Histone deacetylase inhibitor enhances sensitivity of non‐small‐cell lung cancer cells to 5‐FU/S‐1 via down‐regulation of thymidylate synthase expression and up‐regulation of p21^waf1/cip1 expression

Abstract

It is desirable to find more appropriate therapeutic opportunities in non-small-cell lung cancer (NSCLC) due to the current poor prognosis of affected patients. Recently, several histone deacetylase (HDAC) inhibitors, including suberoylanilide hydroxamic acid (SAHA), have been reported to exhibit antitumor activities against NSCLC. S-1, a novel oral fluorouracil anticancer drug, has been developed for clinical use in the treatment of NSCLC in Japan.Using an MTT assay, we analyzed the growth-inhibitory effect of 5-fluorouracil (5-FU), S-1, and SAHA against three NSCLC cell lines, as well as the breast cancer cell line MCF7 which is known to be highly sensitive to 5-FU. Combined treatment with low-dose SAHA enhanced 5-FU-and S-1-mediated cytotoxicity and resulted in synergistic effects, especially in 5-FU-resistant cells. Both the mRNA and protein expression levels of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and orotate phosphoribosyltransferase (OPRT), which are associated with 5-FU sensitivity ⁄ response, were analyzed in the cells undergoing treatment. 5-Fluorouracil-resistant lung cancer cells displayed high expression of TS mRNA and protein. Suberoylanilide hydroxamic acid down-regulated TS mRNA and protein expression, as well as repressed the rapid induction of this factor during 5-FU treatment, in all examined cell types. We also examined the status of the Rb-E2F1 pathway, with SAHA up-regulating p21 waf1 ⁄ cip1 expression via promoter histone acetylation; this, in turn, blocked the Rb-E2F1 pathway. We conclude that combination therapy with SAHA and S-1 in lung cancer may be promising due to its potential to overcome S-1 resistance via modulation of 5-FU ⁄ S-1 sensitivity-associated biomarker (TS) by HDAC inhibitor.

Epigenetic reprogramming reverses the relapse-specific gene expression signature and restores chemosensitivity in childhood B-lymphoblastic leukemia

“…35 In light of several reports suggesting the effect of these agents on various nonhistone proteins and transcription factors, we speculate that down-regulation of these genes may be mediated by an intermediate transcriptional regulator restored by HDAC inhibitor exposure. For example, p21 expression increases with vorinostat treatment in a dose-dependent manner, 36 which in turn might repress FOXM1. 37 The resultant decrease in the levels of FOXM1 may affect the levels of BIRC5, CCNB1, and FANCD2, as described previously.…”

Activation of p21-Dependent G1/G2 Arrest in the Absence of DNA Damage as an Antiapoptotic Response to Metabolic Stress

“…It has been also reported that sensitivity to 5-FU, another TS inhibitor, was increased in cells upon elevation of p21 levels. 28 This effect was associated with decreased expression of TS due to transcriptional regulation of the TS gene through the p21/CDK axis. 29 A connection between folate metabolism and p21 was also demonstrated in the study by Crott et al, in which a decrease of media folate was accompanied by a concomitant increase in the p21 transcript levels.…”

Suberoylanilide hydroxamic acid enhances chemosensitivity to 5-fluorouracil in hepatocellular carcinoma via inhibition of thymidylate synthase

“…HDAC inhibitors have been shown to downregulate the expression of TS and overcome TS-mediated resistance caused by 5-FU in several cancer cell lines [25][26][27]. However, the relationship between HDAC inhibitors and TS in HCC has not been investigated to date.…”

“…However, the relationship between HDAC inhibitors and TS in HCC has not been investigated to date. The effect of combination treatment with 5-FU and HDAC inhibitors has been reported in lung, breast, gastric, pancreas, colon, and renal cancer cell lines [25][26][27][28], whereas little is known about its effect on HCC cell lines.…”