Histone Deacetylase Inhibitor AR-42 Inhibits Breast Cancer Cell Growth and Demonstrates a Synergistic Effect in Combination with 5-FU

Overview

Journal Oncol Lett

Specialty Oncology

Date 2018 Jul 17

PMID 30008890

Citations 5

Authors

Ruihao Zhou

Juan Wu

Xiaofeng Tang

Xin Wei

Cheng Ju

Feifei Zhang

Jun Sun

Deyong Shuai

Zhiping Zhang

Qiong Liu

Xiao-Bin Lv

Affiliations

Soon will be listed here.

Abstract

AR-42 is a member of a novelly discovered class of phenylbutyrate-derived histone deacetylase inhibitors, and has a number of antitumor effects in a variety of tumor types; however, the role of AR-42 and its possible mechanisms have not been reported in the treatment of breast cancer. The aim of the present study was to investigate the antitumor effects of AR-42 and its associated mechanisms in breast cancer. MTT assays and colony formation assays were conducted to measure the proliferation of MCF-7 cells, and flow cytometry was used to analyze cell apoptosis. The results revealed that AR-42 induced cell apoptosis and suppressed cell growth in a dose- and time-dependent manner. Mechanistically, AR-42 treatment increased the acetylation of the p53 protein and prolonged the half-life of the p53 protein; furthermore, AR-42 treatment upregulated p21 and PUMA expression. Notably, AR-42 had a synergistic effect on MCF-7 cells in combination with fluorouracil, which is one of the most commonly used chemotherapeutic agents. In conclusion, the results indicated that AR-42 inhibits breast cancer cell proliferation and induces apoptosis, indicating that AR-42 is a potential therapeutic agent.

Citing Articles

HDAC11 mediates the ubiquitin-dependent degradation of p53 and inhibits the anti-leukemia effect of PD0166285.

Zhou Z, Zhong L, Chu X, Wan P, Dan W, Shao X Med Oncol. 2023; 40(11):325.

PMID: 37805625 DOI: 10.1007/s12032-023-02196-2.

Prevalence, causes and impact of TP53-loss phenocopying events in human tumors.

Fito-Lopez B, Salvadores M, Alvarez M, Supek F BMC Biol. 2023; 21(1):92.

PMID: 37095494 PMC: 10127307. DOI: 10.1186/s12915-023-01595-1.

A phase 1 trial of the histone deacetylase inhibitor AR-42 in patients with neurofibromatosis type 2-associated tumors and advanced solid malignancies.

Collier K, Valencia H, Newton H, Hade E, Sborov D, Cavaliere R Cancer Chemother Pharmacol. 2021; 87(5):599-611.

PMID: 33492438 PMC: 8162746. DOI: 10.1007/s00280-020-04229-3.

Epigenetic Regulation of Multidrug Resistance Protein 1 and Breast Cancer Resistance Protein Transporters by Histone Deacetylase Inhibition.

You D, Richardson J, Aleksunes L Drug Metab Dispos. 2020; 48(6):459-480.

PMID: 32193359 PMC: 7250367. DOI: 10.1124/dmd.119.089953.

VPS33B interacts with NESG1 to modulate EGFR/PI3K/AKT/c-Myc/P53/miR-133a-3p signaling and induce 5-fluorouracil sensitivity in nasopharyngeal carcinoma.

Liang Z, Liu Z, Cheng C, Wang H, Deng X, Liu J Cell Death Dis. 2019; 10(4):305.

PMID: 30944308 PMC: 6447525. DOI: 10.1038/s41419-019-1457-9.

References

Lin T, Fenger J, Murahari S, Bear M, Kulp S, Wang D . AR-42, a novel HDAC inhibitor, exhibits biologic activity against malignant mast cell lines via down-regulation of constitutively activated Kit. Blood. 2010; 115(21):4217-25. PMC: 3398750. DOI: 10.1182/blood-2009-07-231985. View

Lv X, Wu W, Tang X, Wu Y, Zhu Y, Liu Y . Regulation of SOX10 stability via ubiquitination-mediated degradation by Fbxw7α modulates melanoma cell migration. Oncotarget. 2015; 6(34):36370-82. PMC: 4742183. DOI: 10.18632/oncotarget.5639. View

Shi Y, Li Z, Han X, Yi J, Wang Z, Hou J . The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces growth inhibition and enhances taxol-induced cell death in breast cancer. Cancer Chemother Pharmacol. 2010; 66(6):1131-40. DOI: 10.1007/s00280-010-1455-1. View

Zimmerman B, Sargeant A, Landes K, Fernandez S, Chen C, Lairmore M . Efficacy of novel histone deacetylase inhibitor, AR42, in a mouse model of, human T-lymphotropic virus type 1 adult T cell lymphoma. Leuk Res. 2011; 35(11):1491-7. PMC: 3191315. DOI: 10.1016/j.leukres.2011.07.015. View

Fan L, Strasser-Weippl K, Li J, St Louis J, Finkelstein D, Yu K . Breast cancer in China. Lancet Oncol. 2014; 15(7):e279-89. DOI: 10.1016/S1470-2045(13)70567-9. View

Zuco V, Cassinelli G, Cossa G, Gatti L, Favini E, Tortoreto M . Targeting the invasive phenotype of cisplatin-resistant non-small cell lung cancer cells by a novel histone deacetylase inhibitor. Biochem Pharmacol. 2015; 94(2):79-90. DOI: 10.1016/j.bcp.2015.01.002. View

Kim J, Yoon E, Chung H, Park S, Hong K, Lee C . p53 acetylation enhances Taxol-induced apoptosis in human cancer cells. Apoptosis. 2012; 18(1):110-20. DOI: 10.1007/s10495-012-0772-8. View

Min A, Im S, Kim D, Song S, Kim H, Lee K . Histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), enhances anti-tumor effects of the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib in triple-negative breast cancer cells. Breast Cancer Res. 2015; 17:33. PMC: 4425881. DOI: 10.1186/s13058-015-0534-y. View

Siegel R, Miller K, Jemal A . Cancer statistics, 2018. CA Cancer J Clin. 2018; 68(1):7-30. DOI: 10.3322/caac.21442. View

10.

Di Martile M, Del Bufalo D, Trisciuoglio D . The multifaceted role of lysine acetylation in cancer: prognostic biomarker and therapeutic target. Oncotarget. 2016; 7(34):55789-55810. PMC: 5342454. DOI: 10.18632/oncotarget.10048. View

11.

Lu Y, Chou C, Tzen K, Gao M, Cheng A, Kulp S . Radiosensitizing effect of a phenylbutyrate-derived histone deacetylase inhibitor in hepatocellular carcinoma. Int J Radiat Oncol Biol Phys. 2012; 83(2):e181-9. DOI: 10.1016/j.ijrobp.2011.12.022. View

12.

Di Gennaro E, Bruzzese F, Pepe S, Leone A, Delrio P, Subbarayan P . Modulation of thymidilate synthase and p53 expression by HDAC inhibitor vorinostat resulted in synergistic antitumor effect in combination with 5FU or raltitrexed. Cancer Biol Ther. 2009; 8(9):782-91. DOI: 10.4161/cbt.8.9.8118. View

13.

Han Q, Chen R, Wang F, Chen S, Sun X, Guan X . Pre-exposure to 50 Hz-electromagnetic fields enhanced the antiproliferative efficacy of 5-fluorouracil in breast cancer MCF-7 cells. PLoS One. 2018; 13(4):e0192888. PMC: 5884488. DOI: 10.1371/journal.pone.0192888. View

14.

Livak K, Schmittgen T . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2002; 25(4):402-8. DOI: 10.1006/meth.2001.1262. View

15.

Taieb J, Tabernero J, Mini E, Subtil F, Folprecht G, Van Laethem J . Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer (PETACC-8): an open-label, randomised phase 3 trial. Lancet Oncol. 2014; 15(8):862-73. DOI: 10.1016/S1470-2045(14)70227-X. View

16.

Zhang H, Shang Y, Chen H, Li J . Histone deacetylases function as novel potential therapeutic targets for cancer. Hepatol Res. 2016; 47(2):149-159. DOI: 10.1111/hepr.12757. View

17.

Coates A, Millar E, OToole S, Molloy T, Viale G, Goldhirsch A . Prognostic interaction between expression of p53 and estrogen receptor in patients with node-negative breast cancer: results from IBCSG Trials VIII and IX. Breast Cancer Res. 2012; 14(6):R143. PMC: 4053129. DOI: 10.1186/bcr3348. View

18.

Hikisz P, Kilianska Z . PUMA, a critical mediator of cell death--one decade on from its discovery. Cell Mol Biol Lett. 2012; 17(4):646-69. PMC: 6275950. DOI: 10.2478/s11658-012-0032-5. View

19.

Zhu L, Wu K, Ma S, Zhang S . HDAC inhibitors: a new radiosensitizer for non-small-cell lung cancer. Tumori. 2015; 101(3):257-62. DOI: 10.5301/tj.5000347. View

20.

Alaee M, Khaghani S, Behroozfar K, Hesari Z, Ghorbanhosseini S, Nourbakhsh M . Inhibition of Nicotinamide Phosphoribosyltransferase Induces Apoptosis in Estrogen Receptor-Positive MCF-7 Breast Cancer Cells. J Breast Cancer. 2017; 20(1):20-26. PMC: 5378576. DOI: 10.4048/jbc.2017.20.1.20. View