Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

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

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Wortmannin Inhibits Cell Growth and Induces Apoptosis in Colorectal Cancer Cells by Suppressing the PI3K/AKT Pathway

Author(s): Nastaran Bani, Farzad Rahmani, Neda Shakour, Forouzan Amerizadeh, Ghazaleh Khalili-Tanha, Majid Khazaei, Seyed Mahdi Hassanian, Mohammad Amin Kerachian, Mohammad Reza Abbaszadegan, Majid Mojarad, Farzin Hadizadeh, Gordon A. Ferns and Amir Avan*

Volume 24, Issue 12, 2024

Published on: 04 April, 2024

Page: [916 - 927] Pages: 12

DOI: 10.2174/0118715206296355240325113920

Price: $65

Abstract

Background: Colorectal cancer (CRC) remains a significant contributor to mortality, often exacerbated by metastasis and chemoresistance. Novel therapeutic strategies are imperative to enhance current treatments. The dysregulation of the PI3K/Akt signaling pathway is implicated in CRC progression. This study investigates the therapeutic potential of Wortmannin, combined with 5‐fluorouracil (5-FU), to target the PI3K/Akt pathway in CRC.

Methods: Anti-migratory and antiproliferative effects were assessed through wound healing and MTT assays. Apoptosis and cell cycle alterations were evaluated using Annexin V/Propidium Iodide Apoptosis Assay. Wortmannin's impact on the oxidant/antioxidant equilibrium was examined via ROS, SOD, CAT, MDA, and T-SH levels. Downstream target genes of the PI3K/AKT pathway were analyzed at mRNA and protein levels using RTPCR and western blot, respectively.

Results: Wortmannin demonstrated a significant inhibitory effect on cell proliferation, modulating survivin, cyclinD1, PI3K, and p-Akt. The PI3K inhibitor attenuated migratory activity, inducing E-cadherin expression. Combined Wortmannin with 5-FU induced apoptosis, increasing cells in sub-G1 via elevated ROS levels.

Conclusion: This study underscores Wortmannin's potential in inhibiting CRC cell growth and migration through PI3K/Akt pathway modulation. It also highlights its candidacy for further investigation as a promising therapeutic option in colorectal cancer treatment.

Keywords: Colorectal cancer, wortmannin, PI3K/Akt pathway, antitumor effects, 5-FU, propidium iodide apoptosis assay.

« Previous Next »
Graphical Abstract

[1]
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[2]
Cho, M.Y.; Siegel, D.A.; Demb, J.; Richardson, L.C.; Gupta, S. Increasing colorectal cancer incidence before and after age 50: Implications for screening initiation and promotion of “On-Time” screening. Dig. Dis. Sci., 2022, 67(8), 4086-4091.
[http://dx.doi.org/10.1007/s10620-021-07213-w] [PMID: 34486085]
[3]
Morgan, E.; Arnold, M.; Gini, A.; Lorenzoni, V.; Cabasag, C.J.; Laversanne, M.; Vignat, J.; Ferlay, J.; Murphy, N.; Bray, F. Global burden of colorectal cancer in 2020 and 2040: Incidence and mortality estimates from GLOBOCAN. Gut, 2023, 72(2), 338-344.
[http://dx.doi.org/10.1136/gutjnl-2022-327736] [PMID: 36604116]
[4]
Siegel, R.L.; Miller, K.D.; Wagle, N.S.; Jemal, A. Cancer statistics, 2023. CA Cancer J. Clin., 2023, 73(1), 17-48.
[http://dx.doi.org/10.3322/caac.21763] [PMID: 36633525]
[5]
Goldberg, R.M. Advances in the treatment of metastatic colorectal cancer. Oncologist, 2005, 10(S3), 40-48.
[http://dx.doi.org/10.1634/theoncologist.10-90003-40] [PMID: 16368870]
[6]
Xie, Y.H.; Chen, Y.X.; Fang, J.Y. Comprehensive review of targeted therapy for colorectal cancer. Signal Transduct. Target. Ther., 2020, 5(1), 22.
[http://dx.doi.org/10.1038/s41392-020-0116-z] [PMID: 32296018]
[7]
Longley, D.B.; Allen, W.L.; Johnston, P.G. Drug resistance, predictive markers and pharmacogenomics in colorectal cancer. Biochim. Biophys. Acta, 2006, 1766(2), 184-196.
[PMID: 16973289]
[8]
Marjaneh, R.M.; Rahmani, F.; Hassanian, S.M.; Rezaei, N.; Hashemzehi, M.; Bahrami, A.; Ariakia, F.; Fiuji, H.; Sahebkar, A.; Avan, A.; Khazaei, M. Phytosomal curcumin inhibits tumor growth in colitis‐associated colorectal cancer. J. Cell. Physiol., 2018, 233(10), 6785-6798.
[http://dx.doi.org/10.1002/jcp.26538] [PMID: 29737515]
[9]
Xiong, H.; Zhang, Z.G.; Tian, X.Q.; Sun, D.F.; Liang, Q.C.; Zhang, Y.J.; Lu, R.; Chen, Y.X.; Fang, J.Y. Inhibition of JAK1, 2/STAT3 signaling induces apoptosis, cell cycle arrest, and reduces tumor cell invasion in colorectal cancer cells. Neoplasia, 2008, 10(3), 287-297.
[http://dx.doi.org/10.1593/neo.07971] [PMID: 18320073]
[10]
Robbins, H.L.; Hague, A. The PI3K/Akt pathway in tumors of endocrine tissues. Front. Endocrinol. (Lausanne), 2016, 6, 188.
[http://dx.doi.org/10.3389/fendo.2015.00188] [PMID: 26793165]
[11]
Jean, S.; Kiger, A.A. Classes of phosphoinositide 3-kinases at a glance; The Company of Biologists Ltd.: Cambridge, United Kingdom, 2014.
[http://dx.doi.org/10.1242/jcs.093773]
[12]
Zhao, L.; Vogt, P.K. Class I PI3K in oncogenic cellular transformation. Oncogene, 2008, 27(41), 5486-5496.
[http://dx.doi.org/10.1038/onc.2008.244] [PMID: 18794883]
[13]
Barreto, G.E.; Sahebkar, A. Pharmacological Properties of Plant-Derived Natural Products and Implications for Human Health; Springer Nature: Berlin, Germany, 2021, Vol. 1308, .
[http://dx.doi.org/10.1007/978-3-030-64872-5]
[14]
Matsuoka, T.; Yashiro, M. The role of PI3K/Akt/mTOR signaling in gastric carcinoma. Cancers (Basel), 2014, 6(3), 1441-1463.
[http://dx.doi.org/10.3390/cancers6031441] [PMID: 25003395]
[15]
Riquelme, I.; Tapia, O.; Espinoza, J.A.; Leal, P.; Buchegger, K.; Sandoval, A.; Bizama, C.; Araya, J.C.; Peek, R.M.; Roa, J.C. The gene expression status of the PI3K/AKT/mTOR pathway in gastric cancer tissues and cell lines. Pathol. Oncol. Res., 2016, 22(4), 797-805.
[http://dx.doi.org/10.1007/s12253-016-0066-5] [PMID: 27156070]
[16]
Yuan, T.L.; Cantley, L.C. PI3K pathway alterations in cancer: Variations on a theme. Oncogene, 2008, 27(41), 5497-5510.
[http://dx.doi.org/10.1038/onc.2008.245] [PMID: 18794884]
[17]
Loh, A.H.P.; Brennan, R.C.; Lang, W.H.; Hickey, R.J.; Malkas, L.H.; Sandoval, J.A. Dissecting the PI3K signaling axis in pediatric solid tumors: Novel targets for clinical integration. Front. Oncol., 2013, 3, 93.
[http://dx.doi.org/10.3389/fonc.2013.00093] [PMID: 23638435]
[18]
Akinleye, A.; Avvaru, P.; Furqan, M.; Song, Y.; Liu, D. Phosphatidylinositol 3-kinase (PI3K) inhibitors as cancer therapeutics. J. Hematol. Oncol., 2013, 6(1), 88.
[http://dx.doi.org/10.1186/1756-8722-6-88] [PMID: 24261963]
[19]
Pitts, T.M.; Newton, T.P.; Bradshaw-Pierce, E.L.; Addison, R.; Arcaroli, J.J.; Klauck, P.J.; Bagby, S.M.; Hyatt, S.L.; Purkey, A.; Tentler, J.J.; Tan, A.C.; Messersmith, W.A.; Eckhardt, S.G.; Leong, S. Dual pharmacological targeting of the MAP kinase and PI3K/mTOR pathway in preclinical models of colorectal cancer. PLoS One, 2014, 9(11), e113037.
[http://dx.doi.org/10.1371/journal.pone.0113037] [PMID: 25401499]
[20]
Martinelli, E.; Troiani, T.; D’Aiuto, E.; Morgillo, F.; Vitagliano, D.; Capasso, A.; Costantino, S.; Ciuffreda, L.P.; Merolla, F.; Vecchione, L.; De Vriendt, V.; Tejpar, S.; Nappi, A.; Sforza, V.; Martini, G.; Berrino, L.; De Palma, R.; Ciardiello, F. Antitumor activity of pimasertib, a selective MEK 1/2 inhibitor, in combination with PI3K/mTOR inhibitors or with multi‐targeted kinase inhibitors in pimasertib‐resistant human lung and colorectal cancer cells. Int. J. Cancer, 2013, 133(9), 2089-2101.
[http://dx.doi.org/10.1002/ijc.28236] [PMID: 23629727]
[21]
Zhu, Y.; Zhong, Y.; Long, X.; Zhu, Z.; Zhou, Y.; Ye, H.; Zeng, X.; Zheng, X. Deoxyshikonin isolated from Arnebia euchroma inhibits colorectal cancer by down-regulating the PI3K/Akt/mTOR pathway. Pharm. Biol., 2019, 57(1), 412-423.
[http://dx.doi.org/10.1080/13880209.2019.1626447] [PMID: 31230505]
[22]
van Hazel, G.A.; Pavlakis, N.; Goldstein, D.; Olver, I.N.; Tapner, M.J.; Price, D.; Bower, G.D.; Briggs, G.M.; Rossleigh, M.A.; Taylor, D.J.; George, J. Treatment of fluorouracil-refractory patients with liver metastases from colorectal cancer by using yttrium-90 resin microspheres plus concomitant systemic irinotecan chemotherapy. J. Clin. Oncol., 2009, 27(25), 4089-4095.
[http://dx.doi.org/10.1200/JCO.2008.20.8116] [PMID: 19652069]
[23]
Venook, A.P.; Niedzwiecki, D.; Lenz, H.J.; Innocenti, F.; Fruth, B.; Meyerhardt, J.A.; Schrag, D.; Greene, C.; O’Neil, B.H.; Atkins, J.N.; Berry, S.; Polite, B.N.; O’Reilly, E.M.; Goldberg, R.M.; Hochster, H.S.; Schilsky, R.L.; Bertagnolli, M.M.; El-Khoueiry, A.B.; Watson, P.; Benson, A.B., III; Mulkerin, D.L.; Mayer, R.J.; Blanke, C. Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer: A randomized clinical trial. JAMA, 2017, 317(23), 2392-2401.
[http://dx.doi.org/10.1001/jama.2017.7105] [PMID: 28632865]
[24]
Heinemann, V.; von Weikersthal, L.F.; Decker, T.; Kiani, A.; Vehling-Kaiser, U.; Al-Batran, S.E.; Heintges, T.; Lerchenmüller, C.; Kahl, C.; Seipelt, G.; Kullmann, F.; Stauch, M.; Scheithauer, W.; Hielscher, J.; Scholz, M.; Müller, S.; Link, H.; Niederle, N.; Rost, A.; Höffkes, H.G.; Moehler, M.; Lindig, R.U.; Modest, D.P.; Rossius, L.; Kirchner, T.; Jung, A.; Stintzing, S. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): A randomised, open-label, phase 3 trial. Lancet Oncol., 2014, 15(10), 1065-1075.
[http://dx.doi.org/10.1016/S1470-2045(14)70330-4] [PMID: 25088940]
[25]
Al-Batran, S.E.; Homann, N.; Pauligk, C.; Goetze, T.O.; Meiler, J.; Kasper, S.; Kopp, H.G.; Mayer, F.; Haag, G.M.; Luley, K.; Lindig, U.; Schmiegel, W.; Pohl, M.; Stoehlmacher, J.; Folprecht, G.; Probst, S.; Prasnikar, N.; Fischbach, W.; Mahlberg, R.; Trojan, J.; Koenigsmann, M.; Martens, U.M.; Thuss-Patience, P.; Egger, M.; Block, A.; Heinemann, V.; Illerhaus, G.; Moehler, M.; Schenk, M.; Kullmann, F.; Behringer, D.M.; Heike, M.; Pink, D.; Teschendorf, C.; Löhr, C.; Bernhard, H.; Schuch, G.; Rethwisch, V.; von Weikersthal, L.F.; Hartmann, J.T.; Kneba, M.; Daum, S.; Schulmann, K.; Weniger, J.; Belle, S.; Gaiser, T.; Oduncu, F.S.; Güntner, M.; Hozaeel, W.; Reichart, A.; Jäger, E.; Kraus, T.; Mönig, S.; Bechstein, W.O.; Schuler, M.; Schmalenberg, H.; Hofheinz, R.D. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): A randomised, phase 2/3 trial. Lancet, 2019, 393(10184), 1948-1957.
[http://dx.doi.org/10.1016/S0140-6736(18)32557-1] [PMID: 30982686]
[26]
Wang, K.; Huang, W.; Sang, X.; Wu, X.; Shan, Q.; Tang, D.; Xu, X.; Cao, G. Atractylenolide I inhibits colorectal cancer cell proliferation by affecting metabolism and stemness via AKT/mTOR signaling. Phytomedicine, 2020, 68, 153191.
[http://dx.doi.org/10.1016/j.phymed.2020.153191] [PMID: 32135457]
[27]
Zhao, J.X.; Liu, H.; Lv, J.; Yang, X.J. Wortmannin enhances cisplatin-induced apoptosis in human ovarian cancer cells in vitro. Eur. Rev. Med. Pharmacol. Sci., 2014, 18(17), 2428-2434.
[PMID: 25268086]
[28]
Boehle, A.; Kurdow, R.; Boenicke, L.; Schniewind, B.; Faendrich, F.; Dohrmann, P.; Kalthoff, H. Wortmannin inhibits growth of human non-small-cell lung cancer in vitro and in vivo. Langenbecks Arch. Surg., 2002, 387(5-6), 234-239.
[http://dx.doi.org/10.1007/s00423-002-0314-x] [PMID: 12410360]
[29]
Walker, E.H.; Pacold, M.E.; Perisic, O.; Stephens, L.; Hawkins, P.T.; Wymann, M.P.; Williams, R.L. Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol. Cell, 2000, 6(4), 909-919.
[http://dx.doi.org/10.1016/S1097-2765(05)00089-4] [PMID: 11090628]
[30]
Liu, Y.; Shreder, K.R.; Gai, W.; Corral, S.; Ferris, D.K.; Rosenblum, J.S. Wortmannin, a widely used phosphoinositide 3-kinase inhibitor, also potently inhibits mammalian polo-like kinase. Chem. Biol., 2005, 12(1), 99-107.
[http://dx.doi.org/10.1016/j.chembiol.2004.11.009] [PMID: 15664519]
[31]
Yao, R.; Cooper, G.M. Requirement for phosphatidylinositol-3 kinase in the prevention of apoptosis by nerve growth factor. Science, 1995, 267(5206), 2003-2006.
[http://dx.doi.org/10.1126/science.7701324] [PMID: 7701324]
[32]
Rovithi, M.; Avan, A.; Funel, N.; Leon, L.G.; Gomez, V.E.; Wurdinger, T.; Griffioen, A.W.; Verheul, H.M.W.; Giovannetti, E. Development of bioluminescent chick chorioallantoic membrane (CAM) models for primary pancreatic cancer cells: A platform for drug testing. Sci. Rep., 2017, 7(1), 44686.
[http://dx.doi.org/10.1038/srep44686] [PMID: 28304379]
[33]
Fasihi, K.; Amerizadeh, F.; Sabbaghzadeh, R.; Heydari, M.; Rahmani, F.; Mostafapour, A.; Khazaei, M.; Rasouli, E.; Hassanian, S.M.; Ferns, G.A.; Rezayi, M.; Avan, A. The therapeutic potential of γ-Al2O3 nanoparticle containing 5-fluorouracil in the treatment of colorectal cancer. Tissue Cell, 2022, 76, 101755.
[http://dx.doi.org/10.1016/j.tice.2022.101755] [PMID: 35220126]
[34]
Avan, A.; Quint, K.; Nicolini, F.; Funel, N.; Frampton, A.E.; Maftouh, M.; Pelliccioni, S.; Schuurhuis, G.J.; Peters, G.J.; Giovannetti, E. Enhancement of the antiproliferative activity of gemcitabine by modulation of c-Met pathway in pancreatic cancer. Curr. Pharm. Des., 2013, 19(5), 940-950.
[http://dx.doi.org/10.2174/138161213804547312] [PMID: 22973962]
[35]
Avan, A.; Caretti, V.; Funel, N.; Galvani, E.; Maftouh, M.; Honeywell, R.J.; Lagerweij, T.; Van Tellingen, O.; Campani, D.; Fuchs, D.; Verheul, H.M.; Schuurhuis, G.J.; Boggi, U.; Peters, G.J.; Würdinger, T.; Giovannetti, E. Crizotinib inhibits metabolic inactivation of gemcitabine in c-Met-driven pancreatic carcinoma. Cancer Res., 2013, 73(22), 6745-6756.
[http://dx.doi.org/10.1158/0008-5472.CAN-13-0837] [PMID: 24085787]
[36]
Maftouh, M.; Belo, A.I.; Avan, A.; Funel, N.; Peters, G.J.; Giovannetti, E.; van Die, I. Galectin-4 expression is associated with reduced lymph node metastasis and modulation of Wnt/β-catenin signalling in pancreatic adenocarcinoma. Oncotarget, 2014, 5(14), 5335-5349.
[http://dx.doi.org/10.18632/oncotarget.2104] [PMID: 24977327]
[37]
Giovannetti, E.; Wang, Q.; Avan, A.; Funel, N.; Lagerweij, T.; Lee, J.H.; Caretti, V.; van der Velde, A.; Boggi, U.; Wang, Y.; Vasile, E.; Peters, G.J.; Wurdinger, T.; Giaccone, G. Role of CYB5A in pancreatic cancer prognosis and autophagy modulation. J. Natl. Cancer Inst., 2014, 106(1), djt346.
[http://dx.doi.org/10.1093/jnci/djt346] [PMID: 24301457]
[38]
Liang, C.C.; Park, A.Y.; Guan, J.L. In vitro scratch assay: A convenient and inexpensive method for analysis of cell migration in vitro. Nat. Protoc., 2007, 2(2), 329-333.
[http://dx.doi.org/10.1038/nprot.2007.30] [PMID: 17406593]
[39]
Maftouh, M.; Avan, A.; Sciarrillo, R.; Granchi, C.; Leon, L.G.; Rani, R.; Funel, N.; Smid, K.; Honeywell, R.; Boggi, U.; Minutolo, F.; Peters, G.J.; Giovannetti, E. Synergistic interaction of novel lactate dehydrogenase inhibitors with gemcitabine against pancreatic cancer cells in hypoxia. Br. J. Cancer, 2014, 110(1), 172-182.
[http://dx.doi.org/10.1038/bjc.2013.681] [PMID: 24178759]
[40]
Hashemzehi, M.; Behnam-Rassouli, R.; Hassanian, S.M.; Moradi-Binabaj, M.; Moradi-Marjaneh, R.; Rahmani, F.; Fiuji, H.; Jamili, M.; Mirahmadi, M.; Boromand, N.; Piran, M.; Jafari, M.; Sahebkar, A.; Avan, A.; Khazaei, M. Phytosomal‐curcumin antagonizes cell growth and migration, induced by thrombin through AMP‐Kinase in breast cancer. J. Cell. Biochem., 2018, 119(7), 5996-6007.
[http://dx.doi.org/10.1002/jcb.26796] [PMID: 29600521]
[41]
Hashemzehi, M.; Naghibzadeh, N.; Asgharzadeh, F.; Mostafapour, A.; Hassanian, S.M.; Ferns, G.A.; Cho, W.C.; Avan, A.; Khazaei, M. The therapeutic potential of losartan in lung metastasis of colorectal cancer. EXCLI J., 2020, 19, 927-935.
[PMID: 32665776]
[42]
Aebi, H. Catalase in vitro.Methods in enzymology; Elsevier: Amsterdam, Netherlands, 1984, pp. 121-126.
[43]
Amerizadeh, F.; Rezaei, N.; Rahmani, F.; Hassanian, S.M.; Moradi-Marjaneh, R.; Fiuji, H.; Boroumand, N.; Nosrati-Tirkani, A.; Ghayour-Mobarhan, M.; Ferns, G.A.; Khazaei, M.; Avan, A. Crocin synergistically enhances the antiproliferative activity of 5‐flurouracil through Wnt/PI3K pathway in a mouse model of colitis‐associated colorectal cancer. J. Cell. Biochem., 2018, 119(12), 10250-10261.
[http://dx.doi.org/10.1002/jcb.27367] [PMID: 30129057]
[44]
Rahmani, F.; Amerizadeh, F.; Hassanian, S.M.; Hashemzehi, M.; Nasiri, S.N.; Fiuji, H.; Ferns, G.A.; Khazaei, M.; Avan, A. PNU‐74654 enhances the antiproliferative effects of 5‐FU in breast cancer and antagonizes thrombin‐induced cell growth via the Wnt pathway. J. Cell. Physiol., 2019, 234(8), 14123-14132.
[http://dx.doi.org/10.1002/jcp.28104] [PMID: 30633353]
[45]
Hosseinzadeh, H.; Sadeghnia, H.R. Safranal, a constituent of Crocus sativus (saffron), attenuated cerebral ischemia induced oxidative damage in rat hippocampus. J. Pharm. Pharm. Sci., 2005, 8(3), 394-399.
[PMID: 16401389]
[46]
Wu, D.; Yotnda, P. Production and detection of reactive oxygen species (ROS) in cancers. J. Vis. Exp., 2011, (57), e3357.
[PMID: 22127014]
[47]
Baldissera, F.G.; Fazolo, T.; da Silva, M.B.; de Santana Filho, P.C.; da Silva, V.D.; Rivillo Perez, D.M.; Klitzke, J.S.; de Oliveira Soares, E.G.; Rodrigues Júnior, L.C.; Peres, A.; Dallegrave, E.; Navegantes-Lima, K.C.; Monteiro, M.C.; Schrekker, H.S.; Torres Romão, P.R. Imidazolium salts as an alternative for anti-Leishmania drugs: Oxidative and immunomodulatory activities. Front. Immunol., 2023, 13, 1096312.
[http://dx.doi.org/10.3389/fimmu.2022.1096312] [PMID: 36733394]
[48]
Wojciechowski, M.; Lesyng, B. Generalized Born model: Analysis, refinement, and applications to proteins. J. Phys. Chem. B, 2004, 108(47), 18368-18376.
[http://dx.doi.org/10.1021/jp046748b]
[49]
Peters, G.J.; Avan, A.; Ruiz, M.G.; Orsini, V.; Avan, A.; Giovannetti, E.; Smit, E.F. Predictive role of repair enzymes in the efficacy of Cisplatin combinations in pancreatic and lung cancer. Anticancer Res., 2014, 34(1), 435-442.
[PMID: 24403499]
[50]
Rahmani, F.; Asgharzadeh, F.; Avan, A.; Barneh, F.; Parizadeh, M.R.; Ferns, G.A.; Ryzhikov, M.; Ahmadian, M.R.; Giovannetti, E.; Jafari, M.; Khazaei, M.; Hassanian, S.M. Rigosertib potently protects against colitis-associated intestinal fibrosis and inflammation by regulating PI3K/AKT and NF-κB signaling pathways. Life Sci., 2020, 249, 117470.
[http://dx.doi.org/10.1016/j.lfs.2020.117470] [PMID: 32135184]
[51]
Avan, A.; Avan, A.; Le Large, T.Y.S.; Mambrini, A.; Funel, N.; Maftouh, M.; Ghayour-Mobarhan, M.; Cantore, M.; Boggi, U.; Peters, G.J.; Pacetti, P.; Giovannetti, E. AKT1 and SELP polymorphisms predict the risk of developing cachexia in pancreatic cancer patients. PLoS One, 2014, 9(9), e108057.
[http://dx.doi.org/10.1371/journal.pone.0108057] [PMID: 25238546]
[52]
Wise, H.M.; Hermida, M.A.; Leslie, N.R. Prostate cancer, PI3K, PTEN and prognosis. Clin. Sci. (Lond.), 2017, 131(3), 197-210.
[http://dx.doi.org/10.1042/CS20160026] [PMID: 28057891]
[53]
Ying, J.; Xu, Q.; Liu, B.; Zhang, G.; Chen, L.; Pan, H. The expression of the PI3K/AKT/mTOR pathway in gastric cancer and its role in gastric cancer prognosis. OncoTargets Ther., 2015, 8, 2427-2433.
[http://dx.doi.org/10.2147/OTT.S88592] [PMID: 26366097]
[54]
Glaviano, A.; Foo, A.S.C.; Lam, H.Y.; Yap, K.C.H.; Jacot, W.; Jones, R.H.; Eng, H.; Nair, M.G.; Makvandi, P.; Geoerger, B.; Kulke, M.H.; Baird, R.D.; Prabhu, J.S.; Carbone, D.; Pecoraro, C.; Teh, D.B.L.; Sethi, G.; Cavalieri, V.; Lin, K.H.; Javidi-Sharifi, N.R.; Toska, E.; Davids, M.S.; Brown, J.R.; Diana, P.; Stebbing, J.; Fruman, D.A.; Kumar, A.P. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Mol. Cancer, 2023, 22(1), 138.
[http://dx.doi.org/10.1186/s12943-023-01827-6] [PMID: 37596643]
[55]
Danielsen, S.A. Portrait of the PI3K/AKT pathway in colorectal cancer. Biochimica et Biophysica Acta (BBA)-. Rev. Can., 2015, 1855(1), 104-121.
[56]
Lin, F.; Zhang, G.; Yang, X.; Wang, M.; Wang, R.; Wan, M.; Wang, J.; Wu, B.; Yan, T.; Jia, Y. A network pharmacology approach and experimental validation to investigate the anticancer mechanism and potential active targets of ethanol extract of Wei-Tong-Xin against colorectal cancer through induction of apoptosis via PI3K/AKT signaling pathway. J. Ethnopharmacol., 2023, 303, 115933.
[http://dx.doi.org/10.1016/j.jep.2022.115933] [PMID: 36403742]
[57]
Yap, T.A.; Garrett, M.D.; Walton, M.I.; Raynaud, F.; de Bono, J.S.; Workman, P. Targeting the PI3K–AKT–mTOR pathway: Progress, pitfalls, and promises. Curr. Opin. Pharmacol., 2008, 8(4), 393-412.
[http://dx.doi.org/10.1016/j.coph.2008.08.004] [PMID: 18721898]
[58]
Zhang, J.; Roberts, T.M.; Shivdasani, R.A. Targeting PI3K signaling as a therapeutic approach for colorectal cancer. Gastroenterology, 2011, 141(1), 50-61.
[http://dx.doi.org/10.1053/j.gastro.2011.05.010] [PMID: 21723986]
[59]
Yu, M.; Chen, J.; Xu, Z.; Yang, B.; He, Q.; Luo, P.; Yan, H.; Yang, X. Development and safety of PI3K inhibitors in cancer. Arch. Toxicol., 2023, 97(3), 635-650.
[http://dx.doi.org/10.1007/s00204-023-03440-4] [PMID: 36773078]
[60]
Arboleda, M.J.; Lyons, J.F.; Kabbinavar, F.F.; Bray, M.R.; Snow, B.E.; Ayala, R.; Danino, M.; Karlan, B.Y.; Slamon, D.J. Overexpression of AKT2/protein kinase Bbeta leads to up-regulation of β1 integrins, increased invasion, and metastasis of human breast and ovarian cancer cells. Cancer Res., 2003, 63(1), 196-206.
[PMID: 12517798]
[61]
Kim, M.S.; Park, M.J.; Moon, E.J.; Kim, S.J.; Lee, C.H.; Yoo, H.; Shin, S.H.; Song, E.S.; Lee, S.H. Hyaluronic acid induces osteopontin via the phosphatidylinositol 3-kinase/Akt pathway to enhance the motility of human glioma cells. Cancer Res., 2005, 65(3), 686-691.
[http://dx.doi.org/10.1158/0008-5472.686.65.3] [PMID: 15705860]
[62]
Zhang, D.; Bar-Eli, M.; Meloche, S.; Brodt, P. Dual regulation of MMP-2 expression by the type 1 insulin-like growth factor receptor: The phosphatidylinositol 3-kinase/Akt and Raf/ERK pathways transmit opposing signals. J. Biol. Chem., 2004, 279(19), 19683-19690.
[http://dx.doi.org/10.1074/jbc.M313145200] [PMID: 14993222]
[63]
Gallis, B.; Corthals, G.L.; Goodlett, D.R.; Ueba, H.; Kim, F.; Presnell, S.R.; Figeys, D.; Harrison, D.G.; Berk, B.C.; Aebersold, R.; Corson, M.A. Identification of flow-dependent endothelial nitric-oxide synthase phosphorylation sites by mass spectrometry and regulation of phosphorylation and nitric oxide production by the phosphatidylinositol 3-kinase inhibitor LY294002. J. Biol. Chem., 1999, 274(42), 30101-30108.
[http://dx.doi.org/10.1074/jbc.274.42.30101] [PMID: 10514497]
[64]
Sirico, M.; D’Angelo, A.; Gianni, C.; Casadei, C.; Merloni, F.; De Giorgi, U. Current state and future challenges for PI3K inhibitors in cancer therapy. Cancers (Basel), 2023, 15(3), 703.
[http://dx.doi.org/10.3390/cancers15030703] [PMID: 36765661]
[65]
Okkenhaug, K.; Bilancio, A.; Farjot, G.; Priddle, H.; Sancho, S.; Peskett, E.; Pearce, W.; Meek, S.E.; Salpekar, A.; Waterfield, M.D.; Smith, A.J.H.; Vanhaesebroeck, B. Impaired B and T cell antigen receptor signaling in p110δ PI 3-kinase mutant mice. Science, 2002, 297(5583), 1031-1034.
[http://dx.doi.org/10.1126/science.1073560] [PMID: 12130661]
[66]
Zhu, Y.F.; Yu, B.H.; Li, D.L.; Ke, H.L.; Guo, X.Z.; Xiao, X.Y. PI3K expression and PIK3CA mutations are related to colorectal cancer metastases. World J. Gastroenterol., 2012, 18(28), 3745-3751.
[http://dx.doi.org/10.3748/wjg.v18.i28.3745] [PMID: 22851869]
[67]
Zhong, J.; Ding, S.; Zhang, X.; Di, W.; Wang, X.; Zhang, H.; Chen, Y.; Zhang, Y.; Hu, Y. To investigate the occurrence and development of colorectal cancer based on the PI3K/AKT/mTOR signaling pathway. Frontiers in Bioscience-Landmark, 2023, 28(2), 37.
[http://dx.doi.org/10.31083/j.fbl2802037] [PMID: 36866550]
[68]
Safdari, Y.; Khalili, M.; Ebrahimzadeh, M.A.; Yazdani, Y.; Farajnia, S. Natural inhibitors of PI3K/AKT signaling in breast cancer: Emphasis on newly-discovered molecular mechanisms of action. Pharmacol. Res., 2015, 93, 1-10.
[http://dx.doi.org/10.1016/j.phrs.2014.12.004] [PMID: 25533812]
[69]
VanLandingham, N.K.; Nazarenko, A.; Grandis, J.R.; Johnson, D.E. The mutational profiles and corresponding therapeutic implications of PI3K mutations in cancer. Adv. Biol. Regul., 2023, 87, 100934.
[http://dx.doi.org/10.1016/j.jbior.2022.100934] [PMID: 36402737]
[70]
De Roock, W.; Claes, B.; Bernasconi, D.; De Schutter, J.; Biesmans, B.; Fountzilas, G.; Kalogeras, K.T.; Kotoula, V.; Papamichael, D.; Laurent-Puig, P.; Penault-Llorca, F.; Rougier, P.; Vincenzi, B.; Santini, D.; Tonini, G.; Cappuzzo, F.; Frattini, M.; Molinari, F.; Saletti, P.; De Dosso, S.; Martini, M.; Bardelli, A.; Siena, S.; Sartore-Bianchi, A.; Tabernero, J.; Macarulla, T.; Di Fiore, F.; Gangloff, A.O.; Ciardiello, F.; Pfeiffer, P.; Qvortrup, C.; Hansen, T.P.; Van Cutsem, E.; Piessevaux, H.; Lambrechts, D.; Delorenzi, M.; Tejpar, S. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: A retrospective consortium analysis. Lancet Oncol., 2010, 11(8), 753-762.
[http://dx.doi.org/10.1016/S1470-2045(10)70130-3] [PMID: 20619739]
[71]
Nosho, K.; Kawasaki, T.; Longtine, J.A.; Fuchs, C.S.; Ohnishi, M.; Suemoto, Y.; Kirkner, G.J.; Zepf, D.; Yan, L.; Ogino, S. PIK3CA mutation in colorectal cancer: Relationship with genetic and epigenetic alterations. Neoplasia, 2008, 10(6), 534-541.
[http://dx.doi.org/10.1593/neo.08336] [PMID: 18516290]
[72]
Wong, K.K.; Engelman, J.A.; Cantley, L.C. Targeting the PI3K signaling pathway in cancer. Curr. Opin. Genet. Dev., 2010, 20(1), 87-90.
[http://dx.doi.org/10.1016/j.gde.2009.11.002] [PMID: 20006486]
[73]
Kim, M.J.; Lee, S.J.; Ryu, J.H.; Kim, S.H.; Kwon, I.C.; Roberts, T.M. Combination of KRAS gene silencing and PI3K inhibition for ovarian cancer treatment. J. Control. Release, 2020, 318, 98-108.
[http://dx.doi.org/10.1016/j.jconrel.2019.12.019] [PMID: 31838203]
[74]
Teranishi, F.; Takahashi, N.; Gao, N.; Akamo, Y.; Takeyama, H.; Manabe, T.; Okamoto, T. Phosphoinositide 3‐kinase inhibitor (wortmannin) inhibits pancreatic cancer cell motility and migration induced by hyaluronan in vitro and peritoneal metastasis in vivo. Cancer Sci., 2009, 100(4), 770-777.
[http://dx.doi.org/10.1111/j.1349-7006.2009.01084.x] [PMID: 19469020]
[75]
Li, J.; Li, F.; Wang, H.; Wang, X.; Jiang, Y.; Li, D. Wortmannin reduces metastasis and angiogenesis of human breast cancer cells via nuclear factor-κB-dependent matrix metalloproteinase-9 and interleukin-8 pathways. J. Int. Med. Res., 2012, 40(3), 867-876.
[http://dx.doi.org/10.1177/147323001204000305] [PMID: 22906259]
[76]
Yu, Q.; Geng, Y.; Sicinski, P. Specific protection against breast cancers by cyclin D1 ablation. Nature, 2001, 411(6841), 1017-1021.
[http://dx.doi.org/10.1038/35082500] [PMID: 11429595]
[77]
Biliran, H., Jr; Wang, Y.; Banerjee, S.; Xu, H.; Heng, H.; Thakur, A.; Bollig, A.; Sarkar, F.H.; Liao, J.D. Overexpression of cyclin D1 promotes tumor cell growth and confers resistance to cisplatin-mediated apoptosis in an elastase-myc transgene-expressing pancreatic tumor cell line. Clin. Cancer Res., 2005, 11(16), 6075-6086.
[http://dx.doi.org/10.1158/1078-0432.CCR-04-2419] [PMID: 16115953]
[78]
Maeda, K.; Chung, Y.; Kang, S.; Ogawa, M.; Onoda, N.; Nishiguchi, Y.; Ikehara, T.; Nakata, B.; Okuno, M.; Sowa, M. Cyclin D1 overexpression and prognosis in colorectal adenocarcinoma. Oncology, 1998, 55(2), 145-151.
[http://dx.doi.org/10.1159/000011849] [PMID: 9499189]
[79]
Salem, A.M.; Elfeky, M.A.; Nawar, N.; Alattar, A.Z.; Elekiabi, O.A.; Elaidy, M.M. Prognostic value of combined; Cox-2, Cyclin D1 and P21 expression in colorectal cancer (CRC) Patients: An immunohistochemical study. Open J. Pathol., 2018, 8(3), 106-121.
[http://dx.doi.org/10.4236/ojpathology.2018.83013]
[80]
Yun, J.; Lv, Y.G.; Yao, Q.; Wang, L.; Li, Y.P.; Yi, J. Wortmannin inhibits proliferation and induces apoptosis of MCF-7 breast cancer cells. Eur. J. Gynaecol. Oncol., 2012, 33(4), 367-369.
[PMID: 23091892]
[81]
Dai, S.; Yang, S.; Hu, X.; Sun, W.; Tawa, G.; Zhu, W.; Schimmer, A.D.; He, C.; Fang, B.; Zhu, H.; Zheng, W. 17-hydroxy wortmannin restores TRAIL’s response by ameliorating increased beclin 1 level and autophagy function in TRAIL-resistant colon cancer cells. Mol. Cancer Ther., 2019, 18(7), 1265-1277.
[http://dx.doi.org/10.1158/1535-7163.MCT-18-1241] [PMID: 31092562]
[82]
Zhang, M.; Hagan, C.T., IV; Min, Y.; Foley, H.; Tian, X.; Yang, F.; Mi, Y.; Au, K.M.; Medik, Y.; Roche, K.; Wagner, K.; Rodgers, Z.; Wang, A.Z. Nanoparticle co-delivery of wortmannin and cisplatin synergistically enhances chemoradiotherapy and reverses platinum resistance in ovarian cancer models. Biomaterials, 2018, 169, 1-10.
[http://dx.doi.org/10.1016/j.biomaterials.2018.03.055] [PMID: 29631163]
[83]
Tsao, M.S.; Chow, S.; Hedley, D.W. Inhibition of phosphatidylinositide 3-kinase enhances gemcitabine-induced apoptosis in human pancreatic cancer cells. Cancer Res., 2000, 60(19), 5451-5455.
[PMID: 11034087]
[84]
Ng, S.S.; Tsao, M.S.; Nicklee, T.; Hedley, D.W. Wortmannin inhibits pkb/akt phosphorylation and promotes gemcitabine antitumor activity in orthotopic human pancreatic cancer xenografts in immunodeficient mice. Clin. Cancer Res., 2001, 7(10), 3269-3275.
[PMID: 11595724]
[85]
Au, K.M.; Min, Y.; Tian, X.; Zhang, L.; Perello, V.; Caster, J.M.; Wang, A.Z. Improving cancer chemoradiotherapy treatment by dual controlled release of wortmannin and docetaxel in polymeric nanoparticles. ACS Nano, 2015, 9(9), 8976-8996.
[http://dx.doi.org/10.1021/acsnano.5b02913] [PMID: 26267360]
[86]
Ayral-Kaloustian, S.; Gu, J.; Lucas, J.; Cinque, M.; Gaydos, C.; Zask, A.; Chaudhary, I.; Wang, J.; Di, L.; Young, M.; Ruppen, M.; Mansour, T.S.; Gibbons, J.J.; Yu, K. Hybrid inhibitors of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR): Design, synthesis, and superior antitumor activity of novel wortmannin-rapamycin conjugates. J. Med. Chem., 2010, 53(1), 452-459.
[http://dx.doi.org/10.1021/jm901427g] [PMID: 19928864]
[87]
Pastwa, E.; Poplawski, T.; Lewandowska, U.; Somiari, S.B.; Blasiak, J.; Somiari, R.I. Wortmannin potentiates the combined effect of etoposide and cisplatin in human glioma cells. Int. J. Biochem. Cell Biol., 2014, 53, 423-431.
[http://dx.doi.org/10.1016/j.biocel.2014.06.007] [PMID: 24953561]

Rights & Permissions Print Cite
Article Metrics
29
2
Wayfinder Image
© 2024 Bentham Science Publishers | Privacy Policy