PMID- 36999419 OWN - NLM STAT- MEDLINE DCOM- 20230522 LR - 20230604 IS - 1874-4702 (Electronic) IS - 1874-4672 (Linking) VI - 16 IP - 8 DP - 2023 TI - IDO2-siRNA Carried by Salmonella Combined with Nifuroxazide Attenuates Melanoma Growth. PG - 881-893 LID - 10.2174/1874467217666230329102030 [doi] AB - 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. CI - Copyright(c) Bentham Science Publishers; For any queries, please email at epub@benthamscience.net. FAU - Zhao, Tiesuo AU - Zhao T AD - Institute of Precision Medicine, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, 453007, China. AD - Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, Xinxiang 453003, China. AD - Department of Immunology, Xinxiang Medical University, Xinxiang 453003, China. FAU - Guo, Mengmeng AU - Guo M AD - Department of Pathology, Xinxiang Medical University, Xinxiang 453003, China. FAU - Chen, Haoqi AU - Chen H AD - Department of Immunology, Xinxiang Medical University, Xinxiang 453003, China. FAU - Zhou, Lin AU - Zhou L AD - Department of Pathology, Xinxiang Medical University, Xinxiang 453003, China. FAU - Guo, Jing AU - Guo J AD - Institute of Precision Medicine, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, 453007, China. FAU - Liu, Shenzhen AU - Liu S AD - Institute of Precision Medicine, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, 453007, China. FAU - Wang, Zizhong AU - Wang Z AD - Institute of Precision Medicine, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, 453007, China. FAU - Huang, Wenshuai AU - Huang W AD - Institute of Precision Medicine, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, 453007, China. FAU - Zhang, Qiang AU - Zhang Q AD - Institute of Precision Medicine, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, 453007, China. FAU - Zhong, Jiateng AU - Zhong J AD - Institute of Precision Medicine, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, 453007, China. AD - Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, Xinxiang 453003, China. AD - Department of Pathology, Xinxiang Medical University, Xinxiang 453003, China. FAU - Wang, Mingyong AU - Wang M AD - Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, Xinxiang Medical University, Xinxiang 453003, China. FAU - Jia, Huijie AU - Jia H AD - Institute of Precision Medicine, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, 453007, China. AD - Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, Xinxiang 453003, China. AD - Department of Pathology, Xinxiang Medical University, Xinxiang 453003, China. FAU - Zhang, Yongxi AU - Zhang Y AD - Institute of Precision Medicine, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, 453007, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United Arab Emirates TA - Curr Mol Pharmacol JT - Current molecular pharmacology JID - 101467997 RN - 0 (RNA, Small Interfering) RN - PM5LI0P38J (nifuroxazide) RN - 0 (Nitrofurans) RN - 0 (Hydroxybenzoates) SB - IM MH - Animals MH - Mice MH - Dogs MH - RNA, Small Interfering/genetics MH - *Melanoma/drug therapy MH - *Nitrofurans/pharmacology/therapeutic use MH - Hydroxybenzoates/pharmacology/therapeutic use MH - Cell Line, Tumor OTO - NOTNLM OT - IDO2 OT - Melanoma OT - Stat3 OT - nifuroxazide OT - siRNA OT - tumor immunity EDAT- 2023/04/01 06:00 MHDA- 2023/05/22 06:42 CRDT- 2023/03/31 05:03 PHST- 2022/07/21 00:00 [received] PHST- 2022/10/29 00:00 [revised] PHST- 2022/12/08 00:00 [accepted] PHST- 2023/05/22 06:42 [medline] PHST- 2023/04/01 06:00 [pubmed] PHST- 2023/03/31 05:03 [entrez] AID - CMP-EPUB-130442 [pii] AID - 10.2174/1874467217666230329102030 [doi] PST - ppublish SO - Curr Mol Pharmacol. 2023;16(8):881-893. doi: 10.2174/1874467217666230329102030.