2-hexyl-4-pentynoic acid, a potential therapeutic for breast carcinoma by influencing RPA2 hyperphosphorylation-mediated DNA repair

Wenwen Ding; David Lim; Zhendong Wang; Zuchao Cai; Guochao Liu; Fengmei Zhang; Zhihui Feng

doi:10.1016/j.dnarep.2020.102940

2-hexyl-4-pentynoic acid, a potential therapeutic for breast carcinoma by influencing RPA2 hyperphosphorylation-mediated DNA repair

DNA Repair (Amst). 2020 Nov:95:102940. doi: 10.1016/j.dnarep.2020.102940. Epub 2020 Jul 28.

Authors

Wenwen Ding¹, David Lim², Zhendong Wang¹, Zuchao Cai¹, Guochao Liu¹, Fengmei Zhang¹, Zhihui Feng³

Affiliations

¹ Department of Occupational Health and Occupational Medicine, School of Public Health, Cheeloo College of Medicine, Shandong University, China.
² School of Science and Health, Western Sydney University, Campbelltown, New South Wales, Australia; College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia.
³ Department of Occupational Health and Occupational Medicine, School of Public Health, Cheeloo College of Medicine, Shandong University, China. Electronic address: fengzhihui@sdu.edu.cn.

PMID: 32795962
DOI: 10.1016/j.dnarep.2020.102940

Abstract

Breast carcinoma is one of the most common malignancies in women. Previous studies have reported that 500 μM valproic acid can sensitize breast tumor cells to the anti-neoplastic agent hydroxyurea. However, the dose requirements for valproic acid is highly variable due to the wide inter-individuals clinical characteristics. High therapeutic dose of valproic acid required to induce anti-tumor activity in solid tumor was associated with increased adverse effects. There are attempts to locate suitably high-efficient low-toxicity valproic acid derivatives. We demonstrated that lower dose of 2-hexyl-4-pentynoic acid (HPTA; 15 μM) has similar effects as 500 μM VPA in inhibiting breast cancer cell growth and sensitizing the tumor cells to hydroxyurea on MCF7 cells, EUFA423 cells, MCF7 cells with defective RPA2-p gene and primary culture cells derived from tissue-transformed breast tumor cells. We discovered HPTA resulted in more DNA double-strand breaks, the homologous recombination was inhibited through the interference of the hyperphosphorylation of replication protein A2 and recombinase Rad51. Our data postulate that HPTA may be a potential novel sensitizer to hydroxyurea in the treatment of breast carcinoma.

Keywords: Breast cancer; HDACi, histone deacetylase inhibitor; HPTA, 2-hexyl-4-pentynoic acid; HU, hydroxyurea; VPA, valproic acid.

Publication types

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

MeSH terms

Antineoplastic Combined Chemotherapy Protocols / therapeutic use
Breast Neoplasms / drug therapy*
Breast Neoplasms / genetics
Breast Neoplasms / metabolism
Cell Line, Tumor
DNA Breaks, Double-Stranded*
DNA, Neoplasm / metabolism
Fatty Acids, Unsaturated / pharmacology*
Fatty Acids, Unsaturated / therapeutic use
Female
Humans
Hydroxyurea / therapeutic use
MCF-7 Cells
Phosphorylation
Protein Processing, Post-Translational
Rad51 Recombinase / metabolism*
Recombinational DNA Repair*
Replication Protein A / metabolism*

Substances

2-hexyl-4-pentynoic acid
DNA, Neoplasm
Fatty Acids, Unsaturated
Replication Protein A
Rad51 Recombinase
RPA2 protein, human
Hydroxyurea