2. Academic Validation
  3. Combination of a thioxodihydroquinazolinone with cisplatin eliminates ovarian cancer stem cell-like cells (CSC-LCs) and shows preclinical potential

Combination of a thioxodihydroquinazolinone with cisplatin eliminates ovarian cancer stem cell-like cells (CSC-LCs) and shows preclinical potential

  • Oncotarget. 2017 Dec 26;9(5):6042-6054. doi: 10.18632/oncotarget.23679.
Jing Ma 1 2,  Joseph Salamoun 3,  Peter Wipf 3 4,  Robert Edwards 5,  Bennett Van Houten 1,  Wei Qian 1
Affiliations

Affiliations

  • 1 Department of Pharmacology and Chemical Biology, University of Pittsburgh, and UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA.
  • 2 Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College of HuaZhong University of Science and Technology, Wuhan 430030, China.
  • 3 Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
  • 4 Accelerated Chemical Discovery Center, University of Pittsburgh, Pittsburgh, PA 15260, USA.
  • 5 Department of Obstetrics and Gynecology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
PMID: 29464053 DOI: 10.18632/oncotarget.23679
Abstract

Cancer stem cell-like cells (CSC-LCs) contribute to drug resistance and recurrence of ovarian Cancer. Strategies that can eradicate CSC-LCs are expected to substantially improve the outcome of ovarian Cancer treatment. We have previously identified a class of thioxodihydroquinazolinone small molecules, which have strong synergistic antitumor activity with platinum drugs, the standard chemotherapeutic agents for ovarian Cancer treatment. In the current study, using the activity of aldehyde dehydrogenase (ALDH) as a marker of CSC-LCs, we demonstrated that the combination of thioxodihydroquinazolinone compound 19 with cisplatin is able to diminish ALDH-high CSC-LC populations in both platinum-resistant ovarian Cancer cell lines and primary ovarian Cancer cells from metastatic ascites of a cisplatin-resistant patient. Compound 19 enhanced the accumulation of intracellular cisplatin in ALDH-high ovarian CSC-LCs. The combination of compound 19 with cisplatin was also able to reduce the sphere-forming capability of cisplatin-resistant ovarian Cancer cells. Using a spheroid-based in vitro metastasis model of ovarian Cancer, we demonstrated that the co-administration of compound 19 with cisplatin prevents ovarian Cancer spheroid cells from attaching to substratum and spreading. In a cisplatin-resistant in vivo intraperitoneal xenograft mouse model, the combination of compound 19 with cisplatin significantly reduced tumor burden, as compared to cisplatin alone. Taken together, our study demonstrated that thioxodihydroquinazolinones represent a new class of agents that in combination with cisplatin are capable of eliminating CSC-LCs in ovarian Cancer. Further development of thioxodihydroquinazolinone small molecules may yield a more effective treatment for cisplatin-resistant metastatic ovarian Cancer.

Keywords

apoptosis; cancer spheroids; cisplatin resistance; ovarian cancer stem cell-like cells; thioxodihydroquinazolinone small molecule.

Figures
Products