The in vitro apoptotic effects of A248 and A1659, newly synthetic histone deacetylase inhibitors in oral cancer cells

Abstract

These results suggest that A248 and A1659, two new HDAC inhibitors, may be attractive therapeutic drug candidates for targeting Sp1 in human oral cancer cells.

Signal transducer and activators of transcription 3 regulates cryptotanshinone-induced apoptosis in human mucoepidermoid carcinoma cells

“…[ 24 ] Our previous studies also showed that survivin is a key mediator for MEC cell lines and several compounds blocked survivin during apoptotic cell death. [ 25 26 ] It was recently shown that constitutive activation of STAT3 can modify the expression level of survivin protein in malignant cells[ 27 28 ] suggesting that survivin may be regulated by the STAT3 signaling pathway. Thus, we investigated the effects of CT on survivin and the results showed that CT clearly reduced the expression level of survivin protein at a transcriptional level evidenced by the suppression of mRNA and its promoter activity in response to CT. Several pieces of evidence demonstrate that the abnormal activity of STAT3 promotes tumorigenesis by increasing the expression of anti-apoptotic Bcl-2 family members, such as Bcl-2, Bcl-xL, and Mcl-1.…”

Targeting histone deacetylases in head and neck squamous cell carcinoma: molecular mechanisms and therapeutic targets

“…In an endeavor to enhance HDAC inhibition and metabolic stability, Professor Gyoonhee Han synthesized A1659 [145]. This compound exhibited the ability to suppress the expression and nuclear translocation of Sp1, regulate the expression of p27 and cyclin D1, induce apoptosis and markedly decrease the viability of MC-3 and HN22 human oral cancer cell lines [146].…”

“…Another intriguing HDAC inhibitor is A248, a pyridine-based HDAC inhibitor, it could attenuate the expression and nuclear translocation of Sp1, which was involved in the regulation of important cell cycle proteins such as p27 and cyclin D1. Through the modulation of these proteins, A248 could induce apoptosis and significantly reduce the viability of MC-3 and HN22 cells [146]. The manipulation of the CAP and linker region of vorinostat resulted in the creation of alkoxyamide based compound LMK235, a potent HDAC inhibitor exhibiting preferences for class I and class IIb HDACs and demonstrated the ability to sensitize HNSCC cells to chemotherapy [188,189].…”

Histone modifications in oral squamous cell carcinoma and oral potentially malignant disorders

“…TSA inhibited cellular proliferation and induced G2/M phase arrest via modulation of cell cycle mediators, such as upregulation of p21 expression, reduction of cyclin B1 (Anh, Ahn, Kim, Yoon, & Ahn, ; Katsura et al, ; Suzuki et al, ; Yao, Duan, Fan, & Wu, ), increase in cyclin E and cyclin A, and decrease in transcription factor E2F‐1, E2F‐4, and hyperphosphorylated form of retinoblastoma tumor‐suppressor protein Rb (Suzuki et al, ). Cell growth suppression induced by TSA was also mediated by mitochondrial membrane destruction and apoptosis‐regulating proteins, including a cleaved form of PARP, pro‐apoptotic Bcl‐2 family members bak and bax, and anti‐apoptotic proteins Bcl‐2 and Bcl‐XL, cytochrome release, proteolytic activation of caspases, and cytosolic co‐factor enhancement (Jang, Kim, Lee, & Lee, ; Shin et al, ; Suzuki et al, ; Yao et al, ). PTEN/Akt signaling was associated with TSA induced apoptosis and cell growth inhibition (Gan & Zhang, ).…”

“…A248 attenuated the expression of anti‐apoptotic survivin and apoptosis regulator Mcl‐1 through suppressing Sp1 expression (Choi et al, ). With tumor suppressive activity and the ability to inhibit cell viability, A248 and newly synthesized HDACI A1659 reduced Sp1 level and its nuclear translocation, leading to cyclin D1 and p27 modulation to induce apoptosis (Shin et al, ).…”