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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

Embelin Enhances the Sensitivity of Renal Cancer Cells to Axitinib by Inhibiting HIF Signaling Pathway

Author(s): Qiong Fang, Zhiying Li, Ye Xue, Xin Zong, Wenshuang Ma, Guangmin Xi, Xiao Feng Zhang and Zuowei Li*

Volume 23, Issue 7, 2023

Published on: 19 September, 2022

Page: [807 - 816] Pages: 10

DOI: 10.2174/1871520622666220825155125

Price: $65

Abstract

Background: Renal cell carcinoma (RCC) is a common malignant tumor of the urinary system with a high recurrence rate and easy metastasis. Current clinical drugs for renal cell carcinoma include immunotherapies and targeted drugs. Axitinib is a clinically targeted drug for treating renal cell carcinoma, which has shortcomings such as unstable efficacy and easy drug resistance. Therefore, this study aims to determine whether embelin can enhance the sensitivity of renal cancer cells to axitinib and explore its regulatory pathways.

Methods: The enhancing effect of embelin on axitinib was detected using MTT, crystal violet staining, and annexin VFITC staining in two renal cancer cell lines. Western blot was performed to detect the expression of autophagy-related proteins under different conditions. Bioinformatic tools were used to predict the pathways through which embelin may act on renal cancer cells, and pharmacological methods were used to verify the results.

Results: Embelin enhanced the sensitivity of renal cancer cells to axitinib in the following aspects: enhancing the inhibition of cell proliferation by axitinib, and the induction of cell apoptosis. HIF was a potential pathway for embelin’s action. After IOX2 regulated the HIF-1α pathway, the enhancing effect of embelin on axitinib was weakened. Moreover, after PT2977 regulated the HIF-2α pathway, the enhancing effect of embelin on axitinib was weakened.

Conclusions: Embelin enhanced the sensitivity of A498 and 786-O renal cancer cells to axitinib by inhibiting the HIF pathway.

Keywords: Embelin, axitinib, HIF, renal cell carcinoma, apoptosis.

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Graphical Abstract

[1]
Chow, W.H.; Dong, L.M.; Devesa, S.S. Epidemiology and risk factors for kidney cancer. Nat. Rev. Urol., 2010, 7(5), 245-257.
[http://dx.doi.org/10.1038/nrurol.2010.46] [PMID: 20448658]
[2]
Lindblad, P. Epidemiology of renal cell carcinoma. Scand. J. Surg., 2004, 93(2), 88-96.
[http://dx.doi.org/10.1177/145749690409300202] [PMID: 15285559]
[3]
Bergström, A.; Hsieh, C-C.; Lindblad, P.; Lu, C-M.; Cook, N.R.; Wolk, A. Obesity and renal cell cancer-A quantitative review. Br. J. Cancer, 2001, 85(7), 984-990.
[http://dx.doi.org/10.1054/bjoc.2001.2040] [PMID: 11592770]
[4]
Motzer, R.J.; Jonasch, E.; Agarwal, N.; Beard, C.; Bhayani, S.; Bolger, G.B.; Chang, S.S.; Choueiri, T.K.; Derweesh, I.H.; Gupta, S. Kidney cancer, version 2.2014. J. Natl. Compr. Canc. Netw., 2014, 12(2), 175-182.
[5]
Escudier, D.B.; Gore, M. Axitinib for the management of metastatic renal cell carcinoma. Drugs R D., 2011, 11(2), 113-126.
[6]
Rini, B.I.; Escudier, B.; Tomczak, P.; Kaprin, A.; Motzer, R. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): A randomised phase 3 trial. Lancet, 2011, 378(9807), 1931-1939.
[7]
Poojari, R. Embelin - A drug of antiquity: Shifting the paradigm towards modern medicine. Expert Opin. Investig. Drugs, 2014, 23(3), 427-444.
[8]
Atal, C.K.; Siddiqui, M.A.; Zutshi, U.; Amla, V.; Johri, R.K.; Rao, P.G.; Kour, S. Non-narcotic orally effective, centrally acting analgesic from an Ayurvedic drug. J. Ethnopharmacol., 1984, 11(3), 309-317.
[http://dx.doi.org/10.1016/0378-8741(84)90076-X]
[9]
Avisetti, D.R.; Babu, K.S.; Kalivendi, S.V.; Shrikant, A.J.P.O. Activation of p38/JNK pathway is responsible for embelin induced apoptosis in lung cancer cells: Transitional role of reactive oxygen species. PLoS One, 2014, 9(1), e87050.
[http://dx.doi.org/10.1371/journal.pone.0087050] [PMID: 24466324]
[10]
Wang, D.G.; Sun, Y.B.; Ye, F.; Li, W.; Kharbuja, P.; Gao, L.; Zhang, D.Y.; Suo, J. Anti-tumor activity of the X-linked inhibitor of apoptosis (XIAP) inhibitor embelin in gastric cancer cells. Mol. Cell. Biochem., 2014, 386(1-2), 143-152.
[11]
Dai, Y.; Jiao, H.; Teng, G.; Wang, W.; Zhang, R.; Wang, Y.; Hebbard, L.; George, J.; Qiao, L. Embelin reduces colitis-associated tumorigenesis through limiting IL-6/STAT3 signaling. Mol. Cancer Ther., 2014, 13(5), 1206-1216.
[12]
Shah, P.; Djisam, R.; Damulira, H.; Aganze, A.; Danquah, M. Embelin inhibits proliferation, induces apoptosis and alters gene expression profiles in breast cancer cells. Pharmacol. Rep., 2016, 638-644.
[http://dx.doi.org/10.1016/j.pharep.2016.01.004]
[13]
Poojari, R.J. Embelin, a small molecule quinone with a co-clinical power for castrate-resistant prostate cancer. Front. Pharmacol., 2014, 5, 184.
[http://dx.doi.org/10.3389/fphar.2014.00184] [PMID: 25152733]
[14]
Wang, A.; Zhang, B.; Zhang, J.; Wu, W. Embelin-induced brain glioma cell apoptosis and cell cycle arrest via the mitochondrial pathway. Oncol. Rep., 2013, 29(6), 2473-2478.
[http://dx.doi.org/10.3892/or.2013.2369]
[15]
Coutelle, O.; Hornig-Do, H.T.; Witt, A.; Andree, M.; Schiffmann, L.M.; Piekarek, M.; Brinkmann, K.; Seeger, J.M.; Liwschitz, M.; Miwa, S.; Hallek, M.; Krönke, M.; Trifunovic, A.; Eming, S.A.; Wiesner, R.J.; Hacker, U.T.; Kashkar, H. Embelin inhibits endothelial mitochondrial respiration and impairs neoangiogenesis during tumor growth and wound healing. EMBO Mol. Med., 2014, 6(5), 624-639.
[http://dx.doi.org/10.1002/emmm.201303016] [PMID: 24648500]
[16]
Liang, F.; Miller, A.S.; Longerich, S.; Tang, C.; Maranon, D.; Williamson, E.A.; Hromas, R.; Wiese, C.; Kupfer, G.M.; Sung, P. DNA requirement in FANCD2 deubiquitination by USP1-UAF1-RAD51AP1 in the Fanconi anemia DNA damage response. Nat. Commun., 2019, 10(1), 2849.
[http://dx.doi.org/10.1038/s41467-019-10408-5] [PMID: 31253762]
[17]
Manuelli, V.; Pecorari, C.; Filomeni, G.; Zito, E. Regulation of redox signaling in HIF‐1‐dependent tumor angiogenesis. FEBS J., 2021.
[http://dx.doi.org/10.1111/febs.16110] [PMID: 34228878]
[18]
Kaluz, S.; Zhang, Q.; Kuranaga, Y.; Yang, H.; Osuka, S.; Bhattacharya, D.; Devi, N.S.; Mun, J.; Wang, W.; Zhang, R.; Goodman, M.M.; Grossniklaus, H.E.; Van Meir, E.G. Targeting HIF-activated collagen prolyl 4-hydroxylase expression disrupts collagen deposition and blocks primary and metastatic uveal melanoma growth. Oncogene, 2021, 40(33), 5182-5191.
[http://dx.doi.org/10.1038/s41388-021-01919-x] [PMID: 34218269]
[19]
Casillas, A.L.; Chauhan, S.S.; Toth, R.K.; Sainz, A.G.; Clements, A.N.; Jensen, C.C.; Langlais, P.R.; Miranti, C.K.; Cress, A.E.; Warfel, N.A. Direct phosphorylation and stabilization of HIF-1α by PIM1 kinase drives angiogenesis in solid tumors. Oncogene, 2021, 40(32), 5142-5152.
[http://dx.doi.org/10.1038/s41388-021-01915-1] [PMID: 34211090]
[20]
Hoefflin, R.; Harlander, S.; Schäfer, S.; Metzger, P.; Kuo, F.; Schönenberger, D.; Adlesic, M.; Peighambari, A.; Seidel, P.; Chen, C.; Consenza-Contreras, M.; Jud, A.; Lahrmann, B.; Grabe, N.; Heide, D.; Uhl, F.M.; Chan, T.A.; Duyster, J.; Zeiser, R.; Schell, C.; Heikenwalder, M.; Schilling, O.; Hakimi, A.A.; Boerries, M.; Frew, I.J. HIF-1α and HIF-2α differently regulate tumour development and inflammation of clear cell renal cell carcinoma in mice. Nat. Commun., 2020, 11(1), 4111.
[http://dx.doi.org/10.1038/s41467-020-17873-3] [PMID: 32807776]
[21]
Semenza, G.L. Involvement of oxygen-sensing pathways in physiologic and pathologic erythropoiesis. Blood, 2009, 114(10), 2015-2019.
[http://dx.doi.org/10.1182/blood-2009-05-189985] [PMID: 19494350]
[22]
Ke, Q.; Costa, M. Hypoxia-inducible factor-1 (HIF-1). Mol. Pharmacol., 2006, 70(5), 1469-1480.
[http://dx.doi.org/10.1124/mol.106.027029] [PMID: 16887934]
[23]
Xia, X.; Lemieux, M.E.; Li, W.; Carroll, J.S.; Brown, M.; Liu, X.S.; Kung, A.L. Integrative analysis of HIF binding and transactivation reveals its role in maintaining histone methylation homeostasis. Proc. Natl. Acad. Sci. USA, 2009, 106(11), 4260-4265.
[http://dx.doi.org/10.1073/pnas.0810067106] [PMID: 19255431]
[24]
Schödel, J.; Oikonomopoulos, S.; Ragoussis, J.; Pugh, C.W.; Ratcliffe, P.J.; Mole, D.R. High-resolution genome-wide mapping of HIF-binding sites by ChIP-seq. Blood, 2011, 117(23), e207-e217.
[http://dx.doi.org/10.1182/blood-2010-10-314427] [PMID: 21447827]
[25]
Albadari, N.; Deng, S.; Li, W. The transcriptional factors HIF-1 and HIF-2 and their novel inhibitors in cancer therapy. Expert Opin. Drug Discov., 2019, 14(7), 667-682.
[http://dx.doi.org/10.1080/17460441.2019.1613370] [PMID: 31070059]
[26]
Prabhakar, N.R.; Semenza, G.L. Adaptive and maladaptive cardiorespiratory responses to continuous and intermittent hypoxia mediated by hypoxia-inducible factors 1 and 2. Physiol. Rev., 2012, 92(3), 967-1003.
[http://dx.doi.org/10.1152/physrev.00030.2011] [PMID: 22811423]
[27]
Talks, K.L.; Turley, H.; Gatter, K.C.; Maxwell, P.H.; Pugh, C.W.; Ratcliffe, P.J.; Harris, A.L. The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages. Am. J. Pathol., 2000, 157(2), 411-421.
[http://dx.doi.org/10.1016/S0002-9440(10)64554-3] [PMID: 10934146]
[28]
Semenza, G.L.; Wang, G.L. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol. Cell. Biol., 1992, 12(12), 5447-5454.
[PMID: 1448077]
[29]
Hicklin, D.J.; Ellis, L.M. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J. Clin. Oncol., 2005, 23(5), 1011-1027.
[http://dx.doi.org/10.1200/JCO.2005.06.081] [PMID: 15585754]
[30]
Melillo, G.; Musso, T.; Sica, A.; Taylor, L.S.; Cox, G.W.; Varesio, L. A hypoxia-responsive element mediates a novel pathway of activation of the inducible nitric oxide synthase promoter. J. Exp. Med., 1995, 182(6), 1683-1693.
[http://dx.doi.org/10.1084/jem.182.6.1683] [PMID: 7500013]
[31]
Hu, J.; Discher, D.J.; Bishopric, N.H.; Webster, K.A. Hypoxia regulates expression of the endothelin-1 gene through a proximal hypoxia-inducible factor-1 binding site on the antisense strand. Biochem. Biophys. Res. Commun., 1998, 245(3), 894-899.
[http://dx.doi.org/10.1006/bbrc.1998.8543] [PMID: 9588211]
[32]
Simon, M.P.; Tournaire, R.; Pouyssegur, J. The angiopoietin-2 gene of endothelial cells is up-regulated in hypoxia by a HIF binding site located in its first intron and by the central factors GATA-2 and Ets-1. J. Cell. Physiol., 2008, 217(3), 809-818.
[http://dx.doi.org/10.1002/jcp.21558] [PMID: 18720385]
[33]
Chen, C.; Pore, N.; Behrooz, A.; Ismail-Beigi, F.; Maity, A. Regulation of glut1 mRNA by hypoxia-inducible factor-1. J. Biol. Chem., 2001, 276(12), 9519-9525.
[http://dx.doi.org/10.1074/jbc.M010144200] [PMID: 11120745]
[34]
Mathupala, S.P.; Rempel, A.; Pedersen, P.L. Glucose catabolism in cancer cells: Identification and characterization of a marked activation response of the type II hexokinase gene to hypoxic conditions. J. Biol. Chem., 2001, 276(46), 43407-43412.
[http://dx.doi.org/10.1074/jbc.M108181200] [PMID: 11557773]
[35]
Firth, J.D.; Ebert, B.L.; Ratcliffe, P.J. Hypoxic regulation of lactate dehydrogenase A. Interaction between hypoxia-inducible factor 1 and cAMP response elements. J. Biol. Chem., 1995, 270(36), 21021-21027.
[http://dx.doi.org/10.1074/jbc.270.36.21021] [PMID: 7673128]
[36]
Keswani, S.C.; Bosch-Marcé, M.; Reed, N.; Fischer, A.; Semenza, G.L.; Höke, A. Nitric oxide prevents axonal degeneration by inducing HIF-1–dependent expression of erythropoietin. Proc. Natl. Acad. Sci. USA, 2011, 108(12), 4986-4990.
[http://dx.doi.org/10.1073/pnas.1019591108] [PMID: 21383158]
[37]
Feldser, D.; Agani, F.; Iyer, N.V.; Pak, B.; Ferreira, G.; Semenza, G.L. Reciprocal positive regulation of hypoxia-inducible factor 1alpha and insulin-like growth factor 2. Cancer Res., 1999, 59(16), 3915-3918.
[PMID: 10463582]
[38]
Chang, L.H.; Pan, S.L.; Lai, C.Y.; Tsai, A.C.; Teng, C.M. Activated PAR-2 regulates pancreatic cancer progression through ILK/HIF-α-induced TGF-α expression and MEK/VEGF-A-mediated angiogenesis. Am. J. Pathol., 2013, 183(2), 566-575.
[http://dx.doi.org/10.1016/j.ajpath.2013.04.022] [PMID: 23764046]
[39]
Koshiji, M.; Kageyama, Y.; Pete, E.A.; Horikawa, I.; Barrett, J.C.; Huang, L.E. HIF-1α induces cell cycle arrest by functionally counteracting Myc. EMBO J., 2004, 23(9), 1949-1956.
[http://dx.doi.org/10.1038/sj.emboj.7600196] [PMID: 15071503]
[40]
Ladelfa, M.F.; Toledo, M.F.; Laiseca, J.E.; Monte, M. Interaction of p53 with tumor suppressive and oncogenic signaling pathways to control cellular reactive oxygen species production. Antioxid. Redox Signal., 2011, 15(6), 1749-1761.
[http://dx.doi.org/10.1089/ars.2010.3652] [PMID: 20919943]
[41]
Song, Z.C.; Zhou, W.; Shu, R.; Ni, J. Hypoxia induces apoptosis and autophagic cell death in human periodontal ligament cells through HIF ‐1α pathway. Cell Prolif., 2012, 45(3), 239-248.
[http://dx.doi.org/10.1111/j.1365-2184.2012.00810.x] [PMID: 22429763]
[42]
Volm, M.; Koomägi, R. Hypoxia-inducible factor (HIF-1) and its relationship to apoptosis and proliferation in lung cancer. Anticancer Res., 2000, 20(3A), 1527-1533.
[PMID: 10928066]
[43]
Ben-Yosef, Y.; Lahat, N.; Shapiro, S.; Bitterman, H.; Miller, A. Regulation of endothelial matrix metalloproteinase-2 by hypoxia/reoxygenation. Circ. Res., 2002, 90(7), 784-791.
[http://dx.doi.org/10.1161/01.RES.0000015588.70132.DC] [PMID: 11964371]
[44]
Liu, Z.; Li, C.; Meng, X.; Bai, Y.; Qi, J.; Wang, J.; Zhou, Q.; Zhang, W.; Zhang, X. Hypoxia-inducible factor-lα mediates aggrecan and collagen Π expression via NOTCH1 signaling in nucleus pulposus cells during intervertebral disc degeneration. Biochem. Biophys. Res. Commun., 2017, 488(3), 554-561.
[http://dx.doi.org/10.1016/j.bbrc.2017.05.086] [PMID: 28526405]
[45]
Krishnamachary, B.; Berg-Dixon, S.; Kelly, B.; Agani, F.; Feldser, D.; Ferreira, G.; Iyer, N.; LaRusch, J.; Pak, B.; Taghavi, P.; Semenza, G.L. Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Res., 2003, 63(5), 1138-1143.
[PMID: 12615733]
[46]
Imai, T.; Horiuchi, A.; Wang, C.; Oka, K.; Ohira, S.; Nikaido, T.; Konishi, I. Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells. Am. J. Pathol., 2003, 163(4), 1437-1447.
[http://dx.doi.org/10.1016/S0002-9440(10)63501-8] [PMID: 14507651]
[47]
Yang, M.H.; Wu, M.Z.; Chiou, S.H.; Chen, P.M.; Chang, S.Y.; Liu, C.J.; Teng, S.C.; Wu, K.J. Direct regulation of TWIST by HIF-1α promotes metastasis. Nat. Cell Biol., 2008, 10(3), 295-305.
[http://dx.doi.org/10.1038/ncb1691] [PMID: 18297062]
[48]
Krishnamachary, B.; Zagzag, D.; Nagasawa, H.; Rainey, K.; Okuyama, H.; Baek, J.H.; Semenza, G.L. Hypoxia-inducible factor-1-dependent repression of E-cadherin in von Hippel-Lindau tumor suppressor-null renal cell carcinoma mediated by TCF3, ZFHX1A, and ZFHX1B. Cancer Res., 2006, 66(5), 2725-2731.
[http://dx.doi.org/10.1158/0008-5472.CAN-05-3719] [PMID: 16510593]
[49]
Chen, X.; Li, Z.; Yong, H.; Wang, W.; Wang, D.; Chu, S.; Li, M.; Hou, P.; Zheng, J.; Bai, J. Trim21-mediated HIF-1α degradation attenuates aerobic glycolysis to inhibit renal cancer tumorigenesis and metastasis. Cancer Lett., 2021, 508, 115-126.
[http://dx.doi.org/10.1016/j.canlet.2021.03.023] [PMID: 33794309]
[50]
Cowman, S.J.; Fuja, D.G.; Liu, X.D.; Tidwell, R.S.S.; Kandula, N.; Sirohi, D.; Agarwal, A.M.; Emerson, L.L.; Tripp, S.R.; Mohlman, J.S.; Stonhill, M.; Garcia, G.; Conley, C.J.; Olalde, A.A.; Sargis, T.; Ramirez-Torres, A.; Karam, J.A.; Wood, C.G.; Sircar, K.; Tamboli, P.; Boucher, K.; Maughan, B.; Spike, B.T.; Ho, T.H.; Agarwal, N.; Jonasch, E.; Koh, M.Y. Macrophage HIF-1α is an independent prognostic indicator in kidney cancer. Clin. Cancer Res., 2020, 26(18), 4970-4982.
[http://dx.doi.org/10.1158/1078-0432.CCR-19-3890] [PMID: 32586940]
[51]
Murakami, A.; Wang, L.; Kalhorn, S.; Schraml, P.; Rathmell, W.K.; Tan, A.C.; Nemenoff, R.; Stenmark, K.; Jiang, B-H.; Reyland, M.E.; Heasley, L.; Hu, C-J. Context-dependent role for chromatin remodeling component PBRM1/BAF180 in clear cell renal cell carcinoma. Oncogenesis, 2017, 6(1), e287.
[http://dx.doi.org/10.1038/oncsis.2016.89] [PMID: 28092369]
[52]
Micucci, C.; Matacchione, G.; Valli, D.; Orciari, S.; Catalano, A. HIF2α is involved in the expansion of CXCR4-positive cancer stem-like cells in renal cell carcinoma. Br. J. Cancer, 2015, 113(8), 1178-1185.
[http://dx.doi.org/10.1038/bjc.2015.338] [PMID: 26439684]

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