Journal
MOLECULAR CANCER THERAPEUTICS
Volume 18, Issue 5, Pages 969-979Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-18-0770
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Funding
- CCSG [CA016672]
- NIH [CA016672, UH3TR000943, P50 CA217685, R35 CA209904]
- Ovarian Cancer Research Fund, Inc.
- Judi A. Rees Ovarian Cancer Research Fund
- Blanton-Davis Ovarian Cancer Research Program
- American Cancer Society Research Professor Award
- Frank McGraw Memorial Chair in Cancer Research
- NIH 5 P50 SPORE CDP Award [CA116199]
- Marsha Rivkin Center for Ovarian Cancer
- National Comprehensive Cancer Network
- CPRIT Research Training Program [RP101502, RP140106, RP170067]
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EP-100 is a synthetic lytic peptide that specifically targets the gonadotropin-releasing hormone receptor on cancer cells. To extend the utility of EP-100, we aimed to identify effective combination therapies with EP-100 for ovarian cancer and explore potential mechanisms of this combination. A series of in vitro (MTT assay, immunoblot analysis, reverse-phase protein array, comet assay, and immunofluorescence staining) and in vivo experiments were carried out to determine the biological effects of EP-100 alone and in combination with standard-of-care drugs. EP-100 decreased the viability of ovarian cancer cells and reduced tumor growth in orthotopic mouse models. Of five standard drugs tested (cisplatin, paclitaxel, doxorubicin, topotecan, and olaparib), we found that the combination of EP-100 and olaparib was synergistic in ovarian cancer cell lines. Further experiments revealed that combined treatment of EP-100 and olaparib significantly increased the number of nuclear foci of phosphorylated histone H2AX. In addition, the extent of DNA damage was significantly increased after treatment with EP-100 and olaparib in comet assay. We performed reverse-phase protein array analyses and identified that the PI3K/AKT pathway was inhibited by EP-100, which we validated with in vitro experiments. In vivo experiment using the HeyA8 mouse model demonstrated that mice treated with EP-100 and olaparib had lower tumor weights (0.06 +/- 0.13 g) than those treated with a vehicle (1.19 +/- 1.09 g), EP-100 alone (0.62 +/- 0.78 g), or olaparib alone (0.50 +/- 0.63 g). Our findings indicate that combining EP-100 with olaparib is a promising therapeutic strategy for ovarian cancer.
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