Curcumin inhibits human cytomegalovirus by downregulating heat shock protein 90

Lv,Yali; Gong,Lili; Wang,Zihui; Han,Feifei; Liu,He; Lu,Xuechun; Liu,Lihong

doi:10.3892/mmr.2015.3983

Curcumin inhibits human cytomegalovirus by downregulating heat shock protein 90

Authors:
- Yali Lv
- Lili Gong
- Zihui Wang
- Feifei Han
- He Liu
- Xuechun Lu
- Lihong Liu
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Affiliations: Beijing Chao‑Yang Hospital, Capital Medical University, Beijing 100020, P.R. China, Department of Geriatric Hematology, PLA General Hospital, Beijing 100853, P.R. China
Published online on: June 22, 2015 https://doi.org/10.3892/mmr.2015.3983
Pages: 4789-4793

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Abstract

Curcumin is a traditional Chinese medicine extracted from the rhizome of the herb Curcuma longa, which exhibits anti-human cytomegalovirus (HCMV) activity, however, the underlying mechanism remains to be elucidated. The present study reported that the pharmacogenomics of curcumin are similar to that of the antiviral drug, geldanamycin, which targets heat shock protein 90 (Hsp90). Comparative analysis of 3,000 clinical drugs demonstrated that curcumin had a positive association with the gene expression profiles of several drugs, among which the pharmacogenomics of the antiviral drug, geldanamycin, were most similar to that of curcumin. Molecular docking simulation analysis revealed that curcumin fit well in the binding pocket of Hsp90, with hydrogen bonds, hydrophobic interactions and conjugation to maintain adhesion. Consistently, HCMV infection of human embryonic lung fibroblast cells resulted in increased expression of Hsp90α, which was significantly inhibited by treatment with curcumin. These findings suggested that targeting Hsp90 contributed to the anti‑HCMV activity of curcumin.

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1	Weisblum Y, Panet A, Zakay-Rones Z, Haimov-Kochman R, Goldman-Wohl D, Ariel I, Falk H, Natanson-Yaron S, Goldberg MD, Gilad R, Lurain NS, Greenfield C, Yagel S and Wolf DG: Modeling of human cytomegalovirus maternal-fetal transmission in a novel decidual organ culture. J Virol. 85:13204–13213. 2011. View Article : Google Scholar : PubMed/NCBI
2	Reuter JD, Gomez DL, Wilson JH and Van Den Pol AN: Systemic immune deficiency necessary for cytomegalovirus invasion of the mature brain. J Virol. 78:1473–1487. 2004. View Article : Google Scholar : PubMed/NCBI
3	Imai Y, Shum C, Martin DF, Kuppermann BD, Drew WL and Margolis TP: Emergence of drug-resistant cytomegalovirus retinitis in the contralateral eyes of patients with AIDS treated with ganciclovir. J Infect Dis. 189:611–615. 2004. View Article : Google Scholar : PubMed/NCBI
4	Li S, Zhu J, Zhang W, Chen Y, Zhang K, Popescu LM, Ma X, Lau WB, Rong R, Yu X, et al: Signature microRNA expression profile of essential hypertension and its novel link to human cytomegalovirus infection. Circulation. 124:175–184. 2011. View Article : Google Scholar : PubMed/NCBI
5	Huang ZR, Yu LP, Yang XC, Zhang F, Chen YR, Feng F, Qian XS and Cai J: Human cytomegalovirus linked to stroke in a Chinese population. CNS Neurosci Ther. 18:457–460. 2012. View Article : Google Scholar : PubMed/NCBI
6	Shankar TN, Shantha NV, Ramesh HP, Murthy IA and Murthy VS: Toxicity studies on turmeric (Curcuma longa): Acute toxicity studies in rats, guineapigs & monkeys. Indian J Exp Biol. 18:73–75. 1980.PubMed/NCBI
7	Vallee F, Carrez C, Pilorge F, Dupuy A, Parent A, Bertin L, Thompson F, Ferrari P, Fassy F, Lamberton A, Thomas A, et al: Tricyclic series of heat shock protein 90 (Hsp90) inhibitors part I: Discovery of tricyclic imidazo [4,5-c] pyridines as potent inhibitors of the Hsp90 molecular chaperone. J Med Chem. 54:7206–7219. 2011. View Article : Google Scholar
8	Stolina M, Sharma S, Lin Y, Dohadwala M, Gardner B, Luo J, Zhu L, Kronenberg M, Miller PW, Portanova J, et al: Specific inhibition of cyclooxygenase 2 restores antitumor reactivity by altering the balance of IL-10 and IL-12 synthesis. J Immunol. 164:361–370. 2000. View Article : Google Scholar
9	Pfaffl MW: A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 29:e452001. View Article : Google Scholar : PubMed/NCBI
10	Lv YL, Lan AJ, Lan YY, Li C, Lei N, Wu C and Liu LH: Activity of curcumin against human cytomegalovirus in vitro. Afr J Pharm Pharmacol. 6:30–35. 2012.
11	Austen M and Dohrmann C: Phenotype-first screening for the identification of novel drug targets. Drug Discov Today. 10:275–282. 2005. View Article : Google Scholar : PubMed/NCBI
12	Lu XC, Chi XH, Yang B, Zhu HL, Liu LH, Zhang F and Yan JW: Gene expression profile analysis of T lymphocytes involved in pathogenesis of severe aplastic anemia by using bioinformatics method as a novel way of drug screening. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 18:416–420. 2010.In Chinese. PubMed/NCBI
13	Yang B, Lu XC, Liu LH, Zhu HL, Chi XH, Yao SQ, Lou FD and Yu L: Experimental identification of drugs with function of targeted up-regulating ID4 expression: Bioinformatics-based prediction and preliminary validation. Zhonghua Yi Xue Za Zhi. 89:1714–1716. 2009.In Chinese. PubMed/NCBI
14	Burch AD and Weller SK: Herpes simplex virus type 1 DNA polymerase requires the mammalian chaperone hsp90 for proper localization to the nuleus. J Virol. 79:10740–10749. 2005. View Article : Google Scholar : PubMed/NCBI
15	Grenert JP, Sullivan WP, Fadden P, Haystead TA, Clark J, Mimnaugh E, Krutzsch H, Ochel HJ, Schulte TW, Sausville E, et al: The amino-terminal domain of heat shock protein 90 (hsp90) that binds geldanamycin is an ATP/ADP switch domain that regulates hsp90 conformation. J Biol Chem. 272:23843–23850. 1997. View Article : Google Scholar : PubMed/NCBI
16	Geller R, Andino R and Frydman J: Hsp90 inhibitors exhibit resistance-free antiviral activity against respiratory syncytial virus. PLoS One. 8:e567622013. View Article : Google Scholar : PubMed/NCBI
17	Cheng CF, Fan J, Zhao ZW, Woodley DT and Li W: Secreted heat shock protein-90a: A more effective and safer target and for anti-cancer drags. Curr Signal Tranduction Ther. 5:121–127. 2010. View Article : Google Scholar
18	Zhai QQ, Luo Y, Wang QD, Xia M, Xing GW, Li YC, Jiang JH, Liu Z, Liu QY, Wang YF, et al: Determination of SNX-2112, a selective Hsp90 inhibitor, in plasma samples by hish-performance liquid chromatography and its application to pharmacokineties in rats. J Pharm Biomed Anal. 53:1048–1052. 2010. View Article : Google Scholar : PubMed/NCBI
19	Jiang S QL, Zhou F, Huang J, Guo Y and Yang K: Molecular cloning and expression analysis of a heat shock protein (Hsp90) gene from black tiger shrimp (Penaeus monodon). Mol Biol Rep. 36:127–134. 2009. View Article : Google Scholar
20	Meng S SG and Li ZR: Recent progress in the study of Hsp90 inhibitors. Chin J Antibiot. 36:241–248. 2011.
21	Wen KW and Damania B: Hsp90 and Hsp40/Erdj3 are required for the expression and anti-apoptotic function of KSHV K1. Oncogene. 29:3532–3544. 2010. View Article : Google Scholar : PubMed/NCBI
22	Tsou YL, Lin YW, Chang HW, Lin HY, Shao HY, Yu SL, Liu CC, Chitra E, Sia C and Chow YH: Heat shock protein 90: Role in enterovirus 71 entry and assembly and potential target for therapy. PLoS One. 8:e771332013. View Article : Google Scholar : PubMed/NCBI
23	Murata T, Iwata S, Siddiquey MN, Kanazawa T, Goshima F, Kawashima D, Kimura H and Tsurumi T: Heat shock protein 90 inhibitors repress latent membrane protein 1 (LMP1) expression and proliferation of Epstein-Barr virus-positive natural killer cell lymphoma. PLoS One. 8:e635662013. View Article : Google Scholar : PubMed/NCBI
24	Luo Y, Lou S, Deng X, Liu Z, Li Y, Kleiboeker S and Qiu J: Parvovirus B19 infection of human primary erythroid progenitor cells triggers ATR-Chk1 signaling, which promotes B19 virus replication. J Virol. 85:8046–8055. 2011. View Article : Google Scholar : PubMed/NCBI
25	Geller R, Vignuzzi M, Andino R and Frydman J: Evolutionary constraints on chaperone-mediated folding provide an antiviral approach refractory to development of drug resistance. Genes Dev. 21:195–205. 2007. View Article : Google Scholar : PubMed/NCBI
26	Turnell AS and Grand RJ: DNA viruses and the cellular DNA-damage response. J Gen Virol. 93:2076–2097. 2012. View Article : Google Scholar : PubMed/NCBI
27	Xiao A, Wong J and Luo H: Viral interaction with molecular chaperones: Role in regulating viral infection. Arch Virol. 155:1021–1031. 2010. View Article : Google Scholar : PubMed/NCBI