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Mini-Reviews in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1389-5575
ISSN (Online): 1875-5607

Mini-Review Article

Biological Role of AKT and Regulation of AKT Signaling Pathway by Thymoquinone: Perspectives in Cancer Therapeutics

Author(s): Md. Junaid, Yeasmin Akter, Syeda Samira Afrose, Mousumi Tania and Md. Asaduzzaman Khan*

Volume 21, Issue 3, 2021

Published on: 05 October, 2020

Page: [288 - 301] Pages: 14

DOI: 10.2174/1389557520666201005143818

Price: $65

Abstract

Background: AKT/PKB is an important enzyme with numerous biological functions, and its overexpression is related to carcinogenesis. AKT stimulates different signaling pathways that are downstream of activated tyrosine kinases and phosphatidylinositol 3-kinase, hence functions as an important target for anti-cancer drugs.

Objective: In this review article, we have interpreted the role of AKT signaling pathway in cancer and the natural inhibitory effect of Thymoquinone (TQ) in AKT and its possible mechanisms.

Method: We have collected the updated information and data on AKT, its role in cancer and the inhibitory effect of TQ in AKT signaling pathway from Google Scholar, PubMed, Web of Science, Elsevier, Scopus, and many more.

Results: Many drugs are already developed, which can target AKT, but very few among them have passed clinical trials. TQ is a natural compound, mainly found in black cumin, which has been found to have potential anti-cancer activities. TQ targets numerous signaling pathways, including AKT, in different cancers. In fact, many studies revealed that AKT is one of the major targets of TQ. The preclinical success of TQ suggests its clinical studies on cancer.

Conclusion: This review article summarizes the role of AKT in carcinogenesis, its potent inhibitors in clinical trials, and how TQ acts as an inhibitor of AKT and TQ’s future as a cancer therapeutic drug.

Keywords: AKT signaling pathway, carcinogenesis, PIK3, PTEN, thymoquinone, cancer therapeutics.

Graphical Abstract

[1]
Ferlay, J.; Colombet, M.; Soerjomataram, I.; Mathers, C.; Parkin, D.M.; Piñeros, M.; Znaor, A.; Bray, F. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int. J. Cancer, 2019, 144(8), 1941-1953.
[http://dx.doi.org/10.1002/ijc.31937] [PMID: 30350310]
[2]
Rahmani, A.H.; Shabrmi, F.M.; Aly, S.M. Active ingredients of ginger as potential candidates in the prevention and treatment of diseases via modulation of biological activities. Int. J. Physiol. Pathophysiol. Pharmacol., 2014, 6(2), 125-136.
[PMID: 25057339]
[3]
Rahmani, A.H.; Al Zohairy, M.A.; Aly, S.M.; Khan, M.A. Curcumin: a potential candidate in prevention of cancer via modulation of molecular pathways. BioMed Res. Int., 2014, 2014761608
[http://dx.doi.org/10.1155/2014/761608] [PMID: 25295272]
[4]
Asaduzzaman Khan, M.; Tania, M.; Fu, S.; Fu, J. Thymoquinone, as an anticancer molecule: From basic research to clinical investigation. Oncotarget, 2017, 8(31), 51907-51919.
[http://dx.doi.org/10.18632/oncotarget.17206] [PMID: 28881699]
[5]
Mostofa, A.G.M.; Hossain, M.K.; Basak, D.; Bin Sayeed, M.S.; Shahdaat, M. Thymoquinone as a potential adjuvant therapy for cancer treatment: Evidence from preclinical studies. Front. Pharmacol., 2017, 8, 295.
[http://dx.doi.org/10.3389/fphar.2017.00295] [PMID: 28659794]
[6]
Chowdhury, F.A.; Hossain, M.K.; Mostofa, A.G.M.; Akbor, M.M.; Bin Sayeed, M.S.; Shahdaat, M. Therapeutic potential of thymoquinone in glioblastoma treatment: Targeting major gliomagenesis signaling pathways. BioMed Res. Int., 2018, 20184010629
[http://dx.doi.org/10.1155/2018/4010629] [PMID: 29651429]
[7]
Dastjerdi, M.N.; Mehdiabady, E.M.; Iranpour, F.G.; Bahramian, H. Effect of thymoquinone on P53 gene expression and consequence apoptosis in breast cancer cell line. Int. J. Prev. Med., 2016, 7(1), 66.
[http://dx.doi.org/10.4103/2008-7802.180412] [PMID: 27141285]
[8]
El-Mahdy, M.A.; Zhu, Q.; Wang, Q.E.; Wani, G.; Wani, A.A. Thymoquinone induces apoptosis through activation of caspase-8 and mitochondrial events in p53-null myeloblastic leukemia HL-60 cells. Int. J. Cancer, 2005, 117(3), 409-417.
[http://dx.doi.org/10.1002/ijc.21205] [PMID: 15906362]
[9]
Manning, B.D.; Cantley, L.C. AKT/PKB signaling: Navigating downstream. Cell, 2007, 129(7), 1261-1274.
[http://dx.doi.org/10.1016/j.cell.2007.06.009] [PMID: 17604717]
[10]
Liu, P.; Cheng, H.; Roberts, T.M.; Zhao, J.J. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat. Rev. Drug Discov., 2009, 8(8), 627-644.
[http://dx.doi.org/10.1038/nrd2926] [PMID: 19644473]
[11]
Soltani, A.; Torki, S.; Ghahfarokhi, M.S.; Jami, M.S.; Ghatrehsamani, M. Targeting the phosphoinositide 3-kinase/AKT pathways by small molecules and natural compounds as a therapeutic approach for breast cancer cells. Mol. Biol. Rep., 2019, 46(5), 4809-4816.
[http://dx.doi.org/10.1007/s11033-019-04929-x] [PMID: 31313132]
[12]
Testa, J.R.; Bellacosa, A. AKT plays a central role in tumorigenesis. Proc. Natl. Acad. Sci. USA, 2001, 98(20), 10983-10985.
[http://dx.doi.org/10.1073/pnas.211430998] [PMID: 11572954]
[13]
Bellacosa, A.; Kumar, C.C.; Di Cristofano, A.; Testa, J.R. Activation of AKT kinases in cancer: Implications for therapeutic targeting. Adv. Cancer Res., 2005, 94, 29-86.
[http://dx.doi.org/10.1016/S0065-230X(05)94002-5] [PMID: 16095999]
[14]
Yoeli-Lerner, M.; Toker, A. Akt/PKB signaling in cancer: A function in cell motility and invasion. Cell Cycle, 2006, 5(6), 603-605.
[http://dx.doi.org/10.4161/cc.5.6.2561] [PMID: 16582622]
[15]
Xue, G.; Zippelius, A.; Wicki, A.; Mandalà, M.; Tang, F.; Massi, D.; Hemmings, B.A. Integrated Akt/PKB signaling in immunomodulation and its potential role in cancer immunotherapy. J. Natl. Cancer Inst., 2015, 107(7), 171.
[http://dx.doi.org/10.1093/jnci/djv171] [PMID: 26071042]
[16]
Fresno Vara, J.A.; Casado, E.; de Castro, J.; Cejas, P.; Belda-Iniesta, C.; González-Barón, M. PI3K/Akt signalling pathway and cancer. Cancer Treat. Rev., 2004, 30(2), 193-204.
[http://dx.doi.org/10.1016/j.ctrv.2003.07.007] [PMID: 15023437]
[17]
Feng, J.; Park, J.; Cron, P.; Hess, D.; Hemmings, B.A. Identification of a PKB/Akt hydrophobic motif Ser-473 kinase as DNA-dependent protein kinase. J. Biol. Chem., 2004, 279(39), 41189-41196.
[http://dx.doi.org/10.1074/jbc.M406731200] [PMID: 15262962]
[18]
Datta, S.R.; Brunet, A.; Greenberg, M.E. Cellular survival: A play in three Akts. Genes Dev., 1999, 13(22), 2905-2927.
[http://dx.doi.org/10.1101/gad.13.22.2905] [PMID: 10579998]
[19]
Chuang, C-H.; Cheng, T-C.; Leu, Y-L.; Chuang, K-H.; Tzou, S-C.; Chen, C-S. Discovery of Akt kinase inhibitors through structure-based virtual screening and their evaluation as potential anticancer agents. Int. J. Mol. Sci., 2015, 16(2), 3202-3212.
[http://dx.doi.org/10.3390/ijms16023202] [PMID: 25648320]
[20]
Altomare, D.A.; Testa, J.R. Perturbations of the AKT signaling pathway in human cancer. Oncogene, 2005, 24(50), 7455-7464.
[http://dx.doi.org/10.1038/sj.onc.1209085] [PMID: 16288292]
[21]
Chan, C-H.; Jo, U.; Kohrman, A.; Rezaeian, A.H.; Chou, P-C.; Logothetis, C.; Lin, H-K. Posttranslational regulation of Akt in human cancer. Cell Biosci., 2014, 4(1), 59.
[http://dx.doi.org/10.1186/2045-3701-4-59] [PMID: 25309720]
[22]
Ahmed, N.N.; Franke, T.F.; Bellacosa, A.; Datta, K.; Gonzalez-Portal, M.E.; Taguchi, T.; Testa, J.R.; Tsichlis, P.N. The proteins encoded by c-akt and v-akt differ in post-translational modification, subcellular localization and oncogenic potential. Oncogene, 1993, 8(7), 1957-1963.
[PMID: 8510938]
[23]
Yang, W-L.; Wu, C-Y.; Wu, J.; Lin, H-K. Regulation of Akt signaling activation by ubiquitination. Cell Cycle, 2010, 9(3), 487-497.
[http://dx.doi.org/10.4161/cc.9.3.10508] [PMID: 20081374]
[24]
Cheng, J.Q.; Godwin, A.K.; Bellacosa, A.; Taguchi, T.; Franke, T.F.; Hamilton, T.C.; Tsichlis, P.N.; Testa, J.R. AKT2, a putative oncogene encoding a member of a subfamily of protein-serine/threonine kinases, is amplified in human ovarian carcinomas. Proc. Natl. Acad. Sci. USA, 1992, 89(19), 9267-9271.
[http://dx.doi.org/10.1073/pnas.89.19.9267] [PMID: 1409633]
[25]
Cheng, J.Q.; Ruggeri, B.; Klein, W.M.; Sonoda, G.; Altomare, D.A.; Watson, D.K.; Testa, J.R. Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc. Natl. Acad. Sci. USA, 1996, 93(8), 3636-3641.
[http://dx.doi.org/10.1073/pnas.93.8.3636] [PMID: 8622988]
[26]
Ruggeri, B.A.; Huang, L.; Wood, M.; Cheng, J.Q.; Testa, J.R. Amplification and overexpression of the AKT2 oncogene in a subset of human pancreatic ductal adenocarcinomas. Mol. Carcinog., 1998, 21(2), 81-86.
[http://dx.doi.org/10.1002/(SICI)1098-2744(199802)21:2<81:AID-MC1>3.0.CO;2-R] [PMID: 9496907]
[27]
Miwa, W.; Yasuda, J.; Murakami, Y.; Yashima, K.; Sugano, K.; Sekine, T.; Kono, A.; Egawa, S.; Yamaguchi, K.; Hayashizaki, Y.; Sekiya, T. Isolation of DNA sequences amplified at chromosome 19q13.1-q13.2 including the AKT2 locus in human pancreatic cancer. Biochem. Biophys. Res. Commun., 1996, 225(3), 968-974.
[http://dx.doi.org/10.1006/bbrc.1996.1280] [PMID: 8780719]
[28]
Staal, S.P.; Huebner, K.; Croce, C.M.; Parsa, N.Z.; Testa, J.R. The AKT1 proto-oncogene maps to human chromosome 14, band q32. Genomics, 1988, 2(1), 96-98.
[http://dx.doi.org/10.1016/0888-7543(88)90114-0] [PMID: 3384441]
[29]
Alessi, D.R.; Cohen, P. Mechanism of activation and function of protein kinase B. Curr. Opin. Genet. Dev., 1998, 8(1), 55-62.
[http://dx.doi.org/10.1016/S0959-437X(98)80062-2] [PMID: 9529606]
[30]
Sun, M.; Wang, G.; Paciga, J.E.; Feldman, R.I.; Yuan, Z-Q.; Ma, X-L.; Shelley, S.A.; Jove, R.; Tsichlis, P.N.; Nicosia, S.V.; Cheng, J.Q. AKT1/PKBalpha kinase is frequently elevated in human cancers and its constitutive activation is required for oncogenic transformation in NIH3T3 cells. Am. J. Pathol., 2001, 159(2), 431-437.
[http://dx.doi.org/10.1016/S0002-9440(10)61714-2] [PMID: 11485901]
[31]
Liu, A.X.; Testa, J.R.; Hamilton, T.C.; Jove, R.; Nicosia, S.V.; Cheng, J.Q. AKT2, a member of the protein kinase B family, is activated by growth factors, v-Ha-ras, and v-src through phosphatidylinositol 3-kinase in human ovarian epithelial cancer cells. Cancer Res., 1998, 58(14), 2973-2977.
[PMID: 9679957]
[32]
Chan, T.O.; Rittenhouse, S.E.; Tsichlis, P.N. AKT/PKB and other D3 phosphoinositide-regulated kinases: Kinase activation by phosphoinositide-dependent phosphorylation. Annu. Rev. Biochem., 1999, 68(1), 965-1014.
[http://dx.doi.org/10.1146/annurev.biochem.68.1.965] [PMID: 10872470]
[33]
Persad, S.; Attwell, S.; Gray, V.; Mawji, N.; Deng, J.T.; Leung, D.; Yan, J.; Sanghera, J.; Walsh, M.P.; Dedhar, S. Regulation of protein kinase B/Akt-serine 473 phosphorylation by integrin-linked kinase critical roles for kinase activity and amino acids arginine 211 and serine 343. J. Biol. Chem., 2001, 27462-27469.
[34]
Stambolic, V.; Suzuki, A.; de la Pompa, J.L.; Brothers, G.M.; Mirtsos, C.; Sasaki, T.; Ruland, J.; Penninger, J.M.; Siderovski, D.P.; Mak, T.W. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell, 1998, 95(1), 29-39.
[http://dx.doi.org/10.1016/S0092-8674(00)81780-8] [PMID: 9778245]
[35]
Cho, H.; Thorvaldsen, J.L.; Chu, Q.; Feng, F.; Birnbaum, M.J. Akt1/PKBalpha is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J. Biol. Chem., 2001, 276(42), 38349-38352.
[http://dx.doi.org/10.1074/jbc.C100462200] [PMID: 11533044]
[36]
Garofalo, R.S.; Orena, S.J.; Rafidi, K.; Torchia, A.J.; Stock, J.L.; Hildebrandt, A.L.; Coskran, T.; Black, S.C.; Brees, D.J.; Wicks, J.R.; McNeish, J.D.; Coleman, K.G. Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKB β. J. Clin. Invest., 2003, 112(2), 197-208.
[http://dx.doi.org/10.1172/JCI16885] [PMID: 12843127]
[37]
Cho, H.; Mu, J.; Kim, J.K.; Thorvaldsen, J.L.; Chu, Q.; Crenshaw, E.B., III; Kaestner, K.H.; Bartolomei, M.S.; Shulman, G.I.; Birnbaum, M.J. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB β). Science, 2001, 292(5522), 1728-1731.
[http://dx.doi.org/10.1126/science.292.5522.1728] [PMID: 11387480]
[38]
Easton, R.M.; Cho, H.; Roovers, K.; Shineman, D.W.; Mizrahi, M.; Forman, M.S.; Lee, V.M-Y.; Szabolcs, M.; de Jong, R.; Oltersdorf, T.; Ludwig, T.; Efstratiadis, A.; Birnbaum, M.J. Role for Akt3/protein kinase Bgamma in attainment of normal brain size. Mol. Cell. Biol., 2005, 25(5), 1869-1878.
[http://dx.doi.org/10.1128/MCB.25.5.1869-1878.2005] [PMID: 15713641]
[39]
Mattmann, M.E.; Stoops, S.L.; Lindsley, C.W. Inhibition of Akt with small molecules and biologics: Historical perspective and current status of the patent landscape. Expert Opin. Ther. Pat., 2011, 21(9), 1309-1338.
[http://dx.doi.org/10.1517/13543776.2011.587959] [PMID: 21635152]
[40]
Hennessy, B.T.; Smith, D.L.; Ram, P.T.; Lu, Y.; Mills, G.B. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat. Rev. Drug Discov., 2005, 4(12), 988-1004.
[http://dx.doi.org/10.1038/nrd1902] [PMID: 16341064]
[41]
Shaw, R.J.; Cantley, L.C. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature, 2006, 441(7092), 424-430.
[http://dx.doi.org/10.1038/nature04869] [PMID: 16724053]
[42]
Bellacosa, A.; Testa, J.R.; Moore, R.; Larue, L. A portrait of AKT kinases: Human cancer and animal models depict a family with strong individualities. Cancer Biol. Ther., 2004, 3(3), 268-275.
[http://dx.doi.org/10.4161/cbt.3.3.703] [PMID: 15034304]
[43]
Cheng, J.Q.; Lindsley, C.W.; Cheng, G.Z.; Yang, H.; Nicosia, S.V. The Akt/PKB pathway: Molecular target for cancer drug discovery. Oncogene, 2005, 24(50), 7482-7492.
[http://dx.doi.org/10.1038/sj.onc.1209088] [PMID: 16288295]
[44]
Kim, D.H.; Suh, J.; Surh, Y.J.; Na, H.K. Regulation of the tumor suppressor PTEN by natural anticancer compounds. Ann. N. Y. Acad. Sci., 2017, 1401(1), 136-149.
[http://dx.doi.org/10.1111/nyas.13422] [PMID: 28891094]
[45]
Hwang, D-M.; Kundu, J.K.; Shin, J-W.; Lee, J-C.; Lee, H.J.; Surh, Y-J. cis-9,trans-11-conjugated linoleic acid down-regulates phorbol ester-induced NF-kappaB activation and subsequent COX-2 expression in hairless mouse skin by targeting IkappaB kinase and PI3K-Akt. Carcinogenesis, 2007, 28(2), 363-371.
[http://dx.doi.org/10.1093/carcin/bgl151] [PMID: 16950795]
[46]
Kim, B-M.; Kim, D-H.; Park, J-H.; Surh, Y-J.; Na, H-K. Ginsenoside Rg3 inhibits constitutive activation of NF-κB signaling in human breast cancer (MDA-MB-231) cells: ERK and Akt as potential upstream targets. J. Cancer Prev., 2014, 19(1), 23-30.
[http://dx.doi.org/10.15430/JCP.2014.19.1.23] [PMID: 25337569]
[47]
Shan, Z-Z.; Chen, P-N.; Wang, F.; Wang, J.; Fan, Q-X. Expression of P-EGFR and P-Akt protein in esophageal squamous cell carcinoma and its prognosis. Oncol. Lett., 2017, 14(3), 2859-2863.
[http://dx.doi.org/10.3892/ol.2017.6526] [PMID: 28927043]
[48]
Lu, C.; Shervington, A. Chemoresistance in gliomas. Mol. Cell. Biochem., 2008, 312(1-2), 71-80.
[http://dx.doi.org/10.1007/s11010-008-9722-8] [PMID: 18259841]
[49]
Lu, D.; Shi, H-C.; Wang, Z-X.; Gu, X-W.; Zeng, Y.J. Multidrug resistance-associated biomarkers PGP, GST-π, Topo-II and LRP as prognostic factors in primary ovarian carcinoma. Br. J. Biomed. Sci., 2011, 68(2), 69-74.
[http://dx.doi.org/10.1080/09674845.2011.11730326] [PMID: 21706917]
[50]
Kim, J-W.; Lee, H.S.; Nam, K.H.; Ahn, S.; Kim, J.W.; Ahn, S-H.; Park, D.J.; Kim, H-H.; Lee, K-W. PIK3CA mutations are associated with increased tumor aggressiveness and Akt activation in gastric cancer. Oncotarget, 2017, 8(53), 90948-90958.
[http://dx.doi.org/10.18632/oncotarget.18770] [PMID: 29207615]
[51]
Piao, Y.; Li, Y.; Xu, Q.; Liu, J.W.; Xing, C.Z.; Xie, X.D.; Yuan, Y. Association of MTOR and AKT gene polymorphisms with susceptibility and survival of gastric cancer. PLoS One, 2015, 10(8)e0136447
[http://dx.doi.org/10.1371/journal.pone.0136447] [PMID: 26317520]
[52]
Horn, D.; Freudlsperger, C.; Holzinger, D.; Kunzmann, K.; Plinkert, P.; Dyckhoff, G.; Hoffmann, J.; Freier, K.; Hess, J. Upregulation of pAKT(Ser473) expression in progression of HPV-positive oropharyngeal squamous cell carcinoma. Head Neck, 2017, 39(12), 2397-2405.
[http://dx.doi.org/10.1002/hed.24910] [PMID: 28945300]
[53]
West, K.A.; Linnoila, I.R.; Belinsky, S.A.; Harris, C.C.; Dennis, P.A. Tobacco carcinogen-induced cellular transformation increases activation of the phosphatidylinositol 3′-kinase/Akt pathway in vitro and in vivo. Cancer Res., 2004, 64(2), 446-451.
[http://dx.doi.org/10.1158/0008-5472.CAN-03-3241] [PMID: 14744754]
[54]
Chun, K-H.; Kosmeder, J.W., II; Sun, S.; Pezzuto, J.M.; Lotan, R.; Hong, W.K.; Lee, H-Y. Effects of deguelin on the phosphatidylinositol 3-kinase/Akt pathway and apoptosis in premalignant human bronchial epithelial cells. J. Natl. Cancer Inst., 2003, 95(4), 291-302.
[http://dx.doi.org/10.1093/jnci/95.4.291] [PMID: 12591985]
[55]
Guo, Y.; Du, J.; Kwiatkowski, D.J. Molecular dissection of AKT activation in lung cancer cell lines. Mol. Cancer Res., 2013, 11(3), 282-293.
[http://dx.doi.org/10.1158/1541-7786.MCR-12-0558] [PMID: 23319332]
[56]
Yu, X.; Yuan, Y.; Zhi, X.; Teng, B.; Chen, X.; Huang, Q.; Chen, Y.; Guan, Z.; Zhang, Y. Correlation between the protein expression of A-kinase anchor protein 95, cyclin D3 and AKT and pathological indicators in lung cancer tissues. Exp. Ther. Med., 2015, 10(3), 1175-1181.
[http://dx.doi.org/10.3892/etm.2015.2637] [PMID: 26622460]
[57]
Bose, S.; Chandran, S.; Mirocha, J.M.; Bose, N. The Akt pathway in human breast cancer: A tissue-array-based analysis. Mod. Pathol., 2006, 19(2), 238-245.
[http://dx.doi.org/10.1038/modpathol.3800525] [PMID: 16341149]
[58]
Majumder, P.K.; Febbo, P.G.; Bikoff, R.; Berger, R.; Xue, Q.; McMahon, L.M.; Manola, J.; Brugarolas, J.; McDonnell, T.J.; Golub, T.R.; Loda, M.; Lane, H.A.; Sellers, W.R. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat. Med., 2004, 10(6), 594-601.
[http://dx.doi.org/10.1038/nm1052] [PMID: 15156201]
[59]
Malik, S.N.; Brattain, M.; Ghosh, P.M.; Troyer, D.A.; Prihoda, T.; Bedolla, R.; Kreisberg, J.I. Immunohistochemical demonstration of phospho-Akt in high Gleason grade prostate cancer. Clin. Cancer Res., 2002, 8(4), 1168-1171.
[PMID: 11948129]
[60]
Xin, L.; Teitell, M.A.; Lawson, D.A.; Kwon, A.; Mellinghoff, I.K.; Witte, O.N. Progression of prostate cancer by synergy of AKT with genotropic and nongenotropic actions of the androgen receptor. Proc. Natl. Acad. Sci. USA, 2006, 103(20), 7789-7794.
[http://dx.doi.org/10.1073/pnas.0602567103] [PMID: 16682621]
[61]
Majumder, P.K.; Sellers, W.R. Akt-regulated pathways in prostate cancer. Oncogene, 2005, 24(50), 7465-7474.
[http://dx.doi.org/10.1038/sj.onc.1209096] [PMID: 16288293]
[62]
Dai, D.L.; Martinka, M.; Li, G. Prognostic significance of activated Akt expression in melanoma: A clinicopathologic study of 292 cases. J. Clin. Oncol., 2005, 23(7), 1473-1482.
[http://dx.doi.org/10.1200/JCO.2005.07.168] [PMID: 15735123]
[63]
Stahl, J.M.; Sharma, A.; Cheung, M.; Zimmerman, M.; Cheng, J.Q.; Bosenberg, M.W.; Kester, M.; Sandirasegarane, L.; Robertson, G.P. Deregulated Akt3 activity promotes development of malignant melanoma. Cancer Res., 2004, 64(19), 7002-7010.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-1399] [PMID: 15466193]
[64]
Bedogni, B.; Welford, S.M.; Cassarino, D.S.; Nickoloff, B.J.; Giaccia, A.J.; Powell, M.B. The hypoxic microenvironment of the skin contributes to Akt-mediated melanocyte transformation. Cancer Cell, 2005, 8(6), 443-454.
[http://dx.doi.org/10.1016/j.ccr.2005.11.005] [PMID: 16338658]
[65]
McCubrey, J.A.; Steelman, L.S.; Abrams, S.L.; Lee, J.T.; Chang, F.; Bertrand, F.E.; Navolanic, P.M.; Terrian, D.M.; Franklin, R.A.; D’Assoro, A.B.; Salisbury, J.L.; Mazzarino, M.C.; Stivala, F.; Libra, M. Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv. Enzyme Regul., 2006, 46(1), 249-279.
[http://dx.doi.org/10.1016/j.advenzreg.2006.01.004] [PMID: 16854453]
[66]
Kandoth, C.; McLellan, M.D.; Vandin, F.; Ye, K.; Niu, B.; Lu, C.; Xie, M.; Zhang, Q.; McMichael, J.F.; Wyczalkowski, M.A.; Leiserson, M.D.M.; Miller, C.A.; Welch, J.S.; Walter, M.J.; Wendl, M.C.; Ley, T.J.; Wilson, R.K.; Raphael, B.J.; Ding, L. Mutational landscape and significance across 12 major cancer types. Nature, 2013, 502(7471), 333-339.
[http://dx.doi.org/10.1038/nature12634] [PMID: 24132290]
[67]
Ojesina, A.I.; Lichtenstein, L.; Freeman, S.S.; Pedamallu, C.S.; Imaz-Rosshandler, I.; Pugh, T.J.; Cherniack, A.D.; Ambrogio, L.; Cibulskis, K.; Bertelsen, B.; Romero-Cordoba, S.; Treviño, V.; Vazquez-Santillan, K.; Guadarrama, A.S.; Wright, A.A.; Rosenberg, M.W.; Duke, F.; Kaplan, B.; Wang, R.; Nickerson, E.; Walline, H.M.; Lawrence, M.S.; Stewart, C.; Carter, S.L.; McKenna, A.; Rodriguez-Sanchez, I.P.; Espinosa-Castilla, M.; Woie, K.; Bjorge, L.; Wik, E.; Halle, M.K.; Hoivik, E.A.; Krakstad, C.; Gabiño, N.B.; Gómez-Macías, G.S.; Valdez-Chapa, L.D.; Garza-Rodríguez, M.L.; Maytorena, G.; Vazquez, J.; Rodea, C.; Cravioto, A.; Cortes, M.L.; Greulich, H.; Crum, C.P.; Neuberg, D.S.; Hidalgo-Miranda, A.; Escareno, C.R.; Akslen, L.A.; Carey, T.E.; Vintermyr, O.K.; Gabriel, S.B.; Barrera-Saldaña, H.A.; Melendez-Zajgla, J.; Getz, G.; Salvesen, H.B.; Meyerson, M. Landscape of genomic alterations in cervical carcinomas. Nature, 2014, 506(7488), 371-375.
[http://dx.doi.org/10.1038/nature12881] [PMID: 24390348]
[68]
Kandoth, C.; Schultz, N.; Cherniack, A.D.; Akbani, R.; Liu, Y.; Shen, H.; Robertson, A.G.; Pashtan, I.; Shen, R.; Benz, C.C.; Yau, C.; Laird, P.W.; Ding, L.; Zhang, W.; Mills, G.B.; Kucherlapati, R.; Mardis, E.R.; Levine, D.A.; Levine, D.A. Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. Nature, 2013, 497(7447), 67-73.
[http://dx.doi.org/10.1038/nature12113] [PMID: 23636398]
[69]
Du, C.X.; Wang, Y. Expression of P-Akt, NFkappaB and their correlation with human papillomavirus infection in cervical carcinoma. Eur. J. Gynaecol. Oncol., 2012, 33(3), 274-277.
[PMID: 22873098]
[70]
Gupta, A.K.; Lee, J.H.; Wilke, W.W.; Quon, H.; Smith, G.; Maity, A.; Buatti, J.M.; Spitz, D.R. Radiation response in two HPV-infected head-and-neck cancer cell lines in comparison to a non-HPV-infected cell line and relationship to signaling through AKT. Int. J. Radiat. Oncol. Biol. Phys., 2009, 74(3), 928-933.
[http://dx.doi.org/10.1016/j.ijrobp.2009.03.004] [PMID: 19480971]
[71]
Pal, S.K.; Reckamp, K.; Yu, H.; Figlin, R.A. Akt inhibitors in clinical development for the treatment of cancer. Expert Opin. Investig. Drugs, 2010, 19(11), 1355-1366.
[http://dx.doi.org/10.1517/13543784.2010.520701] [PMID: 20846000]
[72]
Lindsley, C.W.; Barnett, S.F.; Yaroschak, M.; Bilodeau, M.T.; Layton, M.E. Recent progress in the development of ATP-competitive and allosteric Akt kinase inhibitors. Curr. Top. Med. Chem., 2007, 7(14), 1349-1363.
[http://dx.doi.org/10.2174/156802607781696864] [PMID: 17692025]
[73]
Chee, K.G.; Longmate, J.; Quinn, D.I.; Chatta, G.; Pinski, J.; Twardowski, P.; Pan, C-X.; Cambio, A.; Evans, C.P.; Gandara, D.R.; Lara, P.N., Jr The AKT inhibitor perifosine in biochemically recurrent prostate cancer: A phase II California/Pittsburgh cancer consortium trial. Clin. Genitourin. Cancer, 2007, 5(7), 433-437.
[http://dx.doi.org/10.3816/CGC.2007.n.031] [PMID: 18272025]
[74]
Cho, D.C.; Hutson, T.E.; Samlowski, W.; Sportelli, P.; Somer, B.; Richards, P.; Sosman, J.A.; Puzanov, I.; Michaelson, M.D.; Flaherty, K.T.; Figlin, R.A.; Vogelzang, N.J. Two phase 2 trials of the novel Akt inhibitor perifosine in patients with advanced renal cell carcinoma after progression on vascular endothelial growth factor-targeted therapy. Cancer, 2012, 118(24), 6055-6062.
[http://dx.doi.org/10.1002/cncr.27668] [PMID: 22674198]
[75]
Molife, L.R.; Yan, L.; Vitfell-Rasmussen, J.; Zernhelt, A.M.; Sullivan, D.M.; Cassier, P.A.; Chen, E.; Biondo, A.; Tetteh, E.; Siu, L.L.; Patnaik, A.; Papadopoulos, K.P.; de Bono, J.S.; Tolcher, A.W.; Minton, S. Phase 1 trial of the oral AKT inhibitor MK-2206 plus carboplatin/paclitaxel, docetaxel, or erlotinib in patients with advanced solid tumors. J. Hematol. Oncol., 2014, 7(1), 1.
[http://dx.doi.org/10.1186/1756-8722-7-1] [PMID: 24387695]
[76]
Yap, T.A.; Yan, L.; Patnaik, A.; Fearen, I.; Olmos, D.; Papadopoulos, K.; Baird, R.D.; Delgado, L.; Taylor, A.; Lupinacci, L.; Riisnaes, R.; Pope, L.L.; Heaton, S.P.; Thomas, G.; Garrett, M.D.; Sullivan, D.M.; de Bono, J.S.; Tolcher, A.W. First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors. J. Clin. Oncol., 2011, 29(35), 4688-4695.
[http://dx.doi.org/10.1200/JCO.2011.35.5263] [PMID: 22025163]
[77]
Do, K.; Speranza, G.; Bishop, R.; Khin, S.; Rubinstein, L.; Kinders, R.J.; Datiles, M.; Eugeni, M.; Lam, M.H.; Doyle, L.A.; Doroshow, J.H.; Kummar, S. Biomarker-driven phase 2 study of MK-2206 and selumetinib (AZD6244, ARRY-142886) in patients with colorectal cancer. Invest. New Drugs, 2015, 33(3), 720-728.
[http://dx.doi.org/10.1007/s10637-015-0212-z] [PMID: 25637165]
[78]
Marshall, J.; Posey, J.; Hwang, J.; Malik, S.; Shen, R.; Kazempour, K.; White, L.; Fraser, K.; Chang, C.; Ahn, C. A phase I trial of RX-0201 (AKT anti-sense) in patients with an advanced cancer. J. Clin. Oncol., 2007.
[79]
Yap, T.A.; Walton, M.I.; Hunter, L-J.K.; Valenti, M.; de Haven Brandon, A.; Eve, P.D.; Ruddle, R.; Heaton, S.P.; Henley, A.; Pickard, L.; Vijayaraghavan, G.; Caldwell, J.J.; Thompson, N.T.; Aherne, W.; Raynaud, F.I.; Eccles, S.A.; Workman, P.; Collins, I.; Garrett, M.D. Preclinical pharmacology, antitumor activity, and development of pharmacodynamic markers for the novel, potent AKT inhibitor CCT128930. Mol. Cancer Ther., 2011, 10(2), 360-371.
[http://dx.doi.org/10.1158/1535-7163.MCT-10-0760] [PMID: 21191045]
[80]
Bidyasar, S.; Kurzrock, R.; Falchook, G.; Naing, A.; Wheler, J.; Durand, J.; Yang, P.; Johansen, M.; Newman, R.; Khan, R.; Hong, D. A first-in-human phase I trial of PBI-05204 (oleandrin), an inhibitor of Akt, FGF-2, NF-Kb, and p70S6K in advanced solid tumor patients. J. Clin. Oncol., 2009.
[81]
Cheraghchi-Bashi, A.; Parker, C.A.; Curry, E.; Salazar, J.F.; Gungor, H.; Saleem, A.; Cunnea, P.; Rama, N.; Salinas, C.; Mills, G.B.; Morris, S.R.; Kumar, R.; Gabra, H.; Stronach, E.A. A putative biomarker signature for clinically effective AKT inhibition: Correlation of in vitro, in vivo and clinical data identifies the importance of modulation of the mTORC1 pathway. Oncotarget, 2015, 6(39), 41736-41749.
[http://dx.doi.org/10.18632/oncotarget.6153] [PMID: 26497682]
[82]
Algazi, A.P.; Muthukumar, A.H.; O’Brien, K.; Lencioni, A.; Tsai, K.K.; Kadafour, M.; Chapman, P.B.; Daud, A. Phase II trial of trametinib in combination with the AKT inhibitor GSK 2141795 in BRAF wild-type melanoma. J. Clin. Oncol., 2015.
[83]
Dumble, M.; Crouthamel, M-C.; Zhang, S-Y.; Schaber, M.; Levy, D.; Robell, K.; Liu, Q.; Figueroa, D.J.; Minthorn, E.A.; Seefeld, M.A.; Rouse, M.B.; Rabindran, S.K.; Heerding, D.A.; Kumar, R. Discovery of novel AKT inhibitors with enhanced anti-tumor effects in combination with the MEK inhibitor. PLoS One, 2014, 9(6)e100880
[http://dx.doi.org/10.1371/journal.pone.0100880] [PMID: 24978597]
[84]
Handrick, R.; Rübel, A.; Faltin, H.; Eibl, H.; Belka, C.; Jendrossek, V. Increased cytotoxicity of ionizing radiation in combination with membrane-targeted apoptosis modulators involves downregulation of protein kinase B/Akt-mediated survival-signaling. Radiother. Oncol., 2006, 80(2), 199-206.
[http://dx.doi.org/10.1016/j.radonc.2006.07.021] [PMID: 16916558]
[85]
Heerding, D.A.; Rhodes, N.; Leber, J.D.; Clark, T.J.; Keenan, R.M.; Lafrance, L.V.; Li, M.; Safonov, I.G.; Takata, D.T.; Venslavsky, J.W.; Yamashita, D.S.; Choudhry, A.E.; Copeland, R.A.; Lai, Z.; Schaber, M.D.; Tummino, P.J.; Strum, S.L.; Wood, E.R.; Duckett, D.R.; Eberwein, D.; Knick, V.B.; Lansing, T.J.; McConnell, R.T.; Zhang, S.; Minthorn, E.A.; Concha, N.O.; Warren, G.L.; Kumar, R. Identification of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-[(3S)-3-piperidinylmethyl]oxy-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a novel inhibitor of AKT kinase. J. Med. Chem., 2008, 51(18), 5663-5679.
[http://dx.doi.org/10.1021/jm8004527] [PMID: 18800763]
[86]
Crouthamel, M-C.; Kahana, J.A.; Korenchuk, S.; Zhang, S-Y.; Sundaresan, G.; Eberwein, D.J.; Brown, K.K.; Kumar, R. Mechanism and management of AKT inhibitor-induced hyperglycemia. Clin. Cancer Res., 2009, 15(1), 217-225.
[http://dx.doi.org/10.1158/1078-0432.CCR-08-1253] [PMID: 19118049]
[87]
Maira, S-M.; Furet, P.; Stauffer, F. Discovery of novel anticancer therapeutics targeting the PI3K/Akt/mTOR pathway. Future Med. Chem., 2009, 1(1), 137-155.
[http://dx.doi.org/10.4155/fmc.09.5] [PMID: 21426073]
[88]
Alzahrani, A.S. PI3K/Akt/mTOR inhibitors in cancer: At the bench and bedside. Semin. Cancer Biol., 2019, 59(59), 125-132.
[http://dx.doi.org/10.1016/j.semcancer.2019.07.009] [PMID: 31323288]
[89]
Hyman, D.; Smyth, L.; Donoghue, M.; Westin, S.; Bedard, P.; Dean, E. AZD5363 has clinical activity in patients with AKT1-mutant solid tumors. Cancer Discov., 2017, 7(7), 662.
[http://dx.doi.org/10.1158/2159-8290.CD-RW2017-093]
[90]
Saura, C.; Roda, D.; Roselló, S.; Oliveira, M.; Macarulla, T.; Pérez-Fidalgo, J.A.; Morales-Barrera, R.; Sanchis-García, J.M.; Musib, L.; Budha, N.; Zhu, J.; Nannini, M.; Chan, W.Y.; Sanabria Bohórquez, S.M.; Meng, R.D.; Lin, K.; Yan, Y.; Patel, P.; Baselga, J.; Tabernero, J.; Cervantes, A. A first-in-human phase I study of the ATP-competitive AKT inhibitor ipatasertib demonstrates robust and safe targeting of AKT in patients with solid tumors. Cancer Discov., 2017, 7(1), 102-113.
[http://dx.doi.org/10.1158/2159-8290.CD-16-0512] [PMID: 27872130]
[91]
Politz, O.; Siegel, F.; Bärfacker, L.; Bömer, U.; Hägebarth, A.; Scott, W.J.; Michels, M.; Ince, S.; Neuhaus, R.; Meyer, K.; Fernández-Montalván, A.E.; Liu, N.; von Nussbaum, F.; Mumberg, D.; Ziegelbauer, K. BAY 1125976, a selective allosteric AKT1/2 inhibitor, exhibits high efficacy on AKT signaling-dependent tumor growth in mouse models. Int. J. Cancer, 2017, 140(2), 449-459.
[http://dx.doi.org/10.1002/ijc.30457] [PMID: 27699769]
[92]
Fukuoka, S.; Kojima, T.; Koga, Y.; Yamauchi, M.; Yasunaga, M.; Matsumura, Y.; Doi, T.; Yoshino, T.; Kuronita, T.; Clark, A.; Elenbaas, B.; Ohtsu, A. M2698, a novel dual inhibitor of p70S6K and Akt: Preclinical efficacy in gastric cancer. Proc. Am. Associat. Cancer Res. Ann. Meeting 2017, Apr 1-5, 2017 Washington,DC2017..
[http://dx.doi.org/10.1158/1538-7445.AM2017-139]
[93]
Vicier, C.; Isambert, N.; Dalenc, F.; Campone, M.; Levy, C.; Rezai, K.; Provansal, M.; Adelaide, J.; Garnier, S.; Guille, A.; Chaffanet, M.; Popovici, C.; Charafe-Jauffret, E.; Pakradouni, J.; Autret, A.; Goncalves, A. TAKTIC: A prospective, multicenter, uncontrolled, phase IB/II study of LY2780301 (LY) in combination with weekly paclitaxel (wP) in HER2-negative locally advanced (LA) or metastatic breast cancer (MBC) patients. J. Clin. Oncol., 2019.
[94]
Bilodeau, M.T.; Balitza, A.E.; Hoffman, J.M.; Manley, P.J.; Barnett, S.F.; Defeo-Jones, D.; Haskell, K.; Jones, R.E.; Leander, K.; Robinson, R.G.; Smith, A.M.; Huber, H.E.; Hartman, G.D. Allosteric inhibitors of Akt1 and Akt2: A naphthyridinone with efficacy in an A2780 tumor xenograft model. Bioorg. Med. Chem. Lett., 2008, 18(11), 3178-3182.
[http://dx.doi.org/10.1016/j.bmcl.2008.04.074] [PMID: 18479914]
[95]
Tagawa, S.T.; Chatta, G.S.; Mazhari, R.; Benaim, E. Archexin, a novel AKT-1–specific inhibitor for the treatment of metastatic renal cancer: Preliminary phase I data. J. Clin. Oncol., 2016, 34(2), 550.
[96]
Mimura, N.; Ohguchi, H.; Cirstea, D.; Cottini, F.; Gorgun, G.T.; Minami, J.; Suzuki, R.; Shimomura, T.; Utsugi, T.; Hideshima, T.; Anderson, K.C. TAS-117, a novel selective Akt inhibitor demonstrates significant growth inhibition in multiple myeloma cells in vitro and in vivo. Blood, 2012, 120(21), 942.
[http://dx.doi.org/10.1182/blood.V120.21.942.942]
[97]
Kim, M.O.; Lee, M-H.; Oi, N.; Kim, S-H.; Bae, K.B.; Huang, Z.; Kim, D.J.; Reddy, K.; Lee, S-Y.; Park, S.J.; Kim, J.Y.; Xie, H.; Kundu, J.K.; Ryoo, Z.Y.; Bode, A.M.; Surh, Y.J.; Dong, Z. [6]-shogaol inhibits growth and induces apoptosis of non-small cell lung cancer cells by directly regulating Akt1/2. Carcinogenesis, 2014, 35(3), 683-691.
[http://dx.doi.org/10.1093/carcin/bgt365] [PMID: 24282290]
[98]
Song, M.; Liu, X.; Liu, K.; Zhao, R.; Huang, H.; Shi, Y.; Zhang, M.; Zhou, S.; Xie, H.; Chen, H.; Li, Y.; Zheng, Y.; Wu, Q.; Liu, F.; Li, E.; Bode, A.M.; Dong, Z.; Lee, M.H. Targeting AKT with oridonin inhibits growth of esophageal squamous cell carcinoma in vitro and patient-derived xenografts in vivo. Mol. Cancer Ther., 2018, 17(7), 1540-1553.
[http://dx.doi.org/10.1158/1535-7163.MCT-17-0823] [PMID: 29695636]
[99]
Kim, D.J.; Lee, M-H.; Liu, K.; Lim, D.Y.; Roh, E.; Chen, H.; Kim, S-H.; Shim, J-H.; Kim, M.O.; Li, W.; Ma, F.; Fredimoses, M.; Bode, A.M.; Dong, Z. Herbacetin suppresses cutaneous squamous cell carcinoma and melanoma cell growth by targeting AKT and ODC. Carcinogenesis, 2017, 38(11), 1136-1146.
[http://dx.doi.org/10.1093/carcin/bgx082] [PMID: 29029040]
[100]
Lee, H-Y.; Oh, S-H.; Woo, J.K.; Kim, W-Y.; Van Pelt, C.S.; Price, R.E.; Cody, D.; Tran, H.; Pezzuto, J.M.; Moriarty, R.M.; Hong, W.K. Chemopreventive effects of deguelin, a novel Akt inhibitor, on tobacco-induced lung tumorigenesis. J. Natl. Cancer Inst., 2005, 97(22), 1695-1699.
[http://dx.doi.org/10.1093/jnci/dji377] [PMID: 16288123]
[101]
Sawai, Y.; Murata, H.; Horii, M.; Koto, K.; Matsui, T.; Horie, N.; Tsuji, Y.; Ashihara, E.; Maekawa, T.; Kubo, T.; Fushiki, S. Effectiveness of sulforaphane as a radiosensitizer for murine osteosarcoma cells. Oncol. Rep., 2013, 29(3), 941-945.
[http://dx.doi.org/10.3892/or.2012.2195] [PMID: 23254561]
[102]
Noori, S.; Hassan, Z.M. Tehranolide inhibits proliferation of MCF-7 human breast cancer cells by inducing G0/G1 arrest and apoptosis. Free Radic. Biol. Med., 2012, 52(9), 1987-1999.
[http://dx.doi.org/10.1016/j.freeradbiomed.2012.01.026] [PMID: 22366652]
[103]
Li, Y.; Zhao, H.; Wang, Y.; Zheng, H.; Yu, W.; Chai, H.; Zhang, J.; Falck, J.R.; Guo, A.M.; Yue, J.; Peng, R.; Yang, J. Isoliquiritigenin induces growth inhibition and apoptosis through downregulating arachidonic acid metabolic network and the deactivation of PI3K/Akt in human breast cancer. Toxicol. Appl. Pharmacol., 2013, 272(1), 37-48.
[http://dx.doi.org/10.1016/j.taap.2013.05.031] [PMID: 23747687]
[104]
Ke, Y.; Bao, T.; Wu, X.; Tang, H.; Wang, Y.; Ge, J.; Fu, B.; Meng, X.; Chen, L.; Zhang, C.; Tan, Y.; Chen, H.; Guo, Z.; Ni, F.; Lei, X.; Shi, Z.; Wei, D.; Wang, L. Scutellarin suppresses migration and invasion of human hepatocellular carcinoma by inhibiting the STAT3/Girdin/Akt activity. Biochem. Biophys. Res. Commun., 2017, 483(1), 509-515.
[http://dx.doi.org/10.1016/j.bbrc.2016.12.114] [PMID: 27998773]
[105]
Zeng, Y-H.; Zhou, L-Y.; Chen, Q-Z.; Li, Y.; Shao, Y.; Ren, W-Y.; Liao, Y-P.; Wang, H.; Zhu, J-H.; Huang, M.; He, F.; Wang, J.; Wu, K.; He, B.C. Resveratrol inactivates PI3K/Akt signaling through upregulating BMP7 in human colon cancer cells. Oncol. Rep., 2017, 38(1), 456-464.
[http://dx.doi.org/10.3892/or.2017.5662] [PMID: 28534975]
[106]
Chai, R.; Fu, H.; Zheng, Z.; Liu, T.; Ji, S.; Li, G. Resveratrol inhibits proliferation and migration through SIRT1 mediated post-translational modification of PI3K/AKT signaling in hepatocellular carcinoma cells. Mol. Med. Rep., 2017, 16(6), 8037-8044.
[http://dx.doi.org/10.3892/mmr.2017.7612] [PMID: 28983625]
[107]
Wright, C.; Iyer, A.K.V.; Yakisich, J.S.; Azad, N. Anti-tumorigenic effects of resveratrol in lung cancer cells through modulation of c-FLIP. Curr. Cancer Drug Targets, 2017, 17(7), 669-680.
[http://dx.doi.org/10.2174/1568009617666170315162932] [PMID: 28302032]
[108]
Li, T.; Chen, X.; Chen, X.; Ma, D.L.; Leung, C.H.; Lu, J.J. Platycodin D potentiates proliferation inhibition and apoptosis induction upon AKT inhibition via feedback blockade in non-small cell lung cancer cells. Sci. Rep., 2016, 6, 37997.
[http://dx.doi.org/10.1038/srep37997] [PMID: 27897231]
[109]
Yeh, P-S.; Wang, W.; Chang, Y-A.; Lin, C-J.; Wang, J-J.; Chen, R-M. Honokiol induces autophagy of neuroblastoma cells through activating the PI3K/Akt/mTOR and endoplasmic reticular stress/ERK1/2 signaling pathways and suppressing cell migration. Cancer Lett., 2016, 370(1), 66-77.
[http://dx.doi.org/10.1016/j.canlet.2015.08.030] [PMID: 26454217]
[110]
Ghosheh, O.A.; Houdi, A.A.; Crooks, P.A. High performance liquid chromatographic analysis of the pharmacologically active quinones and related compounds in the oil of the black seed (Nigella sativa L.). J. Pharm. Biomed. Anal., 1999, 19(5), 757-762.
[http://dx.doi.org/10.1016/S0731-7085(98)00300-8] [PMID: 10698539]
[111]
Gurung, R.L.; Lim, S.N.; Khaw, A.K.; Soon, J.F.F.; Shenoy, K.; Mohamed Ali, S.; Jayapal, M.; Sethu, S.; Baskar, R.; Hande, M.P. Thymoquinone induces telomere shortening, DNA damage and apoptosis in human glioblastoma cells. PLoS One, 2010, 5(8)e12124
[http://dx.doi.org/10.1371/journal.pone.0012124] [PMID: 20711342]
[112]
El-Najjar, N.; Chatila, M.; Moukadem, H.; Vuorela, H.; Ocker, M.; Gandesiri, M.; Schneider-Stock, R.; Gali-Muhtasib, H. Reactive oxygen species mediate thymoquinone-induced apoptosis and activate ERK and JNK signaling. Apoptosis, 2010, 15(2), 183-195.
[http://dx.doi.org/10.1007/s10495-009-0421-z] [PMID: 19882352]
[113]
Kaseb, A.O.; Chinnakannu, K.; Chen, D.; Sivanandam, A.; Tejwani, S.; Menon, M.; Dou, Q.P.; Reddy, G.P-V. Androgen receptor and E2F-1 targeted thymoquinone therapy for hormone-refractory prostate cancer. Cancer Res., 2007, 67(16), 7782-7788.
[http://dx.doi.org/10.1158/0008-5472.CAN-07-1483] [PMID: 17699783]
[114]
Afrose, S.S.; Junaid, M.; Akter, Y.; Tania, M.; Zheng, M.; Khan, M.A. Targeting kinases with thymoquinone: A molecular approach to cancer therapeutics.Drug Discov. Today, 2020.S1359-6446(20)30299-3,
[http://dx.doi.org/10.1016/j.drudis.2020.07.019] [PMID: 32721537]
[115]
Rajput, S.; Kumar, B.N.; Dey, K.K.; Pal, I.; Parekh, A.; Mandal, M. Molecular targeting of Akt by thymoquinone promotes G(1) arrest through translation inhibition of cyclin D1 and induces apoptosis in breast cancer cells. Life Sci., 2013, 93(21), 783-790.
[http://dx.doi.org/10.1016/j.lfs.2013.09.009] [PMID: 24044882]
[116]
Hsu, H-H.; Chen, M-C.; Day, C.H.; Lin, Y-M.; Li, S-Y.; Tu, C-C.; Padma, V.V.; Shih, H-N.; Kuo, W-W.; Huang, C-Y. Thymoquinone suppresses migration of LoVo human colon cancer cells by reducing prostaglandin E2 induced COX-2 activation. World J. Gastroenterol., 2017, 23(7), 1171-1179.
[http://dx.doi.org/10.3748/wjg.v23.i7.1171] [PMID: 28275297]
[117]
Xu, D.; Ma, Y.; Zhao, B.; Li, S.; Zhang, Y.; Pan, S.; Wu, Y.; Wang, J.; Wang, D.; Pan, H.; Liu, L.; Jiang, H. Thymoquinone induces G2/M arrest, inactivates PI3K/Akt and nuclear factor-κB pathways in human cholangiocarcinomas both in vitro and in vivo. Oncol. Rep., 2014, 31(5), 2063-2070.
[http://dx.doi.org/10.3892/or.2014.3059] [PMID: 24603952]
[118]
Dirican, A.; Atmaca, H.; Bozkurt, E.; Erten, C.; Karaca, B.; Uslu, R. Novel combination of docetaxel and thymoquinone induces synergistic cytotoxicity and apoptosis in DU-145 human prostate cancer cells by modulating PI3K-AKT pathway. Clin. Transl. Oncol., 2015, 17(2), 145-151.
[http://dx.doi.org/10.1007/s12094-014-1206-6] [PMID: 25060568]
[119]
Das, S.; Dey, K.K.; Dey, G.; Pal, I.; Majumder, A.; Maiti Choudhury, S.; Kundu, S.C.; Mandal, M. Antineoplastic and apoptotic potential of traditional medicines thymoquinone and diosgenin in squamous cell carcinoma. PLoS One, 2012, 7(10)e46641
[http://dx.doi.org/10.1371/journal.pone.0046641] [PMID: 23077516]
[120]
Dera, A.; Rajagopalan, P. Thymoquinone attenuates phosphorylation of AKT to inhibit kidney cancer cell proliferation. J. Food Biochem., 2019, 43(4)e12793
[http://dx.doi.org/10.1111/jfbc.12793] [PMID: 31353586]
[121]
Feng, L-M.; Wang, X-F.; Huang, Q-X. Thymoquinone induces cytotoxicity and reprogramming of EMT in gastric cancer cells by targeting PI3K/Akt/mTOR pathway. J. Biosci., 2017, 42(4), 547-554.
[http://dx.doi.org/10.1007/s12038-017-9708-3] [PMID: 29229873]
[122]
Iskender, B.; Izgi, K.; Canatan, H. Novel anti-cancer agent myrtucommulone-A and thymoquinone abrogate epithelial-mesenchymal transition in cancer cells mainly through the inhibition of PI3K/AKT signalling axis. Mol. Cell. Biochem., 2016, 416(1-2), 71-84.
[http://dx.doi.org/10.1007/s11010-016-2697-y] [PMID: 27032769]
[123]
Arafa, S.A.; Zhu, Q.; Shah, Z.I.; Wani, G.; Barakat, B.M.; Racoma, I.; El-Mahdy, M.A.; Wani, A.A. Thymoquinone up-regulates PTEN expression and induces apoptosis in doxorubicin-resistant human breast cancer cells. Mutat. Res., 2011, 706(1-2), 28-35.
[http://dx.doi.org/10.1016/j.mrfmmm.2010.10.007] [PMID: 21040738]
[124]
Rajput, S.; Kumar, B.N.; Sarkar, S.; Das, S.; Azab, B.; Santhekadur, P.K.; Das, S.K.; Emdad, L.; Sarkar, D.; Fisher, P.B.; Mandal, M. Targeted apoptotic effects of thymoquinone and tamoxifen on XIAP mediated Akt regulation in breast cancer. PLoS One, 2013, 8(4)e61342
[http://dx.doi.org/10.1371/journal.pone.0061342] [PMID: 23613836]
[125]
Şakalar, Ç.; İzgi, K.; İskender, B.; Sezen, S.; Aksu, H.; Çakır, M.; Kurt, B.; Turan, A.; Canatan, H. The combination of thymoquinone and paclitaxel shows anti-tumor activity through the interplay with apoptosis network in triple-negative breast cancer. Tumour Biol., 2016, 37(4), 4467-4477.
[http://dx.doi.org/10.1007/s13277-015-4307-0] [PMID: 26500095]
[126]
Mu, G.G.; Zhang, L.L.; Li, H.Y.; Liao, Y.; Yu, H.G. Thymoquinone pretreatment overcomes the insensitivity and potentiates the antitumor effect of gemcitabine through abrogation of notch1, PI3K/Akt/mTOR regulated signaling pathways in pancreatic cancer. Dig. Dis. Sci., 2015, 60(4), 1067-1080.
[http://dx.doi.org/10.1007/s10620-014-3394-x] [PMID: 25344906]
[127]
Relles, D.; Chipitsyna, G.I.; Gong, Q.; Yeo, C.J.; Arafat, H.A. Thymoquinone promotes pancreatic cancer cell death and reduction of tumor size through combined inhibition of histone deacetylation and induction of histone acetylation. Adv. Prev. Med., 2016.20161407840
[http://dx.doi.org/10.1155/2016/1407840] [PMID: 28105374]
[128]
Mu, H.Q.; Yang, S.; Wang, Y.J.; Chen, Y.H. Role of NF-κB in the anti-tumor effect of thymoquinone on bladder cancer. Zhonghua Yi Xue Za Zhi, 2012, 92(6), 392-396.
[PMID: 22490899]
[129]
Muralidharan-Chari, V.; Kim, J.; Abuawad, A.; Naeem, M.; Cui, H.; Mousa, S.A. Thymoquinone modulates blood coagulation in vitro via its effects on inflammatory and coagulation pathways. Int. J. Mol. Sci., 2016, 17(4), 474.
[http://dx.doi.org/10.3390/ijms17040474] [PMID: 27043539]
[130]
Yusufi, M.; Banerjee, S.; Mohammad, M.; Khatal, S.; Venkateswara Swamy, K.; Khan, E.M.; Aboukameel, A.; Sarkar, F.H.; Padhye, S. Synthesis, characterization and anti-tumor activity of novel thymoquinone analogs against pancreatic cancer. Bioorg. Med. Chem. Lett., 2013, 23(10), 3101-3104.
[http://dx.doi.org/10.1016/j.bmcl.2013.03.003] [PMID: 23562242]
[131]
Kundu, J.; Kim, D-H.; Kundu, J.K.; Chun, K-S. Thymoquinone induces heme oxygenase-1 expression in HaCaT cells via Nrf2/ARE activation: Akt and AMPKα as upstream targets. Food Chem. Toxicol., 2014, 65, 18-26.
[http://dx.doi.org/10.1016/j.fct.2013.12.015] [PMID: 24355171]
[132]
Kundu, J.K.; Liu, L.; Shin, J-W.; Surh, Y-J. Thymoquinone inhibits phorbol ester-induced activation of NF-κB and expression of COX-2, and induces expression of cytoprotective enzymes in mouse skin in vivo. Biochem. Biophys. Res. Commun., 2013, 438(4), 721-727.
[http://dx.doi.org/10.1016/j.bbrc.2013.07.110] [PMID: 23911786]

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