Deciphering the Mechanism of Indirubin and Its Derivatives in the Inhibition of Imatinib Resistance Using a "drug Target Prediction-gene Microarray Analysis-protein Network Construction" Strategy

Overview

Journal BMC Complement Altern Med

Publisher Biomed Central

Specialty Rehabilitation Medicine

Date 2019 Mar 27

PMID 30909944

Citations 4

Authors

Huayao Li

Lijuan Liu

Jing Zhuang

Cun Liu

Chao Zhou

Jing Yang

Chundi Gao

Gongxi Liu

Changgang Sun

Affiliations

Soon will be listed here.

Abstract

Background: The introduction of imatinib revolutionized the treatment of chronic myeloid leukaemia (CML), substantially extending patient survival. However, imatinib resistance is currently a clinical problem for CML. It is very importantto find a strategy to inhibit imatinib resistance.

Methods: (1) We Identified indirubin and its derivatives and predicted its putative targets; (2) We downloaded data of the gene chip GSE2810 from the Gene Expression Omnibus (GEO) database and performed GEO2R analysis to obtain differentially expressed genes (DEGs); and (3) we constructed a P-P network of putative targets and DEGs to explore the mechanisms of action and to verify the results of molecular docking.

Result: We Identified a total of 42 small-molecule compounds, of which 15 affected 11 putative targets, indicating the potential to inhibit imatinib resistance; the results of molecular docking verified these results. Six biomarkers of imatinib resistance were characterised by analysing DEGs.

Conclusion: The 15 small molecule compounds inhibited imatinib resistance through the cytokine-cytokine receptor signalling pathway, the JAK-stat pathway, and the NF-KB signalling pathway. Indirubin and its derivatives may be new drugsthat can combat imatinib resistance.

Citing Articles

A Thia-Analogous Indirubin -Glycoside Disrupts Mitochondrial Function and Causes the Death of Human Melanoma and Cutaneous Squamous Cell Carcinoma Cells.

Wendt F, Wittig F, Rupprecht A, Ramer R, Langer P, Emmert S Cells. 2023; 12(19).

PMID: 37830623 PMC: 10572502. DOI: 10.3390/cells12192409.

Assessing the Anti-inflammatory Effects of Bacopa-Derived Bioactive Compounds Using Network Pharmacology and Studies.

Jeyasri R, Muthuramalingam P, Adarshan S, Shin H, Ramesh M ACS Omega. 2022; 7(44):40344-40354.

PMID: 36385888 PMC: 9647831. DOI: 10.1021/acsomega.2c05318.

Artificial intelligence in cancer target identification and drug discovery.

You Y, Lai X, Pan Y, Zheng H, Vera J, Liu S Signal Transduct Target Ther. 2022; 7(1):156.

PMID: 35538061 PMC: 9090746. DOI: 10.1038/s41392-022-00994-0.

Cryptotanshinone Is a Intervention for ER-Positive Breast Cancer: An Integrated Approach to the Study of Natural Product Intervention Mechanisms.

Li H, Gao C, Liang Q, Liu C, Liu L, Zhuang J Front Pharmacol. 2021; 11:592109.

PMID: 33505309 PMC: 7832090. DOI: 10.3389/fphar.2020.592109.

References

Kanehisa M, Goto S . KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 1999; 28(1):27-30. PMC: 102409. DOI: 10.1093/nar/28.1.27. View

Lu Y, Jamieson L, Brasier A, Fields A . NF-kappaB/RelA transactivation is required for atypical protein kinase C iota-mediated cell survival. Oncogene. 2001; 20(35):4777-92. DOI: 10.1038/sj.onc.1204607. View

Hilger R, Scheulen M, Strumberg D . The Ras-Raf-MEK-ERK pathway in the treatment of cancer. Onkologie. 2003; 25(6):511-8. DOI: 10.1159/000068621. View

Kirchner D, Duyster J, Ottmann O, Schmid R, Bergmann L, Munzert G . Mechanisms of Bcr-Abl-mediated NF-kappaB/Rel activation. Exp Hematol. 2003; 31(6):504-11. DOI: 10.1016/s0301-472x(03)00069-9. View

Shannon P, Markiel A, Ozier O, Baliga N, Wang J, Ramage D . Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003; 13(11):2498-504. PMC: 403769. DOI: 10.1101/gr.1239303. View

Burridge K, Wennerberg K . Rho and Rac take center stage. Cell. 2004; 116(2):167-79. DOI: 10.1016/s0092-8674(04)00003-0. View

Freije W, Castro-Vargas F, Fang Z, Horvath S, Cloughesy T, Liau L . Gene expression profiling of gliomas strongly predicts survival. Cancer Res. 2004; 64(18):6503-10. DOI: 10.1158/0008-5472.CAN-04-0452. View

Wuchty S, Almaas E . Evolutionary cores of domain co-occurrence networks. BMC Evol Biol. 2005; 5:24. PMC: 1079808. DOI: 10.1186/1471-2148-5-24. View

Zhu K, Fukasawa I, Furuno M, Inaba F, Yamazaki T, Kamemori T . Inhibitory effects of herbal drugs on the growth of human ovarian cancer cell lines through the induction of apoptosis. Gynecol Oncol. 2005; 97(2):405-9. DOI: 10.1016/j.ygyno.2004.12.063. View

10.

. The Gene Ontology (GO) project in 2006. Nucleic Acids Res. 2005; 34(Database issue):D322-6. PMC: 1347384. DOI: 10.1093/nar/gkj021. View

11.

Amikam D, Leshanski L, Sagi M . A novel MLH1 mutation harbored as a germ line aberration by a young woman of an HNPCC-like family and exhibited by a CML patient when occurring prior to the initiation of the blast phase concomitant with a c-MYC amplification. Int J Mol Med. 2006; 17(6):1023-6. View

12.

Nunoda K, Tauchi T, Takaku T, Okabe S, Akahane D, Sashida G . Identification and functional signature of genes regulated by structurally different ABL kinase inhibitors. Oncogene. 2007; 26(28):4179-88. DOI: 10.1038/sj.onc.1210179. View

13.

Constantinescu S, Girardot M, Pecquet C . Mining for JAK-STAT mutations in cancer. Trends Biochem Sci. 2008; 33(3):122-31. DOI: 10.1016/j.tibs.2007.12.002. View

14.

Eck M, Manley P . The interplay of structural information and functional studies in kinase drug design: insights from BCR-Abl. Curr Opin Cell Biol. 2009; 21(2):288-95. DOI: 10.1016/j.ceb.2009.01.014. View

15.

Tanaka R, Squires M, Kimura S, Yokota A, Nagao R, Yamauchi T . Activity of the multitargeted kinase inhibitor, AT9283, in imatinib-resistant BCR-ABL-positive leukemic cells. Blood. 2010; 116(12):2089-95. DOI: 10.1182/blood-2009-03-211466. View

16.

Bratton M, Duong B, Elliott S, Weldon C, Beckman B, McLachlan J . Regulation of ERalpha-mediated transcription of Bcl-2 by PI3K-AKT crosstalk: implications for breast cancer cell survival. Int J Oncol. 2010; 37(3):541-50. PMC: 3613138. DOI: 10.3892/ijo_00000703. View

17.

Tao K, Li Y, Wang D, Qi J, Deng Y, Wang H . Enhancement of specific cellular immune response induced by glycosyl-phosphatidylinositol-anchored BCR/ABL and mIL-12. Cancer Biol Ther. 2011; 12(10):881-7. PMC: 3280903. DOI: 10.4161/cbt.12.10.17674. View

18.

Nam S, Scuto A, Yang F, Chen W, Park S, Yoo H . Indirubin derivatives induce apoptosis of chronic myelogenous leukemia cells involving inhibition of Stat5 signaling. Mol Oncol. 2012; 6(3):276-83. PMC: 3361532. DOI: 10.1016/j.molonc.2012.02.002. View

19.

Wang Y, Liu Z, Li C, Li D, Ouyang Y, Yu J . Drug target prediction based on the herbs components: the study on the multitargets pharmacological mechanism of qishenkeli acting on the coronary heart disease. Evid Based Complement Alternat Med. 2012; 2012:698531. PMC: 3310183. DOI: 10.1155/2012/698531. View

20.

Kim W, Lee M, Kim D, Lee J, Kim J, Kim Y . 5'-OH-5-nitro-Indirubin oxime (AGM130), an Indirubin derivative, induces apoptosis of Imatinib-resistant chronic myeloid leukemia cells. Leuk Res. 2013; 37(4):427-33. DOI: 10.1016/j.leukres.2012.12.017. View