Repurposing of ingenol mebutate for treating human colorectal cancer by targeting S100 calcium-binding protein A4 (S100A4)

Yao-Yu Hsieh; Ya-Wen Cheng; Po-Li Wei; Pei-Ming Yang

doi:10.1016/j.taap.2022.116134

Repurposing of ingenol mebutate for treating human colorectal cancer by targeting S100 calcium-binding protein A4 (S100A4)

Toxicol Appl Pharmacol. 2022 Aug 15:449:116134. doi: 10.1016/j.taap.2022.116134. Epub 2022 Jun 18.

Authors

Yao-Yu Hsieh¹, Ya-Wen Cheng², Po-Li Wei³, Pei-Ming Yang⁴

Affiliations

¹ Division of Hematology and Oncology, Taipei Medical University Shuang Ho Hospital, New Taipei City 23561, Taiwan; Division of Hematology and Oncology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
² TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan; Department of R&D, Calgent Biotechnology Co., Ltd., Taipei 10675, Taiwan.
³ Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan; Cancer Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan; Translational Laboratory, Department of Medical Research, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
⁴ TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan; Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan. Electronic address: yangpm@tmu.edu.tw.

PMID: 35724704
DOI: 10.1016/j.taap.2022.116134

Abstract

Colorectal cancer (CRC) is the world's second most common cause of cancer-related death. Novel treatments are still urgently needed. S100 calcium-binding protein A4 (S100A4) was demonstrated to be an anticancer therapeutic target. Herein, we found that higher S100A4 expression was associated with a poorer prognosis in publicly available cohorts and a Taiwanese CRC patient cohort. To identify repurposed S100A4 inhibitors, we mined the Connectivity Map (CMap) database for clinical drugs mimicking the S100A4-knockdown gene signature. Ingenol mebutate, derived from the sap of the plant Euphorbia peplus, is approved as a topical treatment for actinic keratosis. The CMap analysis predicted ingenol mebutate as a potent S100A4 inhibitor. Indeed, both messenger RNA and protein levels of S100A4 were attenuated by ingenol mebutate in human CRC cells. In addition, CRC cells with higher S100A4 expressions and/or the wild-type p53 gene were more sensitive to ingenol mebutate, and their migration and invasion were inhibited by ingenol mebutate. Therefore, our results suggest the repurposing of ingenol mebutate for treating CRC by targeting S100A4.

Keywords: Colorectal cancer; Connectivity map; Drug repurposing; Ingenol mebutate; S100A4.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Colorectal Neoplasms* / drug therapy
Colorectal Neoplasms* / genetics
Diterpenes* / pharmacology
Diterpenes* / therapeutic use
Drug Repositioning
Humans
S100 Calcium-Binding Protein A4* / antagonists & inhibitors
S100 Calcium-Binding Protein A4* / genetics

Substances

3-ingenyl angelate
Diterpenes
S100 Calcium-Binding Protein A4
S100A4 protein, human