Affiliation:
1. Institute of Precision Medicine, Xinxiang Medical University, 601 Jinsui Road, Xinxiang, 453007, China
2. Xinxiang Key
Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, Xinxiang 453003, China
3. Department of
Immunology, Xinxiang Medical University, Xinxiang 453003, China
4. Department of Pathology, Xinxiang Medical University,
Xinxiang 453003, China
5. Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, Xinxiang Medical
University, Xinxiang 453003, China
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.
Funder
Doctor Launch Fund of Xinxiang Medical University
Key Projects of Scientific Research for Higher Education of Henan Province
Young Backbone Teacher Training Projects of Universities in Henan province
Innovation and Entrepreneurship Training Programmed for a college student
Program for Innovative Research Team (in Science and Technology) in University of Henan Province
Science and Technology Research Project of Xinxiang City
Publisher
Bentham Science Publishers Ltd.
Subject
General Health Professions