Cytotoxic effect of a non-peptidic small molecular inhibitor of the p53-HDM2 interaction on tumor cells

AIM: To investigate if non-peptidic small molecular inhibitors of the p53-HDM2 interaction could restore p53 function and kill tumor cells.METHODS: A series of non-peptidic small HDM2 inhibitors were designed by computer-aided model and synthesized by chemical method. Syl-155 was one of these inhibitors. Cytotoxic effect of syl-155 on three tumor cell lines with various states of p53, HT1080 (wild-type p53), KYSE510 (mutant p53), MG63 (p53 deficiency) was evaluated by MTT assay, Western blot and flow cytometry.RESULTS: Syl-155 stimulated the accumulation of p53 and p21 protein in HT1080 cells expressing wild-type p53, but not in KYSE510 and MG63 cells. Consequently, syl-155 induced cell cycle arrest and apoptosis in HT1080 cells.CONCLUSION: Non-peptidic small molecular inhibitors of the p53-HDM2 interaction show promise in treatment of tumors expressing wild-type p53.

Correlation of matrix metalloproteinase－2, －9, tissue inhibitor－1 of matrix metalloproteinase and CD44 variant 6 in head and neck cancer metastasis

This study aimed to explore the molecular mechanism in tumor invasion and metastasis. The expression of matrix metalloproteinase 2, 9 (MMP 2, MMP 9), tissue inhibitor 1 of matrix metalloproteinase (TIMP 1), cell adhesion molecule 44 variant 6 (CD44v6), HER2/neu and p53 was investigated in 154 patients with head and neck squamous cell carcinoma (SCC) by ABC and ImmunoMax immunohistochemical method. Their clinical relevance and correlation were analysed. The expression of MMP 2, MMP 9, TIMP 1, CD44v6, HER2/neu and p53 was found in cancer cells in 87.01%, 85.71%, 68.18%, 98.05%, 55.19% and 50.65% cases respectively. Linear regression and correlation analysis revealed that there was close positive relationship ( P <0.05) between the expression of MMP 2 and MMP 9, TIMP 1 and CD44v6, HER2/neu and MMP 9, MMP 2 and p53. Up regulation of MMP 2 was accompanied by advanced T stage ( P <0.01) . There was also a trend of MMP 2 expression being related with tumor metastasis. Increased expression of HER2/neu was found in patients with tumor recurrence( P <0.05). The expression of TIMP 1 was higher in laryngeal cancer than that in pharyngeal cancer, and higher in keratinizing and non keratinizing SCC than that in basaloid SCC( P <0.05). These findings suggested that MMP 2 and MMP 9, HER2/neu and MMP 9, MMP 2 and p53 had a coordinate function in aggression of tumor; that MMP 2 had a more important function than MMP 9 in tumor invasion and metastasis; and that HER2/neu might serve as a biomarker for poor prognosis in HNSCC.

Mechanism Study of the Kidney Renal Papillary Cell Carcinoma Proliferation Inhibition and Apoptosis Induction by EZH2

EZH2 is an important target in a variety of tumors, but its role in KIRP (Kidney renal papillary cell carcinoma) has not yet been proven. The aim of this study was to investigate the role of EZH2 in KIRP patients. And to investigate the KIRP, we used two KIRP cell lines, SKRC39 and ACHN in this study. We used CCK8 assay and colony formation assay to study the effect of EHZ2 small molecule inhibitor EPZ6438 on cancer cell proliferation, we used Trypan Blue cell counting experiments to study the effect of EZH2 on cancer cell apoptosis, and we also used qRT-PCR to study the mechanism of EZH2 on cancer cell proliferation. The results showed that EZH2 was elevated in KIRP patients;inhibition of EZH2 could inhibit the proliferation of cancer cells and induce the apoptosis of cancer cells, which is valuable for the control of KIRP in patients. As for the mechanism, we found that inhibition of EZH2 upregulated P53 expression and thus activated this tumor suppressor gene, indicating why EHZ1 inhibits renal cancer cells.

Design,synthesis and structure-activity relationship of 4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-ones as potent p53-MDM2 inhibitors

In the past decade,the p53-MDM2 protein-protein interaction by small molecules has been confirmed as a successful strategy for cancer therapy.In our previous work,pyrrolo[3,4-c]pyrazol-6（1H）-ones were found to be potent p53-MDM2 inhibitors.Further optimization and structure-activity relationship studies were described in the present work.The result revealed that benzyl group on position N1 of imidazole and bromine on C4-phenyl of pyrrolidone showed higher inhibitory activities.In vitro antiproliferative assay demonstrated the potent p53-MDM2 inhibitor 5c with 4-fold selectivity for U2 OS and Saos-2 cells.These data indicated that 4,5-dihydropyrrolo[3,4-c]pyrazol-6（1H）-one moiety is a valuable scaffold for further development of p53-MDM2 inhibitors.