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. 2019 Mar;12(3):441-452.
doi: 10.1016/j.tranon.2018.11.016. Epub 2018 Dec 18.

Quantitative Chemotherapeutic Profiling of Gynecologic Cancer Cell Lines Using Approved Drugs and Bioactive Compounds

Kirill Gorshkov  1 , Ni Sima  2 , Wei Sun  1 , Billy Lu  1 , Wei Huang  2 , Jameson Travers  1 , Carleen Klumpp-Thomas  1 , Samuel G Michael  1 , Tuan Xu  1 , Ruili Huang  1 , Emily M Lee  1 , Xiaodong Cheng  3 , Wei Zheng  4
Affiliations

Quantitative Chemotherapeutic Profiling of Gynecologic Cancer Cell Lines Using Approved Drugs and Bioactive Compounds

Kirill Gorshkov et al. Transl Oncol. 2019 Mar.

Abstract

Heterogeneous response to chemotherapy is a major issue for the treatment of cancer. For most gynecologic cancers including ovarian, cervical, and placental, the list of available small molecule therapies is relatively small compared to options for other cancers. While overall cancer mortality rates have decreased in the United States as early diagnoses and cancer therapies have become more effective, ovarian cancer still has low survival rates due to the lack of effective treatment options, drug resistance, and late diagnosis. To understand chemotherapeutic diversity in gynecologic cancers, we have screened 7914 approved drugs and bioactive compounds in 11 gynecologic cancer cell lines to profile their chemotherapeutic sensitivity. We identified two HDAC inhibitors, mocetinostat and entinostat, as pan-gynecologic cancer suppressors with IC50 values within an order of magnitude of their human plasma concentrations. In addition, many active compounds identified, including the non-anticancer drugs and other compounds, diversely inhibited the growth of three gynecologic cancer cell groups and individual cancer cell lines. These newly identified compounds are valuable for further studies of new therapeutics development, synergistic drug combinations, and new target identification for gynecologic cancers. The results also provide a rationale for the personalized chemotherapeutic testing of anticancer drugs in treatment of gynecologic cancer.

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Figures

Figure 1
Figure 1
Assay development for qHTS screening of chemotherapeutic compounds. (A) Adriamycin time course dose-response curves for PA-1 cells from A, B, and C with IC50 determinations in the inset. (B) Curcubitacin B time course dose-response curves for PA-1 cells from A, B, and C with IC50 determinations in the inset. (C) Doxorubicin time course dose-response curve for CAOV-3 cells from A, B, and C with IC50 determinations in the inset. (D) Curcubitacin B time course dose-response curves for CAOV-3 cells from A, B, and C with IC50 determinations in the inset. Data points representing normalized mean ± S.D. (n = 4 wells per data point). Data were normalized to DMSO control (100% cell viability and lowest luminescence value among the 6 compounds (0% cell viability). Curves represent nonlinear regression curve fit with variable slope.
Figure 2
Figure 2
Chemotherapeutic diversity in cell line killing. (A) Venn diagram illustrating the number of selective compounds (efficacy >70%, IC50 <30 μM, SI >5) in each cancer group. Overlapping circles and number inset indicate number of compounds which are shared between the groups. Compound must be active in at least four of the six ovarian cancer cell lines to be considered ovarian cancer cell line selective. (B) Log scale bar graph depicting the number of compounds which had an SI >5 for each cancer line panel. Heat maps depicting the Log (SI) value for compounds active in at least one cell line with selectivity greater than five-fold for ovarian (C), cervical (D), and placental (E) cancer panels. Black boxes indicate no selectivity could be determined for that cell line.
Figure 3
Figure 3
Pan-cancer killers. Chemical structures and dose-response curves for (A) mocetinostat and (E) entinostat, respectively, for (B, F) cervical, (C, G) ovarian, and (D, H) placental cancer cell lines. See Table 4 for the full list of the best compounds from the confirmation screen.
Figure 4
Figure 4
Representative compounds with selective toxicity and nanomolar potency in a single cell line. Chemical structure and dose-response curves for (A, B) mycophenolate mofetil in PA-1 cells, (C, D) neritinib in TOV-21-G cells, (E, F) milciclib in TOV-21-G cells, and (G, H) LY2974455 in HeLa cells. See Table 4 for the full list of the most effective compounds for a single cell line.
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