Browsing by Subject "Drug Discovery"
Now showing 1 - 2 of 2
- Results Per Page
- Sort Options
Item Elucidation of the Mechanism of Action of a Cell Line Selective Toxin(2019-01-31) Theodoropoulos, Panayotis Christos; Yu, Hongtao; Nijhawan, Deepak; Brown, Michael S.; Ready, Joseph M.; Chen, Zhijian J.A hallmark of targeted cancer therapies is selective toxicity among cancer cell lines. We evaluated results from a viability screen of over 200,000 small molecules to identify two chemical series, oxalamides and benzothiazoles, that were selectively toxic to the same four of 12 lung cancer cell lines at low nanomolar concentrations. Sensitive cell lines expressed cytochrome P450 (CYP) 4F11, which metabolized the compounds into irreversible stearoyl CoA desaturase (SCD) inhibitors. SCD has been recognized as a promising biological target in cancer and metabolic disease. However, SCD is essential to sebocytes, and accordingly SCD inhibitors cause skin toxicity. Mouse sebocytes were unable to activate the benzothiazoles or oxalamides into SCD inhibitors, providing a therapeutic window for inhibiting SCD in vivo. We thus offer a strategy to target SCD in cancer by taking advantage of high CYP expression in a subset of tumors.Item Single-Cell Image Analysis Enables High-Throughput Phenotypic Drug Screen and Elucidates Cell-Fate Decision Principles(2019-05-20) Hsu, Chien-Hsiang; Martinez, Elisabeth; Wu, Lani; Altschuler, Steven J.; Amatruda, James F.; Xie, YangCellular phenotypes encode information that can be used to infer the external signals cells experience. Here we applied quantitative image analysis to enable a one-pass multi-class phenotypic drug screen. Our combined experimental and computational approach can functionally annotate large compound libraries across diverse drug classes in a single-pass screen with high prediction accuracy confirmed via orthogonal, secondary validation assays. We further investigated how heterogeneity arose from an isogenic population. We monitored the dynamics of p21 to understand the proliferation-senescence cell-fate decision in single cells under non-lethal dose of chemotherapy via time-lapse microscopy before, during and days after treatment. Surprisingly, while high p21 is associated with senescence at late times, we find the opposite at early times during drug treatment: most senescence-fated cells have low p21 levels, while proliferation-fated cells have much higher p21 expression. Further, we identify a p21 "Goldilocks zone" for proliferation, in which increasing p21 levels has the undesirable effect of increasing proliferative outcomes. Our study identifies a counter-intuitive role for early p21 dynamics in cell-fate decision and pinpoints the source of proliferative cancer cells that emerge after exposure to non-lethal doses of chemotherapy.