Issue 6, 2019

Ixocarpalactone A from dietary tomatillo inhibits pancreatic cancer growth by targeting PHGDH

Abstract

3-Phosphoglycerate dehydrogenase (PHGDH) catalyzes the first rate-limiting step for the synthesis of glucose-derived serine by converting 3-phosphoglycerate (3-PG) to phosphohydroxypyruvate (p-Pyr), which has been reported to associate with tumorigenesis in many cancers. Iox A, a natural withanolide obtained from dietary tomatillo (Physalis ixocarpa), showed significant PHGDH inhibitory activity with an IC50 value of 1.66 ± 0.28 μM, and it was further confirmed to bind directly to PHGDH by the MST assay. Molecular docking demonstrated that Iox A coordinated at the allosteric site of PHGDH, which was consistent with the non-competitive kinetics. Meanwhile, Iox A selectively inhibited the proliferation of high PHGDH-expressing cancer cell lines (SW1990, MCF-7 and HeLa) and showed no obvious cytotoxicities on normal human cells (LO2, L929 and HPDE6-C7). In particular, Iox A showed a dose-dependent proapoptotic activity against SW1990 cells in a micromolar concentration as detected by flow cytometry and western blot analysis. DARTS and siRNA assays further demonstrated that Iox A directly targets at PHGDH to inhibit the proliferation of SW1990 cells. Furthermore, Iox A significantly inhibited the tumor growth in a SW1990 xenograft mouse model with low toxicities, suggesting its potential therapeutic application in pancreatic cancer treatment. Therefore, Iox A was identified as a novel natural PHGDH inhibitor with high targeting and low toxicities for the treatment of pancreatic cancers.

Graphical abstract: Ixocarpalactone A from dietary tomatillo inhibits pancreatic cancer growth by targeting PHGDH

Supplementary files

Article information

Article type
Paper
Submitted
25 Feb 2019
Accepted
23 Apr 2019
First published
23 Apr 2019

Food Funct., 2019,10, 3386-3395

Ixocarpalactone A from dietary tomatillo inhibits pancreatic cancer growth by targeting PHGDH

M. Zheng, J. Guo, J. Xu, K. Yang, R. Tang, X. Gu, H. Li and L. Chen, Food Funct., 2019, 10, 3386 DOI: 10.1039/C9FO00394K

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