Fig. 4.

Responses of human engineered bone ES tumors and cardiac tissues to linsitinib in isolated platform chambers. A. Non-metastatic (left) and metastatic (right) ES tumors were exposed to linsitinib (12 μM) according to the 3 week drug treatment regimen used in a phase II clinical study. Luminescence as a function of cancer cell number and viability was measured (mean ± s.e.m., n = 6 for day 3, and n = 3 for day 7 and 21). B. At the culmination of the drug treatment regimen, sample protein lysates were collected for both linsitinib and vehicle treated non-metastatic and metastatic engineered ES bone tumors and comparative proteomic analysis of IGF-1 binding proteins was performed (mean ± s.d., n = 3 per group). C. Beat frequency of cardiac tissues after exposure to linsitinib (12 μM) (mean ± s.e.m., n = 11). D. Occurrence of proarrhythmic events/beat after exposure to linsitinib. E. Beat frequency of human cardiac tissues exposed to linsitinib after isoproterenol exposure (mean ± s.e.m., n = 6–9). F. Extracellular LDH before and after linsitinib exposure, as percentage of negative control (mean ± s.e.m., n = 3). G. Calcium transients of cardiac tissues characterized by the full-width half-maximum (FWHM), R₅₀ to and from peak times (50% of the time to and from the maximal peak of the calcium transient) (mean ± s.e.m., n = 17–18). *P < 0.05; **P < 0.01; ***P < 0.001; ****P <0.0001 by two-way ANOVA with Bonferroni post-test or unpaired, two-tailed Student's t test.