Mechanistic studies on the anticancer activity of 2,4-disubstituted quinazoline derivative.

Abstract

BACKGROUND:

Accelerated proliferation of solid tumor and hematologic cancer cells is related to accelerated transcription of ribosomal DNA by the RNA polymerase I to produce elevated level of ribosomal RNA. Therefore, down-regulation of RNA polymerase I transcription in cancer cells is an important anticancer therapeutic strategy.

METHODS:

A variety of methods were used, including cloning, expression and purification of protein, electrophoretic mobility shift assay (EMSA), circular dichroic (CD) spectroscopy, CD-melting, isothermal titration calorimetry (ITC), chromatin immunoprecipitation (Ch-IP), RNA interference, RT-PCR, Western blot, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) cell assay.

RESULTS:

Our results showed that 2,4-disubstituted quinazoline derivative Sysu12d could down-regulate c-myc through stabilization of c-myc promoter G-quadruplex, resulting in down-regulation of nucleolin expression. Sysu12d could also disrupt nucleolin/G-quadruplex complex. Both of the above contributed to the down-regulation of ribosomal RNA synthesis, followed by activation of p53 and then cancer cell apoptosis.

CONCLUSIONS:

These mechanistic studies set up the basis for further development of Sysu12d as a new type of lead compound for cancer treatment.

GENERAL SIGNIFICANCE:

2,4-Disubstituted quinazoline derivatives may have multi-functional effect for cancer treatment.

• Authors: Lijuan Su, Huaqin Zheng, Zeng Li, Jun Qiu, Siqi Chen, Jinggong Liu, Tian-Miao Ou, Jia-Heng Tan, Lian-Quan Gu, Zhi-Shu Huang, Ding Li
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1840 Issue 10 Pg. 3123-30 (Oct 2014) ISSN: 0006-3002 [Print] Netherlands
• PMID: 25018006 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• MYC protein, human
• Proto-Oncogene Proteins c-myc
• Quinazolines
• RNA, Neoplasm
• RNA, Ribosomal
• TP53 protein, human
• Tumor Suppressor Protein p53

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Down-Regulation (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• HEK293 Cells
• HL-60 Cells
• HeLa Cells
• Humans
• Neoplasms (drug therapy, metabolism, pathology)
• Proto-Oncogene Proteins c-myc (biosynthesis)
• Quinazolines (chemistry, pharmacology)
• RNA, Neoplasm (biosynthesis)
• RNA, Ribosomal (biosynthesis)
• Tumor Suppressor Protein p53 (metabolism)