Abstract: Objective To investigate the effect of histone deacetylase (HDAC) inhibitor and PD98059 conjugate on squamous cell carcinomas (SCC) activity in vitro and in vivo. Methods HDAC inhibitory activity of conjugate SAHAPD98059 was evaluated by HDAC assay kit. The antiproliferative activity of conjugate SAHA-PD98059 on A431, HSC-5, Colo16 and SCC-12 was assessed by 5-[3-(carboxymethoxy)phenyl]-3-(4,5-dimethyl-2-thiazolyl)-2-(4-sulfophenyl)-2Htetrazolium inner salt (MTS) assay kit. A431 subcutaneous tumor-bearing mouse model was constructed by continuous intragastric administration for 18 days. The model mice were randomly divided into conjugate SAHA-PD98059 group, SAHA group, PD98059 group and blank control group. The body weight and tumor size of mice were recorded every 2 days. The biological safety of conjugate SAHA-PD98059 was evaluated by H&E staining of main organs of mice. Results The half inhibitory concentration (IC50) of conjugate SAHA-PD98059 inhibitory HDAC activity was (142.9±1.2) nmol/L. Conjugate SAHA-PD98059 was able to form hydrogen bonds with amino acid residues H142, G151 and T312 in HDAC active pocket, and SAHA engaged in hydrogen bonds with amino acid residues H142, H143 and T312. Compared with the parent compound PD98059 and SAHA, the conjugate SAHA-PD98059 displayed stronger anti-proliferative activity against A431, HSC-5, Colo16 and SCC-12. Among them, conjugate SAHA-PD98059 showed the greatest potency against A431 (IC50=1.7 mmol/L±0.2 mmol/L). Moreover, conjugate SAHA-PD98059 was nontoxic to health TE353. sk cells. In vivo biological evaluation exhibited that median lethal dose (LD50) of conjugate SAHA-PD98059 was 647.5 mg/kg, and which could significantly inhibit the growth of A431 tumor in mice. Meanwhile, HE histology data showed that there were no noticeable toxic effects of conjugate SAHA-PD98059 on the major organs. Conclusion The conjugate SAHA-PD98059 is safe and effective for the treatment of SCC, and it its effect is stronger than that the single use of SAHA or PD98059

Key words: skin neoplasms, carcinoma, squamous cell, histone deacetylases, PD98059, SAHA, conjugate, anti-tumor activity