Fig. 2: Jumonji inhibitors block SCLC viability, act on target, and robustly inhibit etoposide-resistant cell lines.
From: Jumonji histone demethylases are therapeutic targets in small cell lung cancer
A Range of IC50 responses to JIB-04, SD70, and GSK-J4 of SCLC cell lines representing all clusters. Each diamond represents the median IC50 across multiple experiments of a particular cell line, measured by 4-day MTS assay (see also Table 1). The IC50 values are shown on a log scale. B Inhibitors act on target as demonstrated by robust decreases in Jumonji enzymatic activity when cells are treated with their corresponding IC50 values for 24 h. Bar graphs display the level of H3K9me3 demethylase activity in H446 and H2171 cell lysates and/or nuclear extracts after the indicated treatment. ** = p ≤ 0.01 and * = p ≤ 0.05 by two-tailed t-test, unequal variance. Data are average ± SEM. C Correlation analysis yields negative correlations between the IC50 of etoposide and the IC50 of each of the three Jumonji inhibitors tested across 31 SCLC cell lines: JIB-04 (pan-JmjC KDM inhibitor with some selectivity for KDM5s), SD70 (relatively selective KDM4 inhibitor) and GSK-J4 (relatively selective KDM6 inhibitor). Pearson R-values are shown. D Heat map of etoposide and Jumonji inhibitor IC50 values represented in a blue to red scale for individual drugs in the indicated concentration ranges. Chemoresistant cell lines in the green box are sensitive to Jumonji inhibitors, particularly to JIB-04. E Dose-response curves demonstrate three etoposide most resistant cell lines (H378, H889, and H510) are highly sensitive to JIB-04. H524 and HCC4003 are sensitive to etoposide and are given for reference. Representative curves of n = 4–8 replicates with SEM are shown. See Table 1 for further details.
