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. 2021 Feb 24;11:4480. doi: 10.1038/s41598-021-83979-3

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© The Author(s) 2021

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Acute knockdown of TKT sensitises p53^null cells to APR-246. (A) Correlation between TKT mRNA levels and APR-246 GI50 (50% growth inhibitory concentration) across the NCI-60 cancer cell line panel³¹. Each point represents an individual cell line. The NCI-60 is a panel of 60 diverse human cancer cell lines used by the National Cancer Institute for therapeutic development³². (B) (left) Cell viability (AlamarBlue) in H1299 cells following 72 h treatment with increasing concentrations of APR-246, administered 24 h after TKT knockdown with siRNA, normalised to vehicle control (siNTC, non-targeting control; siTKT, TKT siRNA (right) Western blots for TKT in H1299 cells following TKT knockdown with siRNA for 96 h, showing actin as a loading control. (C) Cell viability (AlamarBlue) in H1299 parental (p53^null) cells following 72 h APR-246 treatment (12.5 or 25 µM), administered after 24 h TKT knockdown with siRNA, normalised to siNTC vehicle control. (D) Digital microscope images (Incucyte FLR) depicting cell death following 72 h treatment with APR-246 (15 µM), administered 24 h after TKT knockdown with siRNA (scale bars = 100 µm). (E) Interaction between TKT knockdown and APR-246 in H1299, OACP4C, HCT116 and JH-EsoAd1 cells based on the Bliss Independence model. Data represent most synergistic interaction across APR-246 dose response. A coefficient of interaction < 0.8 indicates synergy, 0.8–1.2 indicates additivity and > 1.2 indicates antagonism. Cell viability (AlamarBlue) in (F) OACP4C and (G) HCT116 cells following 72 h treatment with increasing concentrations of APR-246, administered 24 h after TKT knockdown with siRNA, normalised to vehicle control (bottom) Western blots for TKT following 96 h knockdown with siTKT, showing actin as a loading control (siNTC, non-targeting control; siTKT, TKT siRNA. Data represent mean, error bars = SEM, n = 3 for all studies. (C) One-way ANOVA with Dunnett’s multiple comparison post-test. ns, not significant; *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001.