Fig. 4: Time-of-day drug sensitivity is drug and tissue model dependent.
From: Time-of-day effects of cancer drugs revealed by high-throughput deep phenotyping
a Schematic of the experimental setup to screen for time-of-day (ToD) responses. Three clock-resetting steps are performed in 4-h intervals. Drugs are administered 32 or 48 hours post initial reset, resulting in six circadian times (0, 4, 8, 16, 20, 24 h). Growth is monitored by long-term live-cell imaging. Timelines on the right depict experimental (top) and relative circadian times (bottom), color-coded by each ToD tested. b Cell counts of HCC1937 treated with alisertib at different times of the day. Normalization to the respective time of treatment. c Cell numbers 4 days post-treatment versus treatment times, corresponding to (b) (left). ToD response curve (ToD-RC) depicting relative responses to ToD 0 h. Blue arrows mark the maximum ToD response range (ToDMR) (right). d ToD-RCs for HCC1937 (left) or MCF10A (right) cells treated with different drugs (color-coded). e ToD-RCs for 10 cell models treated with paclitaxel (left) or doxorubicin (right). Color coding of cell models according to tissue origin. f Hierarchical clustering of ToDMR-values across drug-cell combinations. Values above 0.2 are shown. Data clustering with the UPGMA method and Euclidian distance. g Bar diagrams ranking ToDMR-values per drug (top) and cell model (bottom). h ToD-RCs for alisertib-treated HCC1937 tumor and MCF10A non-tumor cells overlaid, yielding maximum and minimum benefit times. Data shown in (b–h) represents the mean ( ± s.d.) of two plates. i Polar histograms for benefit times across cell models (n = 7–9 drugs, as indicated in the figure) and j, drugs (n = 9 cell models). k Butterfly charts depicting fold changes relative to MCF10A at benefit times, averaged per cancer cell model (left,) and drug (right). Color-coding of maximum and minimum benefit times is shown in (h–k) in green and red, respectively. Data are shown in (g and k represents mean ± s.d. of tested cell models per drug (n = 9 cell models; alpelisib and cisplatin: n = 8) and vice versa (n = 8 drugs; HCC1806 and SUM149PT: n = 7). For clarity, one-sided error bars are shown. Source data for (b–k are provided as a Source Data file.
