism could be shown for the combination of cisplatin and EPD. Synergism was found for the combination EPD/paclitaxel only in the cell line OVCA-TR3.3 (P = 0.030).…”

“…Combination of the 3 drugs was performed: EPD/cisplatin, EPD/ paclitaxel, EPD/cisplatin/paclitaxel, and cisplatin/paclitaxel, as earlier described. 21 Synergistic drug interactions were evaluated using a simplified version of the Bliss independence model of Wong et al 22 Dose response curves were also performed with the PARP inhibitor, olaparib, with cell lines OVCA-TR3.2 and -3, olaparib was then tested together with cisplatin and paclitaxel and, subsequently, with combinations of EPD, cisplatin, and paclitaxel.…”

“…Eremophila-1(10)-11(13)-dien-12,8A-olide induces apoptosis. 20,21 Also, olaparib, a polymerase enzyme inhibitor, has been tested in vitro in combination with cisplatin as well as paclitaxel.…”