Targeting tumor endothelial cells with methyltransferase inhibitors: Mechanisms of action and the potential of combination therapy

Shu Zhou; Hailong Ou; Yatao Wu; Dan Qi; Xiaming Pei; Xiaohui Yu; Xiaoxiao Hu; Erxi Wu

doi:10.1016/j.pharmthera.2023.108434

Targeting tumor endothelial cells with methyltransferase inhibitors: Mechanisms of action and the potential of combination therapy

Pharmacol Ther. 2023 Jul:247:108434. doi: 10.1016/j.pharmthera.2023.108434. Epub 2023 May 10.

Authors

Shu Zhou¹, Hailong Ou¹, Yatao Wu¹, Dan Qi², Xiaming Pei³, Xiaohui Yu³, Xiaoxiao Hu⁴, Erxi Wu⁵

Affiliations

¹ State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, Molecular Science and Biomedicine Laboratory and Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082, China.
² Department of Neurosurgery, Neuroscience Institute, Baylor Scott & White Health, Temple, TX 78508, USA.
³ Department of Urology, Department of Pathology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Changsha, Hunan 410013, China.
⁴ State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, Molecular Science and Biomedicine Laboratory and Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan 410082, China; Research Institute of Hunan University in Chongqing, Chongqing 401120, China. Electronic address: [email protected].
⁵ Department of Neurosurgery, Neuroscience Institute, Baylor Scott & White Health, Temple, TX 78508, USA; Texas A & M University Schools of Medicine and Pharmacy, College Station, TX 77843, USA; LIVESTRONG Cancer Institutes, Department of Oncology, Dell Medical School, the University of Texas at Austin, Austin, TX 78712, USA. Electronic address: [email protected].

PMID: 37172786
DOI: 10.1016/j.pharmthera.2023.108434

Abstract

Tumor endothelial cells (TECs) reside in the inner lining of blood vessels and represent a promising target for targeted cancer therapy. DNA methylation is a chemical process that involves the transfer of a methyl group to a specific base in the DNA strand, catalyzed by a DNA methyltransferase (DNMT). DNMT inhibitors (DNMTis) can inhibit the activity of DNMTs, thereby preventing the transfer of methyl groups from s-adenosyl methionine (SAM) to cytosine. Currently, the most viable therapy for TECs is the development of DNMTis to release cancer suppressor genes from their repressed state. In this review, we first outline the characteristics of TECs and describe the development of tumor blood vessels and TECs. Abnormal DNA methylation is closely linked to tumor initiation, progression, and cell carcinogenesis, as evidenced by numerous studies. Therefore, we summarize the role of DNA methylation and DNA methyltransferase and the therapeutic potential of four types of DNMTi in targeting TECs. Finally, we discuss the accomplishments, challenges, and opportunities associated with combination therapy with DNMTis for TECs.

Keywords: Combinational therapy; DNA methyltransferase inhibitors; Drug resistance; Epigenetic regulation; Methylation; Targeted therapy; Tumor endothelial cells.

Publication types

Review

MeSH terms

DNA
DNA Methylation
DNA Modification Methylases
Endothelial Cells*
Enzyme Inhibitors / pharmacology
Enzyme Inhibitors / therapeutic use
Humans
Methyltransferases
Neoplasms* / drug therapy
Neoplasms* / genetics

Substances

Methyltransferases
DNA Modification Methylases
DNA
Enzyme Inhibitors