Study summary · research use only
Synergy between Paclitaxel and Anti-Cancer Peptide PNC-27 in the Treatment of Ovarian Cancer
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This study examined whether PNC-27, a peptide composed of amino acids from the p53-MDM-2 binding domain, could act synergistically with paclitaxel against ovarian cancer cells. Surface MDM-2 expression after paclitaxel exposure was assessed by flow cytometry, and ID8 mouse ovarian cancer cells were exposed to paclitaxel for 12 hours followed by various concentrations of PNC-27 for 24 hours, with viability measured by MTT assay; combined weekly paclitaxel plus PNC-27 was tested in an intraperitoneal ID8 mouse model of ovarian cancer. Paclitaxel produced incomplete, time-dependent killing, while PNC-27 produced dose-dependent killing that depended on binding to MDM-2. Cells surviving paclitaxel showed increased MDM-2 expression and increased susceptibility to PNC-27. Isobologram analysis indicated a combination index below 1, and adding PNC-27 to weekly paclitaxel was associated with reduced tumor growth in vivo.
Abstract
Paclitaxel is widely used in the treatment of gynecologic malignancies. It targets tumor cells in the M phase of the cell cycle. Cells in other phases survive the insult and repopulate the tumor. PNC-27 is a peptide synthesized of amino acids of the p53-MDM-2 binding domain. It kills various cancer cell lines in a dose-dependent manner. The goal of this study is to assess ovarian cancer cells' sensitivity to PNC-27 after surviving exposure to paclitaxel and to investigate the potential for synergy between PNC-27 and paclitaxel in the treatment of ovarian cancer. The impact of exposure to paclitaxel on the surface expression of MDM-2 was assessed with the use of flow cytometry. For measurement of cytotoxicity in vitro, ID8 cells were exposed to paclitaxel for 12 hours in various concentrations. At 12 hours, the drug containing media was removed and the cells were cultured in media containing various concentrations of PNC-27 for 24 hours. Viability was assessed with the use of an MTT assay. Survival fractions were plotted against drug concentrations and the data were fit to logistic dose-response curves. Isoeffective combinations were used to create isobolograms. The combined treatment with weekly paclitaxel and PNC-27 was tested in an intraperitoneal mouse model of ovarian cancer (ID8). Exposure to paclitaxel rendered incomplete time-dependent killing, while PNC-27 mediated comprehensive, dose-dependent killing of ID8 cells. The cytotoxic effect of PNC-27 was dependent on its binding to MDM-2. Blocking MDM-2 inhibited the killing by PNC-27. ID8 cells surviving paclitaxel demonstrated increased expression of MDM-2 and increased susceptibility to PNC-27. Isobologram for dose combinations that were isoeffective indicates synergistic effect between the 2 agents (Combination index <1). In an in vivo model of ovarian cancer (ID8), the addition of PNC-27 to weekly paclitaxel administration significantly reduces tumor growth. These data demonstrate synergism between PNC-27 and paclitaxel. PNC-27 could target cells surviving paclitaxel and improve its antitumor effect.
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