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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
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Small Molecule Therapeutics

Targeting Dormant Ovarian Cancer Cells In Vitro and in an In Vivo Mouse Model of Platinum Resistance

Zhiqing Huang, Eiji Kondoh, Zachary R. Visco, Tsukasa Baba, Noriomi Matsumura, Emma Dolan, Regina S. Whitaker, Ikuo Konishi, Shingo Fujii, Andrew Berchuck and Susan K. Murphy
Zhiqing Huang
1Department of Obstetrics and Gynecology, Division of Reproductive Sciences, Duke University Medical Center, Durham, North Carolina.
2Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University Medical Center, Durham, North Carolina.
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Eiji Kondoh
2Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University Medical Center, Durham, North Carolina.
3Department of Gynecology and Obstetrics, Kyoto University, Kyoto, Japan.
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Zachary R. Visco
1Department of Obstetrics and Gynecology, Division of Reproductive Sciences, Duke University Medical Center, Durham, North Carolina.
2Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University Medical Center, Durham, North Carolina.
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  • ORCID record for Zachary R. Visco
Tsukasa Baba
2Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University Medical Center, Durham, North Carolina.
3Department of Gynecology and Obstetrics, Kyoto University, Kyoto, Japan.
4Iwate Medical University, Morioka Iwate, Japan.
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  • ORCID record for Tsukasa Baba
Noriomi Matsumura
3Department of Gynecology and Obstetrics, Kyoto University, Kyoto, Japan.
5Department of Obstetrics and Gynecology, Kindai University, Higashiosaka, Japan.
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Emma Dolan
1Department of Obstetrics and Gynecology, Division of Reproductive Sciences, Duke University Medical Center, Durham, North Carolina.
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  • ORCID record for Emma Dolan
Regina S. Whitaker
2Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University Medical Center, Durham, North Carolina.
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Ikuo Konishi
3Department of Gynecology and Obstetrics, Kyoto University, Kyoto, Japan.
6National Hospital Organization Kyoto Medical Center, Kyoto, Japan.
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Shingo Fujii
3Department of Gynecology and Obstetrics, Kyoto University, Kyoto, Japan.
7Kyoto Okamoto Memorial Hospital, Kyoto, Japan.
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Andrew Berchuck
2Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University Medical Center, Durham, North Carolina.
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Susan K. Murphy
1Department of Obstetrics and Gynecology, Division of Reproductive Sciences, Duke University Medical Center, Durham, North Carolina.
2Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University Medical Center, Durham, North Carolina.
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  • For correspondence: susan.murphy@duke.edu
DOI: 10.1158/1535-7163.MCT-20-0119 Published January 2021
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Abstract

Spheroids exhibit drug resistance and slow proliferation, suggesting involvement in cancer recurrence. The protein kinase C inhibitor UCN-01 (7-hydroxystaurosporine) has shown higher efficacy against slow proliferating and/or quiescent ovarian cancer cells. In this study, tumorigenic potential was assessed using anchorage-independent growth assays and spheroid-forming capacity, which was determined with ovarian cancer cell lines as well as primary ovarian cancers. Of 12 cell lines with increased anchorage-independent growth, 8 formed spheroids under serum-free culture conditions. Spheroids showed reduced proliferation (P < 0.0001) and Ki-67 immunostaining (8% vs. 87%) relative to monolayer cells. Spheroid formation was associated with increased expression of mitochondrial pathway genes (P ≤ 0.001) from Affymetrix HT U133A gene expression data. UCN-01, a kinase inhibitor/mitochondrial uncoupler that has been shown to lead to Puma-induced mitochondrial apoptosis as well as ATP synthase inhibitor oligomycin, demonstrated effectiveness against spheroids, whereas spheroids were refractory to cisplatin and paclitaxel. By live in vivo imaging, ovarian cancer xenograft tumors were reduced after primary treatment with carboplatin. Continued treatment with carboplatin was accompanied by an increase in tumor signal, whereas there was little or no increase in tumor signal observed with subsequent treatment with UCN-01 or oltipraz. Taken together, our findings suggest that genes involved in mitochondrial function in spheroids may be an important therapeutic target in preventing disease recurrence.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Mol Cancer Ther 2021;20:85–95

  • Received February 20, 2020.
  • Revision received July 31, 2020.
  • Accepted September 30, 2020.
  • Published first October 9, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 20 (1)
January 2021
Volume 20, Issue 1
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Targeting Dormant Ovarian Cancer Cells In Vitro and in an In Vivo Mouse Model of Platinum Resistance
Zhiqing Huang, Eiji Kondoh, Zachary R. Visco, Tsukasa Baba, Noriomi Matsumura, Emma Dolan, Regina S. Whitaker, Ikuo Konishi, Shingo Fujii, Andrew Berchuck and Susan K. Murphy
Mol Cancer Ther January 1 2021 (20) (1) 85-95; DOI: 10.1158/1535-7163.MCT-20-0119

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Targeting Dormant Ovarian Cancer Cells In Vitro and in an In Vivo Mouse Model of Platinum Resistance
Zhiqing Huang, Eiji Kondoh, Zachary R. Visco, Tsukasa Baba, Noriomi Matsumura, Emma Dolan, Regina S. Whitaker, Ikuo Konishi, Shingo Fujii, Andrew Berchuck and Susan K. Murphy
Mol Cancer Ther January 1 2021 (20) (1) 85-95; DOI: 10.1158/1535-7163.MCT-20-0119
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Molecular Cancer Therapeutics
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