plitidepsin and Ovarian-Neoplasms

To evaluate the antitumor effects of Plitidepsin against clear cell carcinoma (CCC) of the ovary.. The expression of eEF1A2 in ovarian cancer was assessed by immunohistochemistry. Using ovarian CCC cell lines, the antitumor effect of Plitidepsin was assessed both in vitro and in vivo. By over-expressing or knocking down the eEF1A2 expression, we investigated the role of eEF1A2 in the sensitivity of CCC cells to Plitidepsin.. Immunoreactivity to eEF1A2 was observed in 76.2% of CCC, which was significantly higher than other histological subtypes of ovarian cancer. Plitidepsin exhibited significant antitumor activity toward chemonaive and chemoresistant CCC cells both in vitro and in vivo. Ectopic expression of eEF1A2 in CCC cells resulted in increased sensitivity to Plitidepsin. In contrast, eEF1A2 knockdown decreased sensitivity of CCC cells to plitidepsin.. Plitidepsin, a novel anti-cancer agent that targets eEF1A2, may be a promising agent for treating ovarian CCC.

Topics: Adenocarcinoma, Clear Cell; Animals; Cell Line, Tumor; Cell Proliferation; Cisplatin; Depsipeptides; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Mice; Ovarian Neoplasms; Peptide Elongation Factor 1; Peptides, Cyclic; Up-Regulation; Xenograft Model Antitumor Assays

Aplidin-resistant IGROV-1/APL cells were derived from the human ovarian cancer IGROV-1 cell line by exposing the cells to increasing concentration of Aplidin for eight months, starting from a concentration of 10 nM to a final concentration of 4 microM. IGROV-1/APL cell line possesses five fold relative resistance to Aplidin. IGROV-1/APL resistant cell line shows the typical MDR phenotype: (1) increased expression of membrane-associated P-glycoprotein, (2) cross-resistance to drugs like etoposide, doxorubicin, vinblastine, vincristine, taxol, colchicin and the novel anticancer drug Yondelis (ET-743). The Pgp inhibitor cyclosporin-A restored the sensitivity of IGROV-1/APL cells to Aplidin by increasing the drug intracellular concentration. The resistance to Aplidin was not due to the other proteins, such as LPR-1 and MRP-1, being expressed at the same level in resistant and parental cell line. The finding that cells over-expressing Pgp are resistant to Aplidin was confirmed in CEM/VLB 100 cells, that was found to be 5-fold resistant to Aplidin compared to the CEM parental cell line.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Line, Tumor; Cyclosporine; Depsipeptides; Dose-Response Relationship, Drug; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Enzyme Inhibitors; Female; Genes, MDR; Humans; Isoquinolines; Ovarian Neoplasms; Peptides, Cyclic