Potential Mechanism of Thioridazine in Anti-cervical Cancer

Qin XIE; Chunyang ZHAO; Baosu ZHANG; Hongbo ZHAO

doi:10.12259/j.issn.2095-610X.S20220317

Volume 43 Issue 3

Mar. 2022

Turn off MathJax

Article Contents

Article Navigation > Journal of Kunming Medical University > 2022 > 43(3): 13-20

Qin XIE, Chunyang ZHAO, Baosu ZHANG, Hongbo ZHAO. Potential Mechanism of Thioridazine in Anti-cervical Cancer[J]. Journal of Kunming Medical University, 2022, 43(3): 13-20. doi: 10.12259/j.issn.2095-610X.S20220317

Citation:

Qin XIE, Chunyang ZHAO, Baosu ZHANG, Hongbo ZHAO. Potential Mechanism of Thioridazine in Anti-cervical Cancer[J]. Journal of Kunming Medical University, 2022, 43(3): 13-20. doi: 10.12259/j.issn.2095-610X.S20220317

Citation:

PDF( 871 KB)

Potential Mechanism of Thioridazine in Anti-cervical Cancer

doi: 10.12259/j.issn.2095-610X.S20220317

Institute of Biomedical Engineering & Yunnan Key Laboratory of Stem Cell and Regenerative Medicine，Kunming Medical University，Kunming Yunnan 650500，China

Received Date: 2022-02-01
Available Online: 2022-02-18
Publish Date: 2022-03-22

Abstract

Abstract

Objective To explore the potential mechanism of thioridazine in the treatment of cervical cancer by bioinformatics analysis. Methods The target genes that can interact with thioridazine was predicted by PharmMapper, and then conducted pathway and tissue expression enrichment analysis by STRING online tool. The cervical cancer related genes were screened through GeneCards and DisGeNET databases, and cross the target genes of thioridazine to obtain the interaction genes that thioridazine may act on cervical cancer. The protein-protein interaction（PPI） network was constructed using STRING, and the core targets were speculated and evaluated their importance．The GO and KEGG enrichment analysis were conducted using clusterProfiler package. Results A total of 47 target genes were predicted by PharmMapper, which were enriched in tumor-related pathways and cervical cancer cells. Intersection with 669 cervical cancer genes, 21 common genes were obtained, of which 10 key genes were EGFR, PPARG, AR, NOS3, ALB, ESR1, MAPK1, MAPK14, ANXA5 and MAPK8. These key genes were important in the cervical cancer PPI network. The biological processes involved in interactive genes mainly include positive regulation of anion transport, peptidyl-serine phosphorylation, steroid metabolic process, blood coagulation, and cellular response to chemical stress. Enriched KEGG pathways include pathways in cancer, relaxin signaling pathway, endocrine resistance, proteoglycans in cancer, cellular senescence, GnRH signaling pathway, and VEGF signaling pathway. Conclusion Thioridazine has potential anti-tumor effects and may play a role in the treatment of cervical cancer through multiple targets and multiple signaling pathways.
- Thioridazine,
- Cervical cancer,
- Target,
- Action mechanism

FullText(HTML)

References(37)

References

[1]	Sung H,Ferlay J,Siegel R L,et al. Global cancer statistics 2020:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin,2021,71(3):209-249. doi: 10.3322/caac.21660
[2]	de Foucher T,Bendifallah S,Ouldamer L,et al. Patterns of recurrence and prognosis in locally advanced FIGO stage IB2 to IIB cervical cancer:Retrospective multicentre study from the FRANCOGYN group[J]. Eur J Surg Oncol,2019,45(4):659-665. doi: 10.1016/j.ejso.2018.11.014
[3]	Fenton M,Rathbone J,Reilly J,et al. Thioridazine for schizophrenia[J]. Cochrane Database Syst Rev,2007,2007(3):CD001944.
[4]	Duarte D,Cardoso A,Vale N. Synergistic growth inhibition of HT-29 colon and MCF-7 breast cancer cells with simultaneous and sequential combinations of antineoplastics and CNS drugs[J]. Int J Mol Sci,2021,22(14):7408. doi: 10.3390/ijms22147408
[5]	Tegowski M,Fan C,Baldwin A S. Selective effects of thioridazine on self-renewal of basal-like breast cancer cells[J]. Sci Rep,2019,9(1):18695. doi: 10.1038/s41598-019-55145-3
[6]	Mu J,Xu H,Yang Y,et al. Thioridazine,an antipsychotic drug,elicits potent antitumor effects in gastric cancer[J]. Oncol Rep,2014,31(5):2107-2114. doi: 10.3892/or.2014.3068
[7]	Lu M,Li J,Luo Z,et al. Roles of dopamine receptors and their antagonist thioridazine in hepatoma metastasis[J]. Onco Targets Ther,2015,8(default):1543-1552.
[8]	Cheng H W,Liang Y H,Kuo Y L,et al. Identification of thioridazine,an antipsychotic drug,as an antiglioblastoma and anticancer stem cell agent using public gene expression data[J]. Cell Death Dis,2015,6(5):e1753. doi: 10.1038/cddis.2015.77
[9]	Hercbergs A. Thioridazine:a radiation enhancer in advanced cervical cancer?[J]. Lancet,1988,2(8613):737.
[10]	Mao M,Yu T,Hu J,et al. Dopamine D2 receptor blocker thioridazine induces cell death in human uterine cervical carcinoma cell line SiHa[J]. J Obstet Gynaecol Res,2015,41(8):1240-1245. doi: 10.1111/jog.12691
[11]	Wang X,Shen Y,Wang S,et al. PharmMapper 2017 update:a web server for potential drug target identification with a comprehensive target pharmacophore database[J]. Nucleic Acids Res,2017,45(W1):W356-W360. doi: 10.1093/nar/gkx374
[12]	Szklarczyk D,Gable A L,Lyon D,et al. STRING v11:protein-protein association networks with increased coverage,supporting functional discovery in genome-wide experimental datasets[J]. Nucleic Acids Res,2019,47(D1):D607-D613. doi: 10.1093/nar/gky1131
[13]	Stelzer G,Rosen N,Plaschkes I,et al. The gene cards suite:From gene data mining to disease genome sequence analyses[J]. Curr Protoc Bioinformatics,2016,54:1.30.1-1.30.33.
[14]	Piñero J,Ramírez-Anguita J M,Saüch-Pitarch J,et al. The DisGeNET knowledge platform for disease genomics:2019 update[J]. Nucleic Acids Res,2020,48(D1):D845-D855.
[15]	Chin C H,Chen S H,Wu H H,et al. cytoHubba:identifying hub objects and sub-networks from complex interactome[J]. BMC Syst Biol,2014,8(Suppl 4):S11.
[16]	Wu T,Hu E,Xu S,et al. clusterProfiler 4.0:A universal enrichment tool for interpreting omics data[J]. Innovation (N Y),2021,2(3):100141.
[17]	Hartman Z,Geldenhuys W J,Agazie Y M. A specific amino acid context in EGFR and HER2 phosphorylation sites enables selective binding to the active site of Src homology phosphatase 2 (SHP2)[J]. J Biol Chem,2020,295(11):3563-3575. doi: 10.1074/jbc.RA119.011422
[18]	Peng Z,Wang Q,Zhang Y,et al. EBP50 interacts with EGFR and regulates EGFR signaling to affect the prognosis of cervical cancer patients[J]. Int J Oncol,2016,49(4):1737-1745. doi: 10.3892/ijo.2016.3655
[19]	Ding L and Zhang H. Circ-ATP8A2 promotes cell proliferation and invasion as a ceRNA to target EGFR by sponging miR-433 in cervical cancer[J]. Gene,2019,705:103-108. doi: 10.1016/j.gene.2019.04.068
[20]	Mustafa H A,Albkrye A M S,AbdAlla B M,et al. Computational determination of human PPARG gene:SNPs and prediction of their effect on protein functions of diabetic patients[J]. Clin Transl Med,2020,9(1):7.
[21]	Wuertz B R,Darrah L,Wudel J,et al. Thiazolidinediones abrogate cervical cancer growth[J]. Exp Cell Res,2017,353(2):63-71. doi: 10.1016/j.yexcr.2017.02.020
[22]	Noël J C,Bucella D,Fayt I,et al. Androgen receptor expression in cervical intraepithelial neoplasia and invasive squamous cell carcinoma of the cervix[J]. Int J Gynecol Pathol,2008,27(3):437-441. doi: 10.1097/PGP.0b013e318160c599
[23]	Vannini F,Kashfi K,Nath N. The dual role of iNOS in cancer[J]. Redox Biol,2015,6:334-343. doi: 10.1016/j.redox.2015.08.009
[24]	Topchieva L V,Balan O V,Korneva V A,et al. The nitric oxide metabolite level and NOS2 and NOS3 gene transcripts in patients with essential arterial hypertension[J]. Biology Bulletin,2020,47(3):247-252. doi: 10.1134/S1062359020010161
[25]	Gray S,Axelsson B. The prevalence of deranged C-reactive protein and albumin in patients with incurable cancer approaching death[J]. PLoS One,2018,13(3):e0193693. doi: 10.1371/journal.pone.0193693
[26]	Hoogenboezem E N,Duvall C L. Harnessing albumin as a carrier for cancer therapies[J]. Adv Drug Deliv Rev,2018,130:73-89. doi: 10.1016/j.addr.2018.07.011
[27]	Chung S H,Wiedmeyer K,Shai A,et al. Requirement for estrogen receptor alpha in a mouse model for human papillomavirus-associated cervical cancer[J]. Cancer Res,2008,68(23):9928-9934. doi: 10.1158/0008-5472.CAN-08-2051
[28]	Yu P,Wang Y,Li C,et al. Protective effects of downregulating estrogen receptor alpha expression in cervical cancer[J]. Anticancer Agents Med Chem,2018,18(14):1975-1982.
[29]	Chen Y,Gu Y,Gu Y,et al. Long noncoding RNA LINC00899/miR-944/ESR1 axis regulates cervical cancer cell proliferation,migration,and invasion[J]. J Interferon Cytokine Res,2021,41(6):220-233. doi: 10.1089/jir.2021.0023
[30]	Xiao M,Feng Y,Cao G,et al. A novel MtHSP70-FPR1 fusion protein enhances cytotoxic T lymphocyte responses to cervical cancer cells by activating human monocyte-derived dendritic cells via the p38 MAPK signaling pathway[J]. Biochem Biophys Res Commun,2018,503(3):2108-2116. doi: 10.1016/j.bbrc.2018.07.167
[31]	Li X,Chen L,Liang X J,et al. Annexin A5 protein expression is associated with the histological differentiation of uterine cervical squamous cell carcinoma in patients with an increased serum concentration[J]. Mol Med Rep,2012,6(6):1249-1254. doi: 10.3892/mmr.2012.1078
[32]	Li X,Ma W,Wang X,et al. Annexin A5 overexpression might suppress proliferation and metastasis of human uterine cervical carcinoma cells[J]. Cancer Biomark,2018,23(1):23-32. doi: 10.3233/CBM-171040
[33]	Youn M J,So H S,Cho H J,et al. Berberine,a natural product,combined with cisplatin enhanced apoptosis through a mitochondria/caspase-mediated pathway in HeLa cells[J]. Biol Pharm Bull,2008,31(5):789-795. doi: 10.1248/bpb.31.789
[34]	Ng H H,Shen M,Samuel C S,et al. Relaxin and extracellular matrix remodeling:Mechanisms and signaling pathways[J]. Mol Cell Endocrinol,2019,487:59-65. doi: 10.1016/j.mce.2019.01.015
[35]	Claesson-Welsh L,Welsh M. VEGFA and tumour angiogenesis[J]. J Intern Med,2013,273(2):114-127. doi: 10.1111/joim.12019
[36]	Chuai Y,Rizzuto I,Zhang X,et al. Vascular endothelial growth factor (VEGF) targeting therapy for persistent,recurrent,or metastatic cervical cancer[J]. Cochrane Database Syst Rev,2021,2021(3):CD013348.
[37]	Li J,Yao Q Y,Xue J S,et al. Dopamine D2 receptor antagonist sulpiride enhances dexamethasone responses in the treatment of drug-resistant and metastatic breast cancer[J]. Acta Pharmacol Sin,2017,38(9):1282-1296. doi: 10.1038/aps.2017.24

Relative Articles(20)

Relative Articles

[1]	Yiran YAN, Chengwan SHEN, Xiangyu SHANG, Chan FENG, Jinqiu LI, Hasim AXIANGU. Galangin Inhibits the Migration and Invasion of Cervical Cancer Hela Cells Through Hippo/YAP Pathway. Journal of Kunming Medical University, 2024, 46(): 1-7.
[2]	Liyan MENG, Chaoqun WANG, Xinghui CHEN, Junjing HE, Yaru NIU, Lisha MA. Risk Factors of Persistent HPV Infection in Patients with Early Cervical Cancer after Operation. Journal of Kunming Medical University, 2024, 45(4): 152-156. doi: 10.12259/j.issn.2095-610X.S20240422
[3]	Mei YANG, Ping WANG, Hui YANG, Gonghao HE. Potential Therapeutic Targets and Research Progress of Related Drugs of Heart Failure. Journal of Kunming Medical University, 2023, 44(7): 156-161. doi: 10.12259/j.issn.2095-610X.S20230719
[4]	Qian LIU, Tuerxun HATILA, Hasimu AXIANGU. HLA-G Enhances the Killing Effect of NK Cells on Cervical Cancer Cells by Promoting the Expression of Activated Receptor. Journal of Kunming Medical University, 2022, 43(7): 46-54. doi: 10.12259/j.issn.2095-610X.S20220714
[5]	Yue XU, Chan WANG, Shucheng LIN, Huijie ZHANG, Yi TAN, Shuwei ZHANG, Xiaofeng ZENG, Zhen LI. Advances in the Mechanism of Hepatotoxic Effects Induced by α-amanitin. Journal of Kunming Medical University, 2022, 43(12): 153-158. doi: 10.12259/j.issn.2095-610X.S20221228
[6]	Yang LIU, Jing LIAO, You-hui LU, Chun-yi SUN, Yu-shi MENG. Negative Regulation of hTERT Expression in Cervical Cancer Hela Cell Line by miR-21. Journal of Kunming Medical University, 2021, 42(3): 23-28. doi: 10.12259/j.issn.2095-610X.S20210307
[7]	Juan ZHANG, Hong-yun ZHANG. The Value of Endocervical Curettage in Cervical Cancer Screening. Journal of Kunming Medical University, 2021, 42(8): 123-127. doi: 10.12259/j.issn.2095-610X.S20210822
[8]	Ding-ji TAN, Hong-li YIN, Rui ZHU, Xi ZHANG, Xin YU, Yong FEI, Xin LI, Ming DUAN, Liang HE, Hong-ying YANG. Analysis of Vaginal Microecological in Women with Cervical Intraepithelial Neoplasia and Cervical Cancer. Journal of Kunming Medical University, 2021, 42(8): 118-122. doi: 10.12259/j.issn.2095-610X.S20210821
[9]	Li-jun HAO, Li-xiu XU, Jin-qiu LI, Jun-qi MA, Hasimu AXIANGU. The Effect of Peptide-prolinyl Isomerase（Pin1）on Lipid Metabolism in Cervical Cancer Cells. Journal of Kunming Medical University, 2021, 42(1): 12-16. doi: 10.12259/j.issn.2095-610X.S20210111
[10]	Qing Qing , Liu Yang , Zhou Hong Lin . . Journal of Kunming Medical University, 2020, 41(06): 162-166.
[11]	Zhou Xu Ru , Wang Xi , Tian Jie , Xie Ling Ling , Xu Hong Yu , Li Xiao Lan . . Journal of Kunming Medical University, 2019, 40(01): 87-91.
[12]	Li Zheng Jin . Application of 13 High-risk HPV infection Test Combined with Thinprep Cytologic Test on Screening Cervical Carcinoma in Dali Region， Yunnan Province. Journal of Kunming Medical University,
[13]	Zhu Sheng Zhang . Clinical Analysis of Liquid-based Cervical Cytology Examination in Cervical Cancer Screening in the South of GuiZhou. Journal of Kunming Medical University,
[14]	Zhang Zu Xian . . Journal of Kunming Medical University,
[15]	Lian Yang Yang . . Journal of Kunming Medical University,
[16]	He Hong Fen . . Journal of Kunming Medical University,
[17]	Xiao Xiao . . Journal of Kunming Medical University,
[18]	Wei Jie . . Journal of Kunming Medical University,
[19]	Liu Hui Jin . . Journal of Kunming Medical University,
[20]	Huang Ya . . Journal of Kunming Medical University,