Subacute toxicological evaluation of AT‑533 and AT‑533 gel in Sprague‑Dawley rats

Wu,Yanting; Song,Xiaowei; Qin,Shurong; Chen,Pengxiao; Huang,Lianzhou; Wang,Qiaoli; Shan,Tianhao; Liang,Feng; Liao,Xiaofeng; Liu,Qiuying; Huang,Yunsheng; Wang,Yifei

doi:10.3892/etm.2021.10064

Subacute toxicological evaluation of AT‑533 and AT‑533 gel in Sprague‑Dawley rats

Authors:
- Yanting Wu
- Xiaowei Song
- Shurong Qin
- Pengxiao Chen
- Lianzhou Huang
- Qiaoli Wang
- Tianhao Shan
- Feng Liang
- Xiaofeng Liao
- Qiuying Liu
- Yunsheng Huang
- Yifei Wang
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Affiliations: Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong 510632, P.R. China, College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, P.R. China, Guangzhou (Jinan) Biomedicine Research and Development Center Co. Ltd, Guangzhou, Guangdong 510632, P.R. China, School of Pharmaceutical Sciences, Sun Yat‑Sen University, Guangzhou, Guangdong 510006, P.R. China, Guangdong Medical University, Dongguan, Guangdong 523808, P.R. China
Published online on: April 15, 2021 https://doi.org/10.3892/etm.2021.10064
Article Number: 632
Copyright: © Wu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

As a novel heat shock protein 90 inhibitor, AT‑533 exhibits various biological activities in vitro, including anti‑viral, anti‑tumor and anti‑inflammatory activities. Moreover, AT‑533 gel, a gel dosage form of AT‑533, has been suggested to have anti‑keratitis and herpes simplex virus type‑1 infection‑induced effects on the skin lesions of animals. However, the safety evaluation of AT‑533 and AT‑533 gel has, to the best of our knowledge, not been examined in in vivo toxicological tests. Therefore, these toxicological tests were carried out in the present study. A 30‑day subacute toxicity test for AT‑533 was conducted at doses of 1, 2 and 4 mg/kg in Sprague‑Dawley rats, while that for AT‑533 gel was conducted using a single dose of 5 g/kg. The toxicological tests showed that a high‑dose of AT‑533 caused lethality and side effects in Sprague‑Dawley rats. However, no mortality, loss of appetite and body weight, adverse reactions, or toxicologically relevant alterations in hematology, biochemistry and macroscopic findings (except for skin) occurred in rats exposed to low‑dose AT‑533 and single‑dose AT‑533 gel (5 g/kg) during a 30‑day subacute dermic toxicity study. The aforementioned results suggested that AT‑533 gel is non‑toxic for Sprague‑Dawley rats, as shown by a dermic subacute toxicity test and that except for slight skin irritation, AT‑533 gel had almost no side effects when administered percutaneously for 30 days.

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1	Pearl LH and Prodromou C: Structure and mechanism of the Hsp90 molecular chaperone machinery. Annu Rev Biochem. 75:271–294. 2006.PubMed/NCBI View Article : Google Scholar
2	Goetz MP, Toft DO, Ames MM and Erlichman C: The Hsp90 chaperone complex as a novel target for cancer therapy. Ann Oncol. 14:1169–1176. 2003.PubMed/NCBI View Article : Google Scholar
3	Zininga T, Ramatsui L and Shonhai A: Heat shock proteins as immunomodulants. Molecules. 23(2846)2018.PubMed/NCBI View Article : Google Scholar
4	Whitesell L and Lindquist SL: HSP90 and the chaperoning of cancer. Nat Rev Cancer. 5:761–772. 2005.PubMed/NCBI View Article : Google Scholar
5	Hoter A, El-Sabban ME and Naim HY: The HSP90 family: Structure, regulation, function, and implications in health and disease. Int J Mol Sci. 19(2560)2018.PubMed/NCBI View Article : Google Scholar
6	Workman P: Pharmacogenomics in cancer drug discovery and development: Inhibitors of the Hsp90 molecular chaperone. Cancer Detect Prev. 26:405–410. 2002.PubMed/NCBI View Article : Google Scholar
7	Schulte TW, Akinaga S, Soga S, Sullivan W, Stensgard B, Toft D and Neckers LM: Antibiotic radicicol binds to the N-terminal domain of Hsp90 and shares important biologic activities with geldanamycin. Cell Stress Chaperones. 3:100–108. 1998.PubMed/NCBI View Article : Google Scholar
8	Vilenchik M, Solit D, Basso A, Huezo H, Lucas B, He H, Rosen N, Spampinato C, Modrich P and Chiosis G: Targeting wide-range oncogenic transformation via PU24FCl, a specific inhibitor of tumor Hsp90. Chem Biol. 11:787–797. 2004.PubMed/NCBI View Article : Google Scholar
9	He H, Zatorska D, Kim J, Aguirre J, Llauger L, She Y, Wu N, Immormino RM, Gewirth DT and Chiosis G: Identification of potent water soluble purine-scaffold inhibitors of the heat shock protein 90. J Med Chem. 49:381–390. 2006.PubMed/NCBI View Article : Google Scholar
10	Llauger L, He H, Kim J, Aguirre J, Rosen N, Peters U, Davies P and Chiosis G: Evaluation of 8-arylsulfanyl, 8-arylsulfoxyl, and 8-arylsulfonyl adenine derivatives as inhibitors of the heat shock protein 90. J Med Chem. 48:2892–2905. 2005.PubMed/NCBI View Article : Google Scholar
11	Kasibhatla SR, Hong K, Biamonte MA, Busch DJ, Karjian PL, Sensintaffar JL, Kamal A, Lough RE, Brekken J, Lundgren K, et al: Rationally designed high-affinity 2-amino-6-halopurine heat shock protein 90 inhibitors that exhibit potent antitumor activity. J Med Chem. 50:2767–2778. 2007.PubMed/NCBI View Article : Google Scholar
12	Pearl LH: Review: The HSP90 molecular chaperone-an enigmatic ATPase. Biopolymers. 105:594–607. 2016.PubMed/NCBI View Article : Google Scholar
13	Prodromou C and Pearl LH: Structure and functional relationships of Hsp90. Curr Cancer Drug Targets. 3:301–323. 2003.PubMed/NCBI View Article : Google Scholar
14	Huang KH, Veal JM, Fadden RP, Rice JW, Eaves J, Strachan JP, Barabasz AF, Foley BE, Barta TE, Ma W, et al: Discovery of novel 2-aminobenzamide inhibitors of heat shock protein 90 as potent, selective and orally active antitumor agents. J Med Chem. 52:4288–4305. 2009.PubMed/NCBI View Article : Google Scholar
15	Barta TE, Veal JM, Rice JW, Partridge JM, Fadden RP, Ma W, Jenks M, Geng L, Hanson GJ, Huang KH, et al: Discovery of benzamide tetrahydro-4H-carbazol-4-ones as novel small molecule inhibitors of Hsp90. Bioorg Med Chem Lett. 18:3517–3521. 2008.PubMed/NCBI View Article : Google Scholar
16	Wang S, Wang X, Du Z, Liu Y, Huang D, Zheng K, Liu K, Zhang Y, Zhong X and Wang Y: SNX-25a, a novel Hsp90 inhibitor, inhibited human cancer growth more potently than 17-AAG. Biochem Biophys Res Commun. 450:73–80. 2014.PubMed/NCBI View Article : Google Scholar
17	Li F, Jin F and Wang Y, Zheng D, Liu J, Zhang Z, Wang R, Dong D, Zheng K and Wang Y: Hsp90 inhibitor AT-533 blocks HSV-1 nuclear egress and assembly. J Biochem. 164:397–406. 2018.PubMed/NCBI View Article : Google Scholar
18	Wang Y, Wang R, Li F and Wang Y, Zhang Z, Wang Q, Ren Z, Jin F, Kitazato K and Wang Y: Heat-shock protein 90α is involved in maintaining the stability of VP16 and VP16-mediated transactivation of α genes from herpes simplex virus-1. Mol Med. 24(65)2018.PubMed/NCBI View Article : Google Scholar
19	Xiang YF, Qian CW, Xing GW, Hao J, Xia M and Wang YF: Anti-herpes simplex virus efficacies of 2-aminobenzamide derivatives as novel HSP90 inhibitors. Bioorg Med Chem Lett. 22:4703–4706. 2012.PubMed/NCBI View Article : Google Scholar
20	Li F, Song X, Su G and Wang Y, Wang Z, Qing S, Jia J and Wang Y, Huang L, Zheng K and Wang Y: AT-533, a Hsp90 inhibitor, attenuates HSV-1-induced inflammation. Biochem Pharmacol. 166:82–92. 2019.PubMed/NCBI View Article : Google Scholar
21	Zhang X, Cheng Y, Zhou Q, Huang H, Dong Y, Yang Y, Zhao M and He Q: The effect of Chinese traditional medicine huaiqihuang (HQH) on the protection of nephropathy. Oxid Med Cell Longev. 2020(2153912)2020.PubMed/NCBI View Article : Google Scholar
22	SFDA: Technical guidelines of chronic toxicity for chemical drugs. SFDA Guidelines No. [H] GPT2-12005.
23	Chinese Pharmacopoeia Commission: Chinese pharmacopoeia. China Medical Science and Technology Press, Beijing, pp291-353, 2015.
24	Li CL, Shu XJ, Chen XQ, Liu YW, Yi HL and Ma BM: Determination and comparison of blood physiological and biochemical indicators in SPF SD rats of different ages and genders. J Jianghan Univ (Nat Sci Ed). 44:58–63. 2016.
25	Wang R, Wen XT, Wang H, Tang JL, Guan B and Zeng YL: Establishment of blood routine reference interval in SD rats. Med Equip. 28:11–15. 2015.
26	Wang LM, Wang YH, Han XF, Yang RH and Cao X: Determination and analysis of blood biochemical indicators in SD rats of different ages and genders. Heilongjiang Anim Sci Vet Med. 214-216:268–269. 2018.
27	He XY, Wang H, Tang JL, Guan B, Zeng YL and Shi JF: Preliminary establishment of normal interval of blood biochemical indicators in SD rats. Med Equip. 28:13–15. 2015.
28	Dong YS, Ying JY, Chen C, Zhai WS, Yuan BL, Gao XX, Ding RG and Wang HM: Establishment and application of the normal reference values of organ masses and organ/body coefficients in SD rats. Mil Med Sci. 36:351–353. 2012.
29	Liu YE, Yao BY, Yang DH and Wang J: Analysis on organ weights and their changes trend in Sprague Dawley rats with different ages. Chin J Comp Med. 22:22–27. 2012.
30	SFDA: Technical guidelines of acute toxicity testing for chemical drugs. SFDA Guidelines No. [H] GPT1-12005.
31	Bigoniya P, Sahu T and Tiwari V: Hematological and biochemical effects of sub-chronic artesunate exposure in rats. Toxicol Rep. 2:280–288. 2015.PubMed/NCBI View Article : Google Scholar
32	Tan YJ, Ren YS, Gao L, Li LF, Cui LJ, Li B, Li X, Yang J, Wang MZ, Lv YY, et al: 28-Day oral chronic toxicity study of arctigenin in rats. Front Pharmacol. 9(1077)2018.PubMed/NCBI View Article : Google Scholar
33	Yao Q, Sun R, Bao S, Chen R and Kou L: Bilirubin protects transplanted islets by targeting ferroptosis. Front Pharmacol. 11(907)2020.PubMed/NCBI View Article : Google Scholar
34	Maher PA: Using plants as a source of potential therapeutics for the treatment of Alzheimer's disease. Yale J Biol Med. 93:365–373. 2020.PubMed/NCBI
35	Charoonratana T, Puntarat J, Vinyoocharoenkul S, Sudsai T and Bunluepuech K: Innocuousness of a polyherbal formulation: A case study using a traditional Thai antihypertensive herbal recipe in rodents. Food Chem Toxicol. 112:458–465. 2018.PubMed/NCBI View Article : Google Scholar