Dipyrithione induces cell-cycle arrest and apoptosis in four cancer cell lines in vitro and inhibits tumor growth in a mouse model

BMC Clinical Pharmacology

Zhimin Yin³  Xianglin Duan¹  Yongze Zhang¹  Shengnan Wang¹  Linlin Cai¹  Jie Zhang¹  Yongmao Huang²  Caizhi Liu¹  Yumei Fan¹ 

[1] The Key Lab of Animal Physiology, College of Life Science, Hebei Normal University, Hebei Province, Shijiazhuang 050024, China;Laboratory of Medical Biotechnology, Hebei Chemical and Pharmaceutical College, Hebei Province, Shijiazhuang 050026, China;Jiangsu Province Key Laboratory of Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing 210046, China

关键词: Chemotherapy;    Anti-tumor activity;    PTS2;   

Others  :  860511
DOI  :  10.1186/2050-6511-14-54

 received in 2013-01-08, accepted in 2013-10-14,  发布年份 2013

【 摘 要 】

Background

Dipyrithione (PTS2) is widely used as a bactericide and fungicide. Here, we investigated whether PTS2 has broad-spectrum antitumor activity by studying its cytotoxicity and proapoptotic effects in four cancer cell lines.

Methods

We used MTT assays and trypan blue staining to test the viability of cancer cell lines. Hoechst 33258 and DAPI staining were used to observe cell apoptosis. Cell-cycle percentages were analyzed by flow cytometry. Apoptosis was assayed using caspase-3 and poly (ADP-ribose) polymerase (PARP) combined with Western blotting. Student’s t-test was used for statistical analysis.

Results

PTS2 inhibited proliferation in four cancer cell lines in a dose-dependent manner. Treated cells showed shrinkage, irregular fragments, condensed and dispersed blue fluorescent particles compared with control cells. PTS2 induced cycle-arrest and death. Cleavage of caspase-9, caspase-3, and PARP were detected in PTS2-treated cells. Antitumor activity of PTS2 was more effective against widely used cancer drugs and its precursor.

Conclusions

PTS2 appears to have novel cytotoxicity and potent broad-spectrum antitumor activity, which suggests its potential as the basis of an anticancer drug.

【 授权许可】

   
2013 Fan et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Jang TH, Lee SJ, Woo CH, Lee KJ, Jeon JH, Lee DS, Choi K, Kim IG, Kim YW, Lee TJ, Park HH: Inhibition of genotoxic stress induced apoptosis by novel TAT-fused peptides targeting PIDDosome. Biochem Pharmacol 2012, 83:218-227.
• [2]Sun R, Zhang Y, Lv Q, Liu B, Jin M, Zhang W, He Q, Deng M, Liu X, Li G, Li Y, Zhou G, Xie P, Xie X, Hu J, Duan Z: Toll-like receptor 3 (TLR3) induces apoptosis via death receptors and mitochondria by up-regulating the transactivating p63 isoform alpha (TAP63alpha). J Biol Chem 2011, 286:15918-15928.
• [3]Servida F, Lecis D, Scavullo C, Drago C, Seneci P, Carlo-Stella C, Manzoni L, Polli E, Lambertenghi Deliliers G, Delia D, Onida F: Novel second mitochondria-derived activator of caspases (Smac) mimetic compounds sensitize human leukemic cell lines to conventional chemotherapeutic drug-induced and death receptor-mediated apoptosis. Invest New Drugs 2011, 29:1264-1275.
• [4]Fan Y, Chen H, Qiao B, Luo L, Ma H, Li H, Jiang J, Niu D, Yin Z: Opposing effects of ERK and p38 MAP kinases on HeLa cell apoptosis induced by dipyrithione. Mol Cells 2007, 23:30-38.
• [5]Garrido C, Galluzzi L, Brunet M, Puig PE, Didelot C, Kroemer G: Mechanisms of cytochrome c release from mitochondria. Cell Death Differ 2006, 13:1423-1433.
• [6]Rinner B, Li ZX, Haas H, Siegl V, Sturm S, Stuppner H, Pfragner R: Antiproliferative and pro-apoptotic effects of Uncaria tomentosa in human medullary thyroid carcinoma cells. Anticancer Res 2009, 29:4519-4528.
• [7]Doose CA, Szaleniec M, Behrend P, Muller A, Jastorff B: Chromatographic behavior of pyrithiones. J Chromatogr A 2004, 1052:103-110.
• [8]Mann JJ, Fraker PJ: Zinc pyrithione induces apoptosis and increases expression of Bim. Apoptosis 2005, 10:369-379.
• [9]Kondoh M, Tasaki E, Takiguchi M, Higashimoto M, Watanabe Y, Sato M: Activation of caspase-3 in HL-60 cells treated with pyrithione and zinc. Biol Pharm Bull 2005, 28:757-759.
• [10]Huang H, Pan Y, Ye Y, Gao M, Yin Z, Luo L: Dipyrithione attenuates oleic acid-induced acute lung injury. Pulm Pharmacol Ther 2011, 24:74-80.
• [11]Liu Z, Fan Y, Wang Y, Han C, Pan Y, Huang H, Ye Y, Luo L, Yin Z: Dipyrithione inhibits lipopolysaccharide-induced iNOS and COX-2 up-regulation in macrophages and protects against endotoxic shock in mice. FEBS Lett 2008, 582:1643-1650.
• [12]Han C, Fu J, Liu Z, Huang H, Luo L, Yin Z: Dipyrithione inhibits IFN-gamma-induced JAK/STAT1 signaling pathway activation and IP-10/CXCL10 expression in RAW264.7 cells. Inflamm Res 2010, 59:809-816.
• [13]Fan Y, Wu D, Jin L, Yin Z: Human glutamylcysteine synthetase protects HEK293 cells against UV-induced cell death through inhibition of c-Jun NH2-terminal kinase. Cell Biol Int 2005, 29:695-702.
• [14]Morishita D, Takami M, Yoshikawa S, Katayama R, Sato S, Kukimoto-Niino M, Umehara T, Shirouzu M, Sekimizu K, Yokoyama S, Fujita N: Cell-permeable carboxyl-terminal p27(Kip1) peptide exhibits anti-tumor activity by inhibiting Pim-1 kinase. J Biol Chem 2011, 286:2681-2688.
• [15]Kiraly R, Demeny M, Fesus L: Protein transamidation by transglutaminase 2 in cells: a disputed Ca2 + -dependent action of a multifunctional protein. FEBS J 2011, 278:4717-4739.
• [16]Dulic V, Kaufmann WK, Wilson SJ, Tlsty TD, Lees E, Harper JW, Elledge SJ, Reed SI: p53-dependent inhibition of cyclin-dependent kinase activities in human fibroblasts during radiation-induced G1 arrest. Cell 1994, 76:1013-1023.
• [17]Singh N, Nambiar D, Kale RK, Singh RP: Usnic acid inhibits growth and induces cell cycle arrest and apoptosis in human lung carcinoma A549 cells. Nutr Cancer 2013, 65(Suppl 1):36-43.
• [18]Gulappa T, Reddy RS, Suman S, Nyakeriga AM, Damodaran C: Molecular interplay between cdk4 and p21 dictates G0/G1 cell cycle arrest in prostate cancer cells. Cancer Lett 2013, 337:177-183.
• [19]Lin CH, Lu WC, Wang CW, Chan YC, Chen MK: Capsaicin induces cell cycle arrest and apoptosis in human KB cancer cells. BMC Complement Altern Med 2013, 13:46. BioMed Central Full Text
• [20]Walsh JG, Cullen SP, Sheridan C, Luthi AU, Gerner C, Martin SJ: Executioner caspase-3 and caspase-7 are functionally distinct proteases. Proc Natl Acad Sci U S A 2008, 105:12815-12819.
• [21]Shao L, Guo X, Plate M, Li T, Wang Y, Ma D, Han W: CMTM5-v1 induces apoptosis in cervical carcinoma cells. Biochem Biophys Res Commun 2009, 379:866-871.
• [22]Rodriguez-Hernandez A, Brea-Calvo G, Fernandez-Ayala DJ, Cordero M, Navas P, Sanchez-Alcazar JA: Nuclear caspase-3 and caspase-7 activation, and poly(ADP-ribose) polymerase cleavage are early events in camptothecin-induced apoptosis. Apoptosis 2006, 11:131-139.
• [23]Yang C, Choy E, Hornicek FJ, Wood KB, Schwab JH, Liu X, Mankin H, Duan Z: Histone deacetylase inhibitor PCI-24781 enhances chemotherapy-induced apoptosis in multidrug-resistant sarcoma cell lines. Anticancer Res 2011, 31:1115-1123.
• [24]Malhotra GG, Zatz JL: Investigation of nail permeation enhancement by chemical modification using water as a probe. J Pharm Sci 2002, 91:312-323.