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Anti-Cancer Agents in Medicinal Chemistry

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ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

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Research Article

Indirubin, an Active Component of Indigo Naturalis, Exhibits Inhibitory Effects on Leukemia Cells via Targeting HSP90AA1 and PI3K/Akt Pathway

Author(s): Yuanzhi Yao, Xiaoying Li, Xiaoqin Yang, Hai Mou and Lin Wei*

Volume 24, Issue 9, 2024

Published on: 12 February, 2024

Page: [718 - 727] Pages: 10

DOI: 10.2174/0118715206258293231017063340

Price: $65

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Abstract

Background: This research intended to predict the active ingredients and key target genes of Indigo Naturalis in treating human chronic myeloid leukemia (CML) using network pharmacology and conduct the invitro verification.

Methods: The active components of Indigo Naturalis and the corresponding targets and leukemia-associated genes were gathered through public databases. The core targets and pathways of Indigo Naturalis were predicted through protein-protein interaction (PPI) network, gene ontology (GO) function, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Next, after intersecting with leukemia-related genes, the direct core target gene of Indigo Naturalis active components was identified. Subsequently, HL-60 cells were stimulated with indirubin (IND) and then examined for cell proliferation using CCK-8 assay and cell cycle, cell apoptosis, and mitochondrial membrane potential using flow cytometry. The content of apoptosis-associated proteins (Cleaved Caspase 9, Cleaved Caspase 7, Cleaved Caspase 3, and Cleaved parp) were detected using Western blot, HSP90AA1 protein, and PI3K/Akt signaling (PI3K, p-PI3K, Akt, and p-Akt) within HL-60 cells.

Results: A total of 9 active components of Indigo Naturalis were screened. The top 10 core target genes (TNF, PTGS2, RELA, MAPK14, IFNG, PPARG, NOS2, IKBKB, HSP90AA1, and NOS3) of Indigo Naturalis active components within the PPI network were identified. According to the KEGG enrichment analysis, these targets were associated with leukemia-related pathways (such as acute myeloid leukemia and CML). After intersecting with leukemia-related genes, it was found that IND participated in the most pairs of target information and was at the core of the target network; HSP90AA1 was the direct core gene of IND. Furthermore, the in-vitro cell experiments verified that IND could inhibit the proliferation, elicit G2/M-phase cell cycle arrest, enhance the apoptosis of HL-60 cells, reduce mitochondrial membrane potential, and promote apoptosis-related protein levels. Under IND treatment, HSP90AA1 overexpression notably promoted cell proliferation and inhibited apoptosis. Additionally, IND exerted tumor suppressor effects on leukemia cells by inhibiting HSP90AA1 expression.

Conclusion: IND, an active component of Indigo Naturalis, could inhibit CML progression, which may be achieved via inhibiting HSP90AA1 and PI3K/Akt signaling expression levels.

Keywords: Chronic myeloid leukemia, indigo naturalis, indirubin, HSP90AA1, PI3K/Akt pathway, leukemia cells.

« Previous
[1]
Li, Z.; Luo, J. Epigenetic regulation of HOTAIR in advanced chronic myeloid leukemia. Cancer Manag. Res., 2018, 10, 5349-5362.
[http://dx.doi.org/10.2147/CMAR.S166859] [PMID: 30464631]
[2]
Jabbour, E.; Kantarjian, H. Chronic myeloid leukemia: 2022 update on diagnosis, therapy, and monitoring. Am. J. Hematol., 2022, 97(9), 1236-1256.
[http://dx.doi.org/10.1002/ajh.26642] [PMID: 35751859]
[3]
Shallis, R.M.; Podoltsev, N. What is the best pharmacotherapeutic strategy for treating chronic myeloid leukemia in the elderly? Expert Opin. Pharmacother., 2019, 20(10), 1169-1173.
[http://dx.doi.org/10.1080/14656566.2019.1599357] [PMID: 30951394]
[4]
Deininger, M.; Buchdunger, E.; Druker, B.J. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood, 2005, 105(7), 2640-2653.
[http://dx.doi.org/10.1182/blood-2004-08-3097] [PMID: 15618470]
[5]
Meenakshi Sundaram, D.N.; Jiang, X.; Brandwein, J.M.; Valencia-Serna, J.; Remant, K.C.; Uludağ, H. Current outlook on drug resistance in chronic myeloid leukemia (CML) and potential therapeutic options. Drug Discov. Today, 2019, 24(7), 1355-1369.
[http://dx.doi.org/10.1016/j.drudis.2019.05.007] [PMID: 31102734]
[6]
Chen, Y.; Xu, N.; Yang, Y.; Liu, Z.; Xue, M.; Meng, L.; He, Q.; Chen, C.; Zeng, Q.; Zhu, H.; Du, X.; Zou, J.; He, W.; Guo, J.; Chen, S.; Yuan, G.; Wu, H.; Hong, M.; Cheng, F.; Liu, B.; Zhang, Y.; Li, W. Quality of life, mental health, and perspective on TKI dose reduction as a prelude to discontinuation in chronic phase chronic myeloid leukemia. Cancer Med., 2023, 12(16), 17239-17252.
[http://dx.doi.org/10.1002/cam4.6296] [PMID: 37409506]
[7]
Soverini, S.; Mancini, M.; Bavaro, L.; Cavo, M.; Martinelli, G. Chronic myeloid leukemia: The paradigm of targeting oncogenic tyrosine kinase signaling and counteracting resistance for successful cancer therapy. Mol. Cancer, 2018, 17(1), 49.
[http://dx.doi.org/10.1186/s12943-018-0780-6] [PMID: 29455643]
[8]
Zhang, Y.; Xiao, Y.; Dong, Q.; Ouyang, W.; Qin, Q. Neferine in the lotus plumule potentiates the antitumor effect of imatinib in primary chronic myeloid leukemia cells in vitro. J. Food Sci., 2019, 84(4), 904-910.
[http://dx.doi.org/10.1111/1750-3841.14484] [PMID: 30866043]
[9]
Chen, D.; Luo, C. Salidroside inhibits chronic myeloid leukemia cell proliferation and induces apoptosis by regulating the miR-140-5p/wnt5a/β-catenin axis. Exp. Ther. Med., 2021, 22(5), 1249.
[http://dx.doi.org/10.3892/etm.2021.10684] [PMID: 34539845]
[10]
McDermott, L.; Madan, R.; Rupani, R.; Siegel, D. A review of indigo naturalis as an alternative treatment for nail psoriasis. J. Drugs Dermatol., 2016, 15(3), 319-323.
[PMID: 26954317]
[11]
Kawai, S.; Iijima, H.; Shinzaki, S.; Hiyama, S.; Yamaguchi, T.; Araki, M.; Iwatani, S.; Shiraishi, E.; Mukai, A.; Inoue, T.; Hayashi, Y.; Tsujii, M.; Motooka, D.; Nakamura, S.; Iida, T.; Takehara, T. Indigo Naturalis ameliorates murine dextran sodium sulfate-induced colitis via aryl hydrocarbon receptor activation. J. Gastroenterol., 2017, 52(8), 904-919.
[http://dx.doi.org/10.1007/s00535-016-1292-z] [PMID: 27900483]
[12]
Zhang, Q.; Xie, J.; Li, G.; Wang, F.; Lin, J.; Yang, M.; Du, A.; Zhang, D.; Han, L. Psoriasis treatment using Indigo Naturalis: Progress and strategy. J. Ethnopharmacol., 2022, 297, 115522.
[http://dx.doi.org/10.1016/j.jep.2022.115522] [PMID: 35872288]
[13]
Tu, P.; Tian, R.; Lu, Y.; Zhang, Y.; Zhu, H.; Ling, L.; Li, H.; Chen, D. Beneficial effect of Indigo Naturalis on acute lung injury induced by influenza A virus. Chin. Med., 2020, 15(1), 128.
[http://dx.doi.org/10.1186/s13020-020-00415-w] [PMID: 33349263]
[14]
Lou, Y.; Ma, Y.; Jin, J.; Zhu, H. Oral realgar-indigo naturalis formula plus retinoic acid for acute promyelocytic leukemia. Front. Oncol., 2021, 10, 597601.
[http://dx.doi.org/10.3389/fonc.2020.597601] [PMID: 33614484]
[15]
Huang, H.; Li, Y.; Dai, Y.; Zhang, Y.; Lu, Q.; Xu, Q.; Zhang, Y. Antileukemic effects of indigo naturalis constituents by “target constituent knock out” coupled with semipreparative liquid chromatography and quadrupole time of flight mass spectrometry. Biomed. Chromatogr., 2021, 35(12), e5216.
[http://dx.doi.org/10.1002/bmc.5216] [PMID: 34254701]
[16]
Wang, Y.; Zhang, Y.; Wang, Y.; Shu, X.; Lu, C.; Shao, S.; Liu, X.; Yang, C.; Luo, J.; Du, Q. Using network pharmacology and molecular docking to explore the mechanism of Shan Ci Gu (Cremastra appendiculata) against non-small cell lung cancer. Front Chem., 2021, 9, 682862.
[http://dx.doi.org/10.3389/fchem.2021.682862] [PMID: 34178945]
[17]
Li, H.; Liu, L.; Liu, C.; Zhuang, J.; Zhou, C.; Yang, J.; Gao, C.; Liu, G.; Lv, Q.; Sun, C. Deciphering key pharmacological pathways of qingdai acting on chronic myeloid leukemia using a network pharmacology-based strategy. Med. Sci. Monit., 2018, 24, 5668-5688.
[http://dx.doi.org/10.12659/MSM.908756] [PMID: 30108199]
[18]
Zhou, C.; Liu, L.; Zhuang, J.; Wei, J.; Zhang, T.; Gao, C.; Liu, C.; Li, H.; Si, H.; Sun, C. A systems biology-based approach to uncovering molecular mechanisms underlying effects of traditional Chinese medicine Qingdai in chronic myelogenous leukemia, involving integration of network pharmacology and molecular docking technology. Med. Sci. Monit., 2018, 24, 4305-4316.
[http://dx.doi.org/10.12659/MSM.908104] [PMID: 29934492]
[19]
Yang, L. Pharmacological properties of indirubin and its derivatives. Biomed. Pharmacother, 2022, 151, 113112.
[http://dx.doi.org/10.1016/j.biopha.2022.113112]
[20]
Xu, X.; Zhang, W.; Huang, C.; Li, Y.; Yu, H.; Wang, Y.; Duan, J.; Ling, Y. A novel chemometric method for the prediction of human oral bioavailability. Int. J. Mol. Sci., 2012, 13(6), 6964-6982.
[http://dx.doi.org/10.3390/ijms13066964] [PMID: 22837674]
[21]
Szklarczyk, D.; Kirsch, R.; Koutrouli, M.; Nastou, K.; Mehryary, F.; Hachilif, R.; Gable, A.L.; Fang, T.; Doncheva, N.T.; Pyysalo, S.; Bork, P.; Jensen, L.J.; von Mering, C. The STRING database in 2023: protein–protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res., 2023, 51(D1), D638-D646.
[http://dx.doi.org/10.1093/nar/gkac1000] [PMID: 36370105]
[22]
Safran, M. GeneCards Version 3: The human gene integrator. Database, 2010, 2010, baq020.
[http://dx.doi.org/10.1093/database/baq020]
[23]
Xie, L.; Shi, F.; Tan, Z.; Li, Y.; Bode, A.M.; Cao, Y. Mitochondrial network structure homeostasis and cell death. Cancer Sci., 2018, 109(12), 3686-3694.
[http://dx.doi.org/10.1111/cas.13830] [PMID: 30312515]
[24]
Ding, L.; Chen, Q.; Chen, K.; Jiang, Y.; Li, G.; Chen, Q.; Bai, D.; Gao, D.; Deng, M.; Zhang, H.; Xu, B. Simvastatin potentiates the cell-killing activity of imatinib in imatinib-resistant chronic myeloid leukemia cells mainly through PI3K/AKT pathway attenuation and Myc downregulation. Eur. J. Pharmacol., 2021, 913, 174633.
[http://dx.doi.org/10.1016/j.ejphar.2021.174633] [PMID: 34843676]
[25]
Li, L.; Qi, Y.; Ma, X.; Xiong, G.; Wang, L.; Bao, C. TRIM22 knockdown suppresses chronic myeloid leukemia via inhibiting PI3K/Akt/mTOR signaling pathway. Cell Biol. Int., 2018, 42(9), 1192-1199.
[http://dx.doi.org/10.1002/cbin.10989] [PMID: 29762880]
[26]
Schäfer, M.; Semmler, M.L.; Bernhardt, T.; Fischer, T.; Kakkassery, V.; Ramer, R.; Hein, M.; Bekeschus, S.; Langer, P.; Hinz, B.; Emmert, S.; Boeckmann, L. Small molecules in the treatment of squamous cell carcinomas: Focus on indirubins. Cancers (Basel), 2021, 13(8), 1770.
[http://dx.doi.org/10.3390/cancers13081770] [PMID: 33917267]
[27]
Lee, M.Y.; Li, Y.Z.; Huang, K.J.; Huang, H.C.; Lin, C.Y.; Lee, Y.R. Indirubin-3′-oxime suppresses human cholangiocarcinoma through cell-cycle arrest and apoptosis. Eur. J. Pharmacol., 2018, 839, 57-65.
[http://dx.doi.org/10.1016/j.ejphar.2018.09.023] [PMID: 30267650]
[28]
Rajagopalan, P.; Dera, A.; Abdalsamad, M.R.; C Chandramoorthy, H. Rational combinations of indirubin and arylidene derivatives exhibit synergism in human non-small cell lung carcinoma cells. J. Food Biochem., 2019, 43(7), e12861.
[http://dx.doi.org/10.1111/jfbc.12861] [PMID: 31353710]
[29]
Marko, D.; Schätzle, S.; Friedel, A.; Genzlinger, A.; Zankl, H.; Meijer, L.; Eisenbrand, G. Inhibition of cyclin-dependent kinase 1 (CDK1) by indirubin derivatives in human tumour cells. Br. J. Cancer, 2001, 84(2), 283-289.
[http://dx.doi.org/10.1054/bjoc.2000.1546] [PMID: 11161389]
[30]
Wei, Y.F.; Su, J.; Deng, Z.L.; Zhu, C.; Yuan, L.; Lu, Z.J.; Zhu, Q.Y. Indirubin inhibits the proliferation of prostate cancer PC-3 cells. Zhonghua Nan Ke Xue, 2015, 21(9), 788-791.
[PMID: 26552210]
[31]
Gaboriaud-Kolar, N.; Myrianthopoulos, V.; Vougogiannopoulou, K.; Gerolymatos, P.; Horne, D.A.; Jove, R.; Mikros, E.; Nam, S.; Skaltsounis, A.L. Natural-based indirubins display potent cytotoxicity toward wild-type and t315i-resistant leukemia cell lines. J. Nat. Prod., 2016, 79(10), 2464-2471.
[http://dx.doi.org/10.1021/acs.jnatprod.6b00285] [PMID: 27726390]
[32]
Lee, M.Y.; Liu, Y.W.; Chen, M.H.; Wu, J.Y.; Ho, H.Y.; Wang, Q.F.; Chuang, J.J. Indirubin-3′-monoxime promotes autophagic and apoptotic death in JM1 human acute lymphoblastic leukemia cells and K562 human chronic myelogenous leukemia cells. Oncol. Rep., 2013, 29(5), 2072-2078.
[http://dx.doi.org/10.3892/or.2013.2334] [PMID: 23468088]
[33]
Barnwal, B.; Karlberg, H.; Mirazimi, A.; Tan, Y.J. The non-structural protein of crimean-congo hemorrhagic fever virus disrupts the mitochondrial membrane potential and induces apoptosis. J. Biol. Chem., 2016, 291(2), 582-592.
[http://dx.doi.org/10.1074/jbc.M115.667436] [PMID: 26574543]
[34]
Chu, S.; Liu, Y.; Zhang, L.; Liu, B.; Li, L.; Shi, J.; Li, L. Regulation of survival and chemoresistance by HSP90AA1 in ovarian cancer SKOV3 cells. Mol. Biol. Rep., 2013, 40(1), 1-6.
[http://dx.doi.org/10.1007/s11033-012-1930-3] [PMID: 23135731]
[35]
Abdalla, A.N.; Abdallah, M.E.; Aslam, A.; Bader, A.; Vassallo, A.; Tommasi, N.D.; Malki, W.H.; Gouda, A.M.; Mukhtar, M.H.; El-Readi, M.Z.; Alkahtani, H.M.; Abdel-Aziz, A.A.M.; El-Azab, A.S. Synergistic anti leukemia effect of a novel Hsp90 and a pan cyclin dependent kinase inhibitors. Molecules, 2020, 25(9), 2220.
[http://dx.doi.org/10.3390/molecules25092220] [PMID: 32397330]
[36]
Al-Rawashde, F.A.; Al-wajeeh, A.S.; Vishkaei, M.N.; Saad, H.K.M.; Johan, M.F.; Taib, W.R.W.; Ismail, I.; Al-Jamal, H.A.N. Thymoquinone inhibits JAK/STAT and PI3K/Akt/mTOR signaling pathways in MV4-11 and K562 myeloid leukemia cells. Pharmaceuticals (Basel), 2022, 15(9), 1123.
[http://dx.doi.org/10.3390/ph15091123] [PMID: 36145344]
[37]
Xiao, X.; Wang, W.; Li, Y.; Yang, D.; Li, X.; Shen, C.; Liu, Y.; Ke, X.; Guo, S.; Guo, Z. HSP90AA1-mediated autophagy promotes drug resistance in osteosarcoma. J. Exp. Clin. Cancer Res., 2018, 37(1), 201.
[http://dx.doi.org/10.1186/s13046-018-0880-6] [PMID: 30153855]

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