Inhibition Mechanism of Novel Pyrazolo[1,5-a]pyrazin-4(5H)-one Derivatives Against Proliferation of A549 and H322 Cancer Cells<sup>△</sup>

Shao Jin-hui; Feng Gui-hua

Your Location：

Home >

Browse articles >

Inhibition Mechanism of Novel Pyrazolo[1,5-a]pyrazin-4(5H)-one Derivatives Against Proliferation of A549 and H322 Cancer Cells^△

中国医学科学杂志（英文版） 2015年30卷第4期页码：260-265

Orginal Article | Updated：2024-04-10

- Inhibition Mechanism of Novel Pyrazolo[1,5-a]pyrazin-4(5H)-one Derivatives Against Proliferation of A549 and H322 Cancer Cells^△
- Affiliations：
  
  1. 1Department of Medical Morphology, School of Medicine, Hubei University of Art and Science, Xiangyang 441053, Hubei, China
  2. 2Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Jinan 250100, China
- Author bio：
  
  *Corresponding author Tel: 86-710-3591126, E-mail: jhshao666@163.com
- Funds：
  
  △Supported by the Doctoral Research Fund of Hubei University of Art and Science (2013B009) and the Post-doctoral Research Fund of Shandong University (111935).
- DOI：
  中图分类号：
- 网络出版日期：2015-08-20，
  
  纸质出版日期：2015-08
- Accepted：
Scan QR Code
Inhibition Mechanism of Novel Pyrazolo[1,5-a]pyrazin-4(5H)-one Derivatives Against Proliferation of A549 and H322 Cancer Cells^△[J]. 中国医学科学杂志（英文版）, 2015,30(4):260-265.

Shao Jin-hui, Feng Gui-hua. Inhibition Mechanism of Novel Pyrazolo[1,5-a]pyrazin-4(5H)-one Derivatives Against Proliferation of A549 and H322 Cancer Cells^△[J]. Chinese medical sciences journal, 2015, 30(4): 260-265.
Inhibition Mechanism of Novel Pyrazolo[1,5-a]pyrazin-4(5H)-one Derivatives Against Proliferation of A549 and H322 Cancer Cells^△[J]. 中国医学科学杂志（英文版）, 2015,30(4):260-265. DOI：

Shao Jin-hui, Feng Gui-hua. Inhibition Mechanism of Novel Pyrazolo[1,5-a]pyrazin-4(5H)-one Derivatives Against Proliferation of A549 and H322 Cancer Cells^△[J]. Chinese medical sciences journal, 2015, 30(4): 260-265. DOI：

摘要

Abstract

Objective

To explore the inhibition mechanism and safety of pyrazolo[1

5-a]pyrazin-4(5H)-one derivatives against proliferation of human lung cancer A549 cells

H322 cells

and human umbilical vein endothelial cell (HUVEC).

Methods

Cells were treated with 40 μmol/L of the ppo3a

ppo3b

ppo3i

and 0.1% DMSO (control) for 48 hours

respectively. Apoptosis was determined by Hoechst 33258 staining assay in H322 and A549 cells. Cell cycle distribution was determined by flow cytometry analysis in A549 cell. LC3-II

p53

and heat shock protein (HSP) 70 protein levels were detected by Western blotting in A549 cells treated with ppo3b for 48 hours. The morphology and viability of HUVEC were observed by inverted microscope and sulforhodamine B (SRB) assay.

Results

Ppo3a

ppo3b

and ppo3i significantly induced apoptosis in H322 and A549 cells. A strong G1-phase arrest was concomitant with the growth inhibitory effect on A549 cells. Ppo3b effectively elevated the p53 protein level

but significantly reduced the HSP70 protein level. There were no significantly inhibitory effect on the morphology and viability of HUVEC when treated with ppo3a

ppo3b

and ppo3i.

Conclusions

ppo3a

ppo3b

and ppo3i could inhibit H322 proliferation through apoptosis and inhibit A549 through apoptosis and G1-phase arrest. The protein p53 and HSP70 might involve in the inhibition effects. These derivatives might be a clue to find effective and safe drug for lung cancers.

关键词

Keywords

references

Jemal A , Siegel R , Ward E , et al. Cancer statistics, 2008. CA Cancer J Clin 2008 ; 58 : 71 - 96 .

Kemnitzer W , Jiang S , Wang Y , et al. Discovery of 4-aryl-4H-chromenes as a new series of apoptosis inducers using a cell- and caspase-based HTS assay. Part 5: modifications of the 2- and 3-positions. Bioorg Med Chem Lett 2008 ; 18 : 603 - 7 .

Zheng LW , Li Y , Ge D , et al. Synthesis of novel oxime-containing pyrazole derivatives and discovery of regulators for apoptosis and autophagy in A549 lung cancer cells. Bioorg Med Chem Lett 2010 ; 20 : 4766 - 70 .

Anzaldi M , Macciò C , Mazzei M , et al. Antiproliferative and proapoptotic activities of a new class of pyrazole deriva- tives in HL-60 cells. Chem Biodivers 2009 ; 6 : 1674 - 87 .

5.Liu N , Zhang JH , Zhao BX , et al . Microwave-assisted synthesis, crystal structure of pyrazolo[1,5-a]pyrazin- 4(5H)-ones and their selective effects on lung cancer cells. Eur J Med Chem 2011 ; 46 : 2359 - 67 .

6.Zheng LW , Shao JH , Zhao BX , et al . Synthesis of novel pyrazolo[1,5-a]pyrazin-4(5H)-one derivatives and their inhibition against growth of A549 and H322 lung cancer cells. Bioorg Med Chem Lett 2011 ; 21 : 3909 - 13 .

Jaffe EA , Nachman RL , Becker CG , et al. Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. J Clin Invest 1973 ; 52 : 2745 - 56 .

Shi J , Zheng D , Liu Y , et al. Overexpression of soluble TRAIL induces apoptosis in human lung adenocarcinoma and inhibits growth of tumor xenografts in nude mice. Cancer Res 2005 ; 65 : 1687 - 92 .

Xu N , Wang YS , Pan WB , et al. Human alpha-defensin-1 inhibits growth of human lung adenocarcinoma xenograft in nude mice. Mol Cancer Ther 2008 ; 7 : 1588 - 97 .

Lee PJ , Alam J , Wiegand GW , et al. Overexpression of heme oxygenase-1 in human pulmonary epithelial cells results in cell growth arrest and increased resistance to hyperoxia. Proc Natl Acad Sci USA 1996 ; 93 : 10393 - 8 .

Lee JY , Leonhardt LG , Obeid LM. Cell-cycle-dependent changes in ceramide levels preceding retinoblastoma protein dephosphorylation in G2/M. Biochem J 1998 ; 334 : 457 - 61 .

Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976 ; 72 : 248 - 54 .

Lian S , Su H , Zhao BX , et al. Synthesis and discovery of pyrazole-5-carbohydrazide N-glycosides as inducer of autophagy in A549 lung cancer cells. Bioorg Med Chem 2009 ; 17 : 7085 - 92 .

Yoshimori T. Autophagy: a regulated bulk degradation process inside cells. Biochem Biophys Res Commun 2004 ; 313 : 453 - 8 .

Klionsky DJ , Abeliovich H , Agostinis P , et al. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 2008 ; 4 : 151 - 75 .

Zheltukhin AO , Chumakov PM. Constitutive and induced functions of the p53 gene. Biochemistry (Mosc) 2010 ; 75 : 1692 - 721 .

Gu B , Zhu WG. Surf the post-translational modification network of p53 regulation. Int J Biol Sci 2012 ; 8 : 672 - 84 .

Nylandsted J , Brand K , Jäättelä M. Heat shock protein 70 is required for the survival of cancer cells. Ann N Y Acad Sci 2000 ; 926 : 122 - 5 .

Hatfield MP , Lovas S. Role of Hsp70 in cancer growth and survival. Protein Pept Lett 2012 ; 19 : 616 - 24 .

浏览量

Downloads

CSCD

文章被引用时，请邮件提醒。

Submit

关联资源

Up-regulation of Let-7a Expression Induces Gastric Carcinoma Cell Apoptosis In Vitro

Influence of Photodynamic Therapy on Apoptosis and Invasion of Human Cholangiocarcinoma QBC939 Cell Line