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. Author manuscript; available in PMC: 2014 Oct 1.
Published in final edited form as: Mol Cancer Ther. 2013 Aug 12;12(10):1958–1967. doi: 10.1158/1535-7163.MCT-12-1028

Figure 1.

Figure 1

Short-term antiproliferative effects of MLN4924 alone and in combination with cisplatin in ovarian cancer cells. Cell viability was assessed using WST-1 assays A. ES2 clear cell ovarian carcinoma cells were treated with DMSO, MLN4924 (1uM), cisplatin (25uM) or the combination for 24h. MLN4924 inhibits cullin neddylation resulting in stabilization of CRL substrates such as p27. The combination treated cells reveal increased apoptosis as evidenced by PARP cleavage. B. Left Panel: Dose response to single agent MLN4924 in SKOV3 (serous carcinoma) and ES2 (clear cell) ovarian carcinoma cells compared to that in HCT116 colon cancer cells. Error bars represent sd. Right Panel: Dose response in 9 primary (patient-derived) high grade serous ovarian cancer cell lines. C. MLN4924 sensitizes ovarian cancer cells to cisplatin cytotoxicity. OVT32 (platinum resistant high grade serous carcinoma), OVT50 (serous borderline tumor), and OVT73 (clear cell carcinoma) were treated as indicated and cell survival was assayed after 24h of treatment by WST1 assays. Cell viability is presented as fold change compared to vehicle treated cells. Error bars represent sd. Significance of interaction between the two drugs was tested using two-way ANOVA with P<0.001 for all three cell lines D. Cell viability following single and combination treatment in additional primary ovarian cancer cell lines. Asterisks note p values between treatments for each cell line. Error bars represent sd. E. Dose response of ES2 cells to 24h treatment with carboplatin alone or in combination with MLN4924 (using WST-1 assay). Error bars represent + sd. F. Combination indices between MLN4924 and cisplatin in SKOV3 cells and OVT84 ovarian clear cell carcinoma primary cell line. Each cell line was treated with a constant dose of MLN4924 (SKOV3-1.0uM and OVT84-0.5uM) in combination with a range of cisplatin concentrations (SKOV3: 1-5uM, 2-10uM, 3-20uM, 4-50uM, 5-100uM, 6-200uM, 7-500uM, and 8-1mM; OVT84: 1-10uM, 2-25uM, 3-50uM, 4-75uM, 5-100uM, 6-150uM). Combination indices of 1.0, less than1.0, and greater than 1.0 indicate additive, synergistic, and antagonistic effects, respectively. Fractional inhibitory effect of 1.0 signifies 100% cell death.