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Current Molecular Pharmacology

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ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

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Research Article

IDO2-siRNA Carried by Salmonella Combined with Nifuroxazide Attenuates Melanoma Growth

Author(s): Tiesuo Zhao, Mengmeng Guo, Haoqi Chen, Lin Zhou, Jing Guo, Shenzhen Liu, Zizhong Wang, Wenshuai Huang, Qiang Zhang, Jiateng Zhong, Mingyong Wang*, Huijie Jia* and Yongxi Zhang

Volume 16, Issue 8, 2023

Published on: 31 March, 2023

Article ID: e290323215107 Pages: 13

DOI: 10.2174/1874467217666230329102030

Price: $65

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Abstract

Background: Melanoma, a highly malignant skin cancer, is a hot topic in oncology treatment research. Nowadays, tumor immunotherapy, especially immunotherapy combined with other therapies, has attracted more and more attention. Indoleamine 2,3-dioxygenase 2 (IDO2), a ratelimiting enzyme of the tryptophan metabolism pathway in the urine of dogs with immunosuppression, is highly expressed in melanoma tissue. Additionally, IDO2 significantly inhibits the anti-tumor immunity of the body and has become a novel target of melanoma treatment. Nifuroxazide, as an intestinal antibacterial agent, was found to be able to inhibit Stat3 expression and exert an anti-tumor effect. Therefore, the present study aimed to examine the therapeutic effect of a self-designed IDO2-small interfering RNA (siRNA) delivered by attenuated Salmonella combined with nifuroxazide on melanoma- bearing mice, as well as determine its underlying mechanism.

Methods: The effect of nifuroxazide on melanoma was detected by flow cytometry, CCK-8 and colony- forming ability assays, respectively, in vitro. The plasmid of siRNA-IDO2 was constructed, and the mice-bearing melanoma model was established. After the treatment, the tumor growth and survival rate were monitored, and the morphological changes of tumor tissue were detected by HE staining. The expression of related proteins was detected by Western blotting, and the expression of CD4 and CD8 positive T cells in tumor tissue was detected by IHC and IF, and the proportion of CD4 and CD8 positive T cells in spleen was detected by flow cytometry.

Results: The results demonstrated that the combination therapy effectively inhibited the phosphorylation of Stat3 and the expression level of IDO2 in melanoma cells, which effectively inhibited tumor growth and prolonged the survival time of tumor-bearing mice. The mechanistic study revealed that, compared with control groups and monotherapy groups, the combination treatment group reduced the atypia of tumor cells, increased the apoptotic rate, enhanced the infiltration of T lymphocytes in tumor tissue and increased the CD4+ and CD8+ T lymphocytes in the spleen, suggesting that the mechanism may be associated with the inhibition of tumor cell proliferation, the increase of apoptosis and the enhancement of the cellular immunity.

Conclusion: In conclusion, IDO2-siRNA combined with nifuroxazide therapy could serve a significant role in the treatment of melanoma-bearing mice, enhance the tumor immunity and provide an experimental basis for identifying a novel combination method for the treatment of melanoma clinically.

Graphical Abstract

[1]
Rajaonarison, L.A.; Razafindrasata, R.S. Multiple hemorragic brain lesions revealing metastatic melanoma. Pan Afr. Med. J., 2019, 33(78)
[2]
Tie, N.E.; Na, L.H.; Hicks, R.J.; Spillane, J.; Speakman, D.; Henderson, M.A.; Gyorki, D.E. The prognosis and natural history of in-transit melanoma metastases at a high-volume centre. Ann. Surg. Oncol., 2019, 26, 4673-4680.
[3]
Zhai, L.; Spranger, S.; Binder, D.C.; Gritsina, G.; Lauing, K.L.; Giles, F.J.; Wainwright, D.A. Molecular pathways: Targeting IDO1 and other tryptophan dioxygenases for cancer immunotherapy. Clin. Cancer Res., 2015, 21(24), 5427-5433.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-0420] [PMID: 26519060]
[4]
Yamamoto, S.; Hayaishi, O. Tryptophan pyrrolase of rabbit intestine. D- and L-tryptophan-cleaving enzyme or enzymes. J. Biol. Chem., 1967, 242(22), 5260-5266.
[http://dx.doi.org/10.1016/S0021-9258(18)99420-2] [PMID: 6065097]
[5]
Martinez-Marcos, P.; Carvajal-Serna, M.; Lazaro-Gaspar, S.; Perez-Pe, R.; Muino-Blanco, T.; Cebrian-Perez, J. A.; Casao, A. Presence of melatonin-catabolizing non-specific enzymes myeloperoxidase and indoleamine 2,3-dioxygenase in the ram reproductive tract. Reproduction in domestic animals = Zuchthygiene, 2019, 54(12), 1643-1650.
[6]
Duan, H.C.; Peng, L.X.; Hu, Y.C.; Luo, Q.; Liu, X.Y.; Sun, X.; Liang, L.; Gan, Y.; Liu, W.; Wan, H.; Shi, H.B.; Zhao, G.; Hu, J.P. The ad-vances of the structure and function of indoleamine 2, 3- dioxygenase 1 and its inhibitors. Curr. Protein Pept. Sci., 2020, 21(10), 1027-1039.
[http://dx.doi.org/10.2174/1389203721666200526122304] [PMID: 32452326]
[7]
Yang, D.; Zhang, S.; Fang, X.; Guo, L.; Hu, N.; Guo, Z.; Li, X.; Yang, S.; He, J.C.; Kuang, C.; Yang, Q. N -Benzyl/Aryl substituted tryptan-thrin as dual inhibitors of indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase. J. Med. Chem., 2019, 62(20), 9161-9174.
[http://dx.doi.org/10.1021/acs.jmedchem.9b01079] [PMID: 31580660]
[8]
Jia, H.; Ren, W.; Feng, Y.; Wei, T.; Guo, M.; Guo, J.; Zhao, J.; Song, X.; Wang, M.; Zhao, T.; Wang, H.; Feng, Z.; Tian, Z. The enhanced anti-tumour response of pimozide combined with the IDO inhibitor L MT in melanoma. Int. J. Oncol., 2018, 53(3), 949-960.
[http://dx.doi.org/10.3892/ijo.2018.4473] [PMID: 30015838]
[9]
Ball, H.J.; Yuasa, H.J.; Austin, C.J.D.; Weiser, S.; Hunt, N.H. Indoleamine 2,3-dioxygenase-2; a new enzyme in the kynurenine pathway. Int. J. Biochem. Cell Biol., 2009, 41(3), 467-471.
[http://dx.doi.org/10.1016/j.biocel.2008.01.005] [PMID: 18282734]
[10]
Metz, R.; Smith, C.; DuHadaway, J.B.; Chandler, P.; Baban, B.; Merlo, L.M.F.; Pigott, E.; Keough, M.P.; Rust, S.; Mellor, A.L.; Mandik-Nayak, L.; Muller, A.J.; Prendergast, G.C. Corrigendum: IDO2 is critical for IDO1-mediated T-cell regulation and exerts a non-redundant function in inflammation. Int. Immunol., 2019, 31(3), 181-182.
[http://dx.doi.org/10.1093/intimm/dxz003] [PMID: 31222337]
[11]
Pawelek, J.M.; Low, K.B.; Bermudes, D. Tumor-targeted Salmonella as a novel anticancer vector. Cancer Res., 1997, 57(20), 4537-4544.
[PMID: 9377566]
[12]
Zhao, T.; Wei, T.; Guo, J.; Wang, Y.; Shi, X.; Guo, S.; Jia, X.; Jia, H.; Feng, Z. PD-1-siRNA delivered by attenuated Salmonella enhances the antimelanoma effect of pimozide. Cell Death Dis., 2019, 10(3), 164.
[http://dx.doi.org/10.1038/s41419-019-1418-3] [PMID: 30778049]
[13]
Venancio, P.A.; Consolaro, M.E.L.; Derchain, S.F.; Boccardo, E.; Villa, L.L.; Maria-Engler, S.S.; Campa, A.; Discacciati, M.G. Indoleamine 2,3‐dioxygenase and tryptophan 2,3‐dioxygenase expression in HPV infection, SILs, and cervical cancer. Cancer Cytopathol., 2019, 127(9), 586-597.
[http://dx.doi.org/10.1002/cncy.22172] [PMID: 31412167]
[14]
Badie, F.; Ghandali, M.; Tabatabaei, S.A.; Safari, M.; Khorshidi, A.; Shayestehpour, M.; Mahjoubin-Tehran, M.; Morshedi, K.; Jalili, A.; Tajiknia, V.; Hamblin, M.R.; Mirzaei, H. Use of salmonella bacteria in cancer therapy: Direct, drug delivery and combination approaches. Front. Oncol., 2021, 11, 624759.
[15]
Jia, H.; Li, Y.; Zhao, T.; Li, X.; Hu, J.; Yin, D.; Guo, B.; Kopecko, D.J.; Zhao, X.; Zhang, L.; Xu, D.Q. Antitumor effects of Stat3-siRNA and endostatin combined therapies, delivered by attenuated Salmonella, on orthotopically implanted hepatocarcinoma. Cancer Immunol. Immunother., 2012, 61(11), 1977-1987.
[http://dx.doi.org/10.1007/s00262-012-1256-y] [PMID: 22527247]
[16]
Jia, X.; Guo, J.; Guo, S.; Zhao, T.; Liu, X.; Cheng, C.; Wang, L.; Zhang, B.; Meng, C.; Jia, H.; Luo, E. Antitumor effects and mechanisms of CpG ODN combined with attenuated Salmonella-delivered siRNAs against PD-1. Int. Immunopharmacol., 2021, 90, 107052.
[http://dx.doi.org/10.1016/j.intimp.2020.107052]
[17]
Hillmer, E.J.; Zhang, H.; Li, H.S.; Watowich, S.S. STAT3 signaling in immunity. Cytokine Growth Factor Rev., 2016, 31, 1-15.
[http://dx.doi.org/10.1016/j.cytogfr.2016.05.001]
[18]
Hu, Y.S.; Han, X.; Liu, X.H. STAT3: A potential drug target for tumor and inflammation. Curr. Top. Med. Chem., 2019, 19(15), 1305-1317.
[http://dx.doi.org/10.2174/1568026619666190620145052] [PMID: 31218960]
[19]
Lee, H.; Jeong, A.J.; Ye, S.K. Highlighted STAT3 as a potential drug target for cancer therapy. BMB Rep., 2019, 52(7), 415-423.
[http://dx.doi.org/10.5483/BMBRep.2019.52.7.152] [PMID: 31186087]
[20]
Li, F.; Sun, Y.; Huang, J.; Xu, W.; Liu, J.; Yuan, Z. CD4/CD8 + T cells, DC subsets, Foxp3, and IDO expression are predictive indictors of gastric cancer prognosis. Cancer Med., 2019, 8(17), 7330-7344.
[http://dx.doi.org/10.1002/cam4.2596] [PMID: 31631566]
[21]
Jia, H.; Cui, J.; Jia, X.; Zhao, J.; Feng, Y.; Zhao, P.; Zang, D.; Yu, J.; Zhao, T.; Wang, H.; Xu, K. Therapeutic effects of STAT3 inhibition by nifuroxazide on murine acute graft graft-vs.-host disease: Old drug, new use. Mol. Med. Rep., 2017, 16(6), 9480-9486.
[http://dx.doi.org/10.3892/mmr.2017.7825] [PMID: 29152660]
[22]
Nelson, E.A.; Walker, S.R.; Kepich, A.; Gashin, L.B.; Hideshima, T.; Ikeda, H.; Chauhan, D.; Anderson, K.C.; Frank, D.A. Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3. Blood, 2008, 112(13), 5095-5102.
[http://dx.doi.org/10.1182/blood-2007-12-129718] [PMID: 18824601]
[23]
Zhao, T.; Feng, Y.; Guo, M.; Zhang, C.; Wu, Q.; Chen, J.; Guo, S.; Liu, S.; Zhou, Q.; Wang, Z.; Fan, W.; Zhang, Y.; Jia, H.; Feng, Z. Combina-tion of attenuated Salmonella carrying PD‐1 siRNA with nifuroxazide for colon cancer therapy. J. Cell. Biochem., 2020, 121(2), 1973-1985.
[http://dx.doi.org/10.1002/jcb.29432] [PMID: 31692041]
[24]
Zhao, T.; Jia, H.; Cheng, Q.; Xiao, Y.; Li, M.; Ren, W.; Li, C.; Feng, Y.; Feng, Z.; Wang, H.; Zheng, J. Nifuroxazide prompts antitumor im-mune response of TCL-loaded DC in mice with orthotopically-implanted hepatocarcinoma. Oncol. Rep., 2017, 37(6), 3405-3414.
[http://dx.doi.org/10.3892/or.2017.5629] [PMID: 28498414]
[25]
Jia, H.; Zhao, T.; Ji, Y.; Jia, X.; Ren, W.; Li, C.; Li, M.; Xiao, Y.; Wang, H.; Xu, K. Combined nifuroxazide and SAT05f therapy reduces graft-versus-host disease after experimental allogeneic bone marrow transplantation. Cell Death Dis., 2016, 7(12), e2507.
[http://dx.doi.org/10.1038/cddis.2016.399] [PMID: 27906171]
[26]
Zhang, L.; Gao, L.; Zhao, L.; Guo, B.; Ji, K.; Tian, Y.; Wang, J.; Yu, H.; Hu, J.; Kalvakolanu, D.V.; Kopecko, D.J.; Zhao, X.; Xu, D.Q. Intra-tumoral delivery and suppression of prostate tumor growth by attenuated Salmonella enterica serovar typhimurium carrying plasmid-based small interfering RNAs. Cancer Res., 2007, 67(12), 5859-5864.
[http://dx.doi.org/10.1158/0008-5472.CAN-07-0098] [PMID: 17575154]
[27]
Yamasuge, W.; Yamamoto, Y.; Fujigaki, H.; Hoshi, M.; Nakamoto, K.; Kunisawa, K.; Mouri, A.; Nabeshima, T.; Saito, K. Indoleamine 2,3‐dioxygenase 2 depletion suppresses tumor growth in a mouse model of Lewis lung carcinoma. Cancer Sci., 2019, 110(10), 3061-3067.
[http://dx.doi.org/10.1111/cas.14179] [PMID: 31444833]
[28]
Kearns, A.C.; Velasquez, S.; Liu, F.; Dai, S.; Chen, Y.; Lehmicke, G.; Gordon, J.; Rappaport, J.; Qin, X. Elevated indoleamine-2,3-dioxygenase enzyme activity in a novel mouse model of HIV-associated atherosclerosis. AIDS, 2019, 33(10), 1557-1564.
[http://dx.doi.org/10.1097/QAD.0000000000002255] [PMID: 31306164]
[29]
Winters, M.; DuHadaway, J.B.; Pham, K.N.; Lewis-Ballester, A.; Badir, S.; Wai, J.; Sheikh, E.; Yeh, S.R.; Prendergast, G.C.; Muller, A.J.; Malachowski, W.P. Diaryl hydroxylamines as pan or dual inhibitors of indoleamine 2,3-dioxygenase-1, indoleamine 2,3-dioxygenase-2 and tryptophan dioxygenase. Eur. J. Med. Chem., 2019, 162, 455-464.
[30]
Yang, F.; Hu, M.; Lei, Q.; Xia, Y.; Zhu, Y.; Song, X.; Li, Y.; Jie, H.; Liu, C.; Xiong, Y.; Zuo, Z.; Zeng, A.; Li, Y.; Yu, L.; Shen, G.; Wang, D.; Xie, Y.; Ye, T.; Wei, Y. Nifuroxazide induces apoptosis and impairs pulmonary metastasis in breast cancer model. Cell Death Dis., 2015, 6, e1701.
[http://dx.doi.org/10.1038/cddis.2015.63]
[31]
Pizzini, A.; Kurz, K.; Santifaller, J.; Tschurtschenthaler, C.; Theurl, I.; Fuchs, D.; Weiss, G.; Bellmann-Weiler, R. Assessment of neopterin and indoleamine 2,3‐dioxygenase activity in patients with seasonal influenza: A pilot study. Influenza Other Respir. Viruses, 2019, 13(6), 603-609.
[http://dx.doi.org/10.1111/irv.12677] [PMID: 31489989]
[32]
Yamamoto, Y.; Yamasuge, W.; Imai, S.; Kunisawa, K.; Hoshi, M.; Fujigaki, H.; Mouri, A.; Nabeshima, T.; Saito, K. Lipopolysaccharide shock reveals the immune function of indoleamine 2,3-dioxygenase 2 through the regulation of IL-6/stat3 signalling. Sci. Rep., 2018, 8(1), 15917.
[http://dx.doi.org/10.1038/s41598-018-34166-4] [PMID: 30374077]
[33]
Liu, Y.; Liu, H.; Xiang, Y.; Chen, X.; Xu, P.; Min, W. Knockdown of indoleamine 2, 3-dioxygenase 2 (IDO2)gene inhibits tumor growth and enhances immune function in mice bearing melanoma. Chinese J. Cell. Mol. Immunol., 2017, 33(12), 1605-1609.
[34]
Ebokaiwe, A.P.; Njoya, E.M.; Sheng, Y.; Zhang, Z.; Li, S.; Zhou, Z.; Qiang, Z.; Peng, T.; Hussein, A.A.; Zhang, G.; Lu, X.; Li, L.; Wang, F. Salinomycin promotes T-cell proliferation by inhibiting the expression and enzymatic activity of immunosuppressive indoleamine-2,3-dioxygenase in human breast cancer cells. Toxicol. Appl. Pharmacol., 2020, 404, 115203.

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