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Review Article

PI3K/ Akt/ mTOR Pathway as a Therapeutic Target for Colorectal Cancer: A Review of Preclinical and Clinical Evidence

Author(s): Arunaksharan Narayanankutty*

Volume 20, Issue 12, 2019

Page: [1217 - 1226] Pages: 10

DOI: 10.2174/1389450120666190618123846

Price: $65

Abstract

Background: Phosphoinositide 3-kinase (PI3Ks) is a member of intracellular lipid kinases and involved in the regulation of cellular proliferation, differentiation and survival. Overexpression of the PI3K/Akt/mTOR signalling has been reported in various forms of cancers, especially in colorectal cancers (CRC). Due to their significant roles in the initiation and progression events of colorectal cancer, they are recognized as a striking therapeutic target.

Objective: The present review is aimed to provide a detailed outline on the role of PI3K/Akt/mTOR pathway in the initiation and progression events of colorectal cancers as well as its function in drug resistance. Further, the role of PI3K/Akt/mTOR inhibitors alone and in combination with other chemotherapeutic drugs, in alleviating colorectal cancer is also discussed. The review contains preclinical and clinical evidence as well as patent literature of the pathway inhibitors which are natural and synthetic in origin.

Methods: The data were obtained from PubMed/Medline databases, Scopus and Google patent literature.

Results: PI3K/Akt/mTOR signalling is an important event in colorectal carcinogenesis. In addition, it plays significant roles in acquiring drug resistance as well as metastatic initiation events of CRCs. Several small molecules of natural and synthetic origin have been found to be potent inhibitors of CRCs by effectively downregulating the pathway. Data from various clinical studies also support these pathway inhibitors and several among them are patented.

Conclusion: Inhibitors of the PI3K/mTOR pathway have been successful for the treatment of primary and metastatic colorectal cancers, rendering the pathway as a promising clinical cancer therapeutic target.

Keywords: Anticancer activity, metastasis, PI3K pathway, natural products, colon cancer, synthetic inhibitors.

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Graphical Abstract

[1]
Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002; 296(5573): 1655-7.
[http://dx.doi.org/10.1126/science.296.5573.1655] [PMID: 12040186]
[2]
Zhang X, Jin B, Huang C. The PI3K/Akt pathway and its downstream transcriptional factors as targets for chemoprevention. Curr Cancer Drug Targets 2007; 7(4): 305-16.
[http://dx.doi.org/10.2174/156800907780809741] [PMID: 17979625]
[3]
Papadatos-Pastos D, Rabbie R, Ross P, Sarker D. The role of the PI3K pathway in colorectal cancer. Crit Rev Oncol Hematol 2015; 94(1): 18-30.
[http://dx.doi.org/10.1016/j.critrevonc.2014.12.006] [PMID: 25591826]
[4]
Qin H, Liu L, Sun S, et al. The impact of PI3K inhibitors on breast cancer cell and its tumor microenvironment. PeerJ 2018.6e5092
[http://dx.doi.org/10.7717/peerj.5092] [PMID: 29942710]
[5]
Golob-Schwarzl N, Krassnig S, Toeglhofer AM, et al. New liver cancer biomarkers: PI3K/AKT/mTOR pathway members and eukaryotic translation initiation factors. Eur J Cancer 2017; 83: 56-70.
[http://dx.doi.org/10.1016/j.ejca.2017.06.003] [PMID: 28715695]
[6]
Murthy D, Attri KS, Singh PK. Phosphoinositide 3-Kinase Signaling Pathway in Pancreatic Ductal Adenocarcinoma Progression, Pathogenesis, and Therapeutics. Front Physiol 2018; 9: 335.
[http://dx.doi.org/10.3389/fphys.2018.00335] [PMID: 29670543]
[7]
Langhans J, Schneele L, Trenkler N, et al. The effects of PI3K-mediated signalling on glioblastoma cell behaviour. Oncogenesis 2017; 6(11): 398.
[http://dx.doi.org/10.1038/s41389-017-0004-8] [PMID: 29184057]
[8]
Fan Q-W, Weiss WA. Targeting the RTK-PI3K-mTOR axis in malignant glioma: overcoming resistance. Curr Top Microbiol Immunol 2010; 347: 279-96.
[http://dx.doi.org/10.1007/82_2010_67] [PMID: 20535652]
[9]
Li X, Wu C, Chen N, et al. PI3K/Akt/mTOR signaling pathway and targeted therapy for glioblastoma. Oncotarget 2016; 7(22): 33440-50.
[http://dx.doi.org/10.18632/oncotarget.7961] [PMID: 26967052]
[10]
Beelen K, Hoefnagel LDC, Opdam M, et al. PI3K/AKT/mTOR pathway activation in primary and corresponding metastatic breast tumors after adjuvant endocrine therapy. Int J Cancer 2014; 135(5): 1257-63.
[http://dx.doi.org/10.1002/ijc.28769] [PMID: 24501006]
[11]
Costa RLB, Han HS, Gradishar WJ. Targeting the PI3K/AKT/mTOR pathway in triple-negative breast cancer: a review. Breast Cancer Res Treat 2018; 169(3): 397-406.
[http://dx.doi.org/10.1007/s10549-018-4697-y] [PMID: 29417298]
[12]
Dey N, De P, Leyland-Jones B. PI3K-AKT-mTOR inhibitors in breast cancers: From tumor cell signaling to clinical trials. Pharmacol Ther 2017; 175: 91-106.
[http://dx.doi.org/10.1016/j.pharmthera.2017.02.037] [PMID: 28216025]
[13]
Lee JJ, Loh K, Yap Y-S. PI3K/Akt/mTOR inhibitors in breast cancer. Cancer Biol Med 2015; 12(4): 342-54.
[PMID: 26779371]
[14]
Xu Z, Hu J, Cao H, et al. Loss of Pten synergizes with c-Met to promote hepatocellular carcinoma development via mTORC2 pathway. Exp Mol Med 2018; 50(1)e417
[http://dx.doi.org/10.1038/emm.2017.158] [PMID: 29303510]
[15]
Hu J, Che L, Li L, et al. Co-activation of AKT and c-Met triggers rapid hepatocellular carcinoma development via the mTORC1/FASN pathway in mice. Sci Rep 2016; 6: 20484.
[http://dx.doi.org/10.1038/srep20484] [PMID: 26857837]
[16]
Zhou Q, Lui VW, Yeo W. Targeting the PI3K/Akt/mTOR pathway in hepatocellular carcinoma. Future Oncol 2011; 7(10): 1149-67.
[http://dx.doi.org/10.2217/fon.11.95] [PMID: 21992728]
[17]
Matter MS, Decaens T, Andersen JB, Thorgeirsson SS. Targeting the mTOR pathway in hepatocellular carcinoma: current state and future trends. J Hepatol 2014; 60(4): 855-65.
[http://dx.doi.org/10.1016/j.jhep.2013.11.031] [PMID: 24308993]
[18]
Westin JR. Status of PI3K/Akt/mTOR pathway inhibitors in lymphoma. Clin Lymphoma Myeloma Leuk 2014; 14(5): 335-42.
[http://dx.doi.org/10.1016/j.clml.2014.01.007] [PMID: 24650973]
[19]
Bhatti M, Ippolito T, Mavis C, et al. Pre-clinical activity of targeting the PI3K/Akt/mTOR pathway in Burkitt lymphoma. Oncotarget 2018; 9(31): 21820-30.
[http://dx.doi.org/10.18632/oncotarget.25072] [PMID: 29774105]
[20]
Ennishi D, Bashashati A, Saberi S, Mottok A, Meissner B, Boyle M, et al. Frequent Genetic Alterations of PI3K-AKT Pathway and Their Clinical Significance in Germinal Center B-Cell-like Diffuse Large B-Cell Lymphoma. Blood 2016; 128: 607.
[21]
Edlind MP, Hsieh AC. PI3K-AKT-mTOR signaling in prostate cancer progression and androgen deprivation therapy resistance. Asian J Androl 2014; 16(3): 378-86.
[http://dx.doi.org/10.4103/1008-682X.122876] [PMID: 24759575]
[22]
Crumbaker M, Khoja L, Joshua AM. AR Signaling and the PI3K Pathway in Prostate Cancer. Cancers (Basel) 2017; 9(4): 34.
[http://dx.doi.org/10.3390/cancers9040034] [PMID: 28420128]
[23]
Festuccia C. Targeting the PI3K/AKT/mTOR Pathway in Prostate Cancer Development and Progression: Insight to Therapy. Clin Cancer Drugs 2016; 3: 36-62.
[http://dx.doi.org/10.2174/2212697X0301160328201324]
[24]
Iglesias-Bartolome R, Martin D, Gutkind JS. Exploiting the head and neck cancer oncogenome: widespread PI3K-mTOR pathway alterations and novel molecular targets. Cancer Discov 2013; 3(7): 722-5.
[http://dx.doi.org/10.1158/2159-8290.CD-13-0239] [PMID: 23847349]
[25]
Cai Y, Dodhia S, Su GH. Dysregulations in the PI3K pathway and targeted therapies for head and neck squamous cell carcinoma. Oncotarget 2017; 8(13): 22203-17.
[http://dx.doi.org/10.18632/oncotarget.14729] [PMID: 28108737]
[26]
Isaacsson Velho PH, Castro G Jr, Chung CH. Targeting the PI3K Pathway in Head and Neck Squamous Cell Carcinoma. Am Soc Clin Oncol Educ Book 2015; 123-8.
[http://dx.doi.org/10.14694/EdBook_AM.2015.35.123] [PMID: 25993150]
[27]
Beck JT, Ismail A, Tolomeo C. Targeting the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway: an emerging treatment strategy for squamous cell lung carcinoma. Cancer Treat Rev 2014; 40(8): 980-9.
[http://dx.doi.org/10.1016/j.ctrv.2014.06.006] [PMID: 25037117]
[28]
Fumarola C, Bonelli MA, Petronini PG, Alfieri RR. Targeting PI3K/AKT/mTOR pathway in non small cell lung cancer. Biochem Pharmacol 2014; 90(3): 197-207.
[http://dx.doi.org/10.1016/j.bcp.2014.05.011] [PMID: 24863259]
[29]
Francipane MG, Lagasse E. mTOR pathway in colorectal cancer: an update. Oncotarget 2014; 5(1): 49-66.
[http://dx.doi.org/10.18632/oncotarget.1548] [PMID: 24393708]
[30]
Johnson SM, Gulhati P, Rampy BA, et al. Novel expression patterns of PI3K/Akt/mTOR signaling pathway components in colorectal cancer. J Am Coll Surg 2010; 210(5): 767-76.
[31]
Pandurangan AK. Potential targets for prevention of colorectal cancer: a focus on PI3K/Akt/mTOR and Wnt pathways. Asian Pac J Cancer Prev 2013; 14(4): 2201-5.
[http://dx.doi.org/10.7314/APJCP.2013.14.4.2201] [PMID: 23725112]
[32]
Ericson K, Gan C, Cheong I, et al. Genetic inactivation of AKT1, AKT2, and PDPK1 in human colorectal cancer cells clarifies their roles in tumor growth regulation. Proc Natl Acad Sci USA 2010; 107(6): 2598-603.
[http://dx.doi.org/10.1073/pnas.0914018107] [PMID: 20133737]
[33]
Suman S, Kurisetty V, Das TP, et al. Activation of AKT signaling promotes epithelial-mesenchymal transition and tumor growth in colorectal cancer cells. Mol Carcinog 2014; 53(Suppl. 1): E151-60.
[http://dx.doi.org/10.1002/mc.22076] [PMID: 24000138]
[34]
Rychahou PG, Kang J, Gulhati P, et al. Akt2 overexpression plays a critical role in the establishment of colorectal cancer metastasis. Proc Natl Acad Sci USA 2008; 105(51): 20315-20.
[http://dx.doi.org/10.1073/pnas.0810715105] [PMID: 19075230]
[35]
Liu W, Wang S, Sun Q, Yang Z, Liu M, Tang H. DCLK1 promotes epithelial-mesenchymal transition via the PI3K/Akt/NF-κB pathway in colorectal cancer. Int J Cancer 2018; 142(10): 2068-79.
[http://dx.doi.org/10.1002/ijc.31232] [PMID: 29277893]
[36]
Gao T, Wang M, Xu L, Wen T, Liu J, An G. DCLK1 is up-regulated and associated with metastasis and prognosis in colorectal cancer. J Cancer Res Clin Oncol 2016; 142(10): 2131-40.
[http://dx.doi.org/10.1007/s00432-016-2218-0] [PMID: 27520310]
[37]
Mirzaei A, Tavoosidana G, Modarressi MH, et al. Upregulation of circulating cancer stem cell marker, DCLK1 but not Lgr5, in chemoradiotherapy-treated colorectal cancer patients. Tumour Biol 2015; 36(6): 4801-10.
[http://dx.doi.org/10.1007/s13277-015-3132-9] [PMID: 25631749]
[38]
Sun Y, Ji B, Feng Y, et al. TRIM59 facilitates the proliferation of colorectal cancer and promotes metastasis via the PI3K/AKT pathway. Oncol Rep 2017; 38(1): 43-52.
[http://dx.doi.org/10.3892/or.2017.5654] [PMID: 28534983]
[39]
Wu W, Chen J, Wu J, Lin J, Yang S, Yu H. Knockdown of tripartite motif-59 inhibits the malignant processes in human colorectal cancer cells. Oncol Rep 2017; 38(4): 2480-8.
[http://dx.doi.org/10.3892/or.2017.5896] [PMID: 28849218]
[40]
Zhao Q, Xu L, Sun X, et al. MFG-E8 overexpression promotes colorectal cancer progression via AKT/MMPs signalling. Tumour Biol 2017; 39(6)1010428317707881
[http://dx.doi.org/10.1177/1010428317707881] [PMID: 28653875]
[41]
Li G, Hu F, Luo X, Hu J, Feng Y. SIX4 promotes metastasis via activation of the PI3K-AKT pathway in colorectal cancer. PeerJ 2017.5e3394
[http://dx.doi.org/10.7717/peerj.3394] [PMID: 28584719]
[42]
Tan X, Chen S, Wu J, et al. PI3K/AKT-mediated upregulation of WDR5 promotes colorectal cancer metastasis by directly targeting ZNF407. Cell Death Dis 2017; 8(3)e2686
[http://dx.doi.org/10.1038/cddis.2017.111] [PMID: 28300833]
[43]
Das D, Satapathy SR, Siddharth S, Nayak A, Kundu CN. NECTIN-4 increased the 5-FU resistance in colon cancer cells by inducing the PI3K-AKT cascade. Cancer Chemother Pharmacol 2015; 76(3): 471-9.
[http://dx.doi.org/10.1007/s00280-015-2794-8] [PMID: 26122960]
[44]
Wang J, Wang W, Cai H, et al. MACC1 facilitates chemoresistance and cancer stem cell-like properties of colon cancer cells through the PI3K/AKT signaling pathway. Mol Med Rep 2017; 16(6): 8747-54.
[http://dx.doi.org/10.3892/mmr.2017.7721] [PMID: 28990068]
[45]
Kim HJ, Moon SJ, Kim S-H, Heo K, Kim JH. DBC1 regulates Wnt/β-catenin-mediated expression of MACC1, a key regulator of cancer progression, in colon cancer. Cell Death Dis 2018; 9(8): 831.
[http://dx.doi.org/10.1038/s41419-018-0899-9] [PMID: 30082743]
[46]
Lee JH, Yun CW, Lee SH. Cellular Prion Protein Enhances Drug Resistance of Colorectal Cancer Cells via Regulation of a Survival Signal Pathway. Biomol Ther (Seoul) 2018; 26(3): 313-21.
[http://dx.doi.org/10.4062/biomolther.2017.033] [PMID: 28822989]
[47]
Liu B, Liu Y, Zhao L, et al. Upregulation of microRNA-135b and microRNA-182 promotes chemoresistance of colorectal cancer by targeting ST6GALNAC2 via PI3K/AKT pathway. Mol Carcinog 2017; 56(12): 2669-80.
[http://dx.doi.org/10.1002/mc.22710] [PMID: 28767179]
[48]
Jia L, Luo S, Ren X, et al. miR-182 and miR-135b Mediate the Tumorigenesis and Invasiveness of Colorectal Cancer Cells via Targeting ST6GALNAC2 and PI3K/AKT Pathway. Dig Dis Sci 2017; 62(12): 3447-59.
[http://dx.doi.org/10.1007/s10620-017-4755-z] [PMID: 29030743]
[49]
Liu B, Pan S, Xiao Y, Liu Q, Xu J, Jia L. LINC01296/miR- 26a/GALNT3 axis contributes to colorectal cancer progression by regulating O-glycosylated MUC1 via PI3K/AKT pathway. J Exp Clin Cancer Res 2018; 18: 018-0994.
[50]
Liang L, Gao C, Li Y, et al. miR-125a-3p/FUT5-FUT6 axis mediates colorectal cancer cell proliferation, migration, invasion and pathological angiogenesis via PI3K-Akt pathway. Cell Death Dis 2017; 8(8)e2968
[http://dx.doi.org/10.1038/cddis.2017.352] [PMID: 28771224]
[51]
Duan S, Huang W, Liu X, Chen N, Xu Q, Hu Y, et al. IMPDH2 promotes colorectal cancer progression through activation of the PI3K/AKT/mTOR and PI3K/AKT/FOXO1 signaling pathways. J Exp Clin Cancer Res 2018; 37: 018-0980.
[52]
Shen P, Reineke LC, Knutsen E, et al. Metformin blocks MYC protein synthesis in colorectal cancer via mTOR-4EBP-eIF4E and MNK1-eIF4G-eIF4E signaling. Mol Oncol 2018; 12(11): 1856-70.
[http://dx.doi.org/10.1002/1878-0261.12384] [PMID: 30221473]
[53]
Arisan ED, Ergül Z, Bozdağ G, et al. Diclofenac induced apoptosis via altering PI3K/Akt/MAPK signaling axis in HCT 116 more efficiently compared to SW480 colon cancer cells. Mol Biol Rep 2018; 45(6): 2175-84.
[http://dx.doi.org/10.1007/s11033-018-4378-2] [PMID: 30406888]
[54]
Kapral M, Wawszczyk J, Jesse K, Paul-Samojedny M, Kuśmierz D, Węglarz L. Inositol Hexaphosphate Inhibits Proliferation and Induces Apoptosis of Colon Cancer Cells by Suppressing the AKT/mTOR Signaling Pathway. Molecules 2017; 22(10)E1657
[http://dx.doi.org/10.3390/molecules22101657] [PMID: 28972559]
[55]
Nagappan A, Lee WS, Yun JW, et al. Tetraarsenic hexoxide induces G2/M arrest, apoptosis, and autophagy via PI3K/Akt suppression and p38 MAPK activation in SW620 human colon cancer cells. PLoS One 2017; 12(3)e0174591
[http://dx.doi.org/10.1371/journal.pone.0174591] [PMID: 28355296]
[56]
Liu L, Gao H, Wang H, et al. Catalpol promotes cellular apoptosis in human HCT116 colorectal cancer cells via microRNA-200 and the downregulation of PI3K-Akt signaling pathway. Oncol Lett 2017; 14(3): 3741-7.
[http://dx.doi.org/10.3892/ol.2017.6580] [PMID: 28927141]
[57]
Ponnurangam S, Standing D, Rangarajan P, Subramaniam D. Tandutinib inhibits the Akt/mTOR signaling pathway to inhibit colon cancer growth. Mol Cancer Ther 2013; 12(5): 598-609.
[http://dx.doi.org/10.1158/1535-7163.MCT-12-0907] [PMID: 23427297]
[58]
Gaudio E, Tarantelli C, Kwee I, et al. Combination of the MEK inhibitor pimasertib with BTK or PI3K-delta inhibitors is active in preclinical models of aggressive lymphomas. Ann Oncol 2016; 27(6): 1123-8.
[http://dx.doi.org/10.1093/annonc/mdw131] [PMID: 26961147]
[59]
Martinelli E, Troiani T, D’Aiuto E, et al. 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): 2089-101.
[http://dx.doi.org/10.1002/ijc.28236] [PMID: 23629727]
[60]
Zhang YJ, Bao YJ, Dai Q, et al. mTOR signaling is involved in indomethacin and nimesulide suppression of colorectal cancer cell growth via a COX-2 independent pathway. Ann Surg Oncol 2011; 18(2): 580-8.
[http://dx.doi.org/10.1245/s10434-010-1268-9] [PMID: 20803081]
[61]
Chen Y, Lee CH, Tseng BY, et al. AZD8055 Exerts Antitumor Effects on Colon Cancer Cells by Inhibiting mTOR and Cell-cycle Progression. Anticancer Res 2018; 38(3): 1445-54.
[PMID: 29491070]
[62]
Alqurashi N, Hashimi SM, Alowaidi F, Ivanovski S, Wei MQ. Dual mTOR/PI3K inhibitor NVP-BEZ235 arrests colorectal cancer cell growth and displays differential inhibition of 4E-BP1. Oncol Rep 2018; 40(2): 1083-92.
[http://dx.doi.org/10.3892/or.2018.6457] [PMID: 29845289]
[63]
Oh I, Cho H, Lee Y, Cheon M, Park D, Lee Y. Blockage of Autophagy Rescues the Dual PI3K/mTOR Inhibitor BEZ235-induced Growth Inhibition of Colorectal Cancer Cells. Dev Reprod 2016; 20(1): 1-10.
[http://dx.doi.org/10.12717/DR.2016.20.1.001] [PMID: 27294206]
[64]
Potter DS, Kelly P, Denneny O, et al. BMX acts downstream of PI3K to promote colorectal cancer cell survival and pathway inhibition sensitizes to the BH3 mimetic ABT-737. Neoplasia 2014; 16(2): 147-57.
[http://dx.doi.org/10.1593/neo.131376] [PMID: 24709422]
[65]
Roper J, Richardson MP, Wang WV, et al. The dual PI3K/mTOR inhibitor NVP-BEZ235 induces tumor regression in a genetically engineered mouse model of PIK3CA wild-type colorectal cancer. PLoS One 2011; 6(9)e25132
[http://dx.doi.org/10.1371/journal.pone.0025132] [PMID: 21966435]
[66]
Amerizadeh F, Rezaei N, Rahmani F, et al. 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): 10250-61.
[http://dx.doi.org/10.1002/jcb.27367] [PMID: 30129057]
[67]
Palvai S, Kuman MM, Sengupta P, Basu S. Hyaluronic Acid Layered Chimeric Nanoparticles: Targeting MAPK-PI3K Signaling Hub in Colon Cancer Cells. ACS Omega 2017; 2(11): 7868-80.
[http://dx.doi.org/10.1021/acsomega.7b01315] [PMID: 30023564]
[68]
Kim JS, Kim JE, Kim K, et al. The Impact of Cetuximab Plus AKT- or mTOR- Inhibitor in a Patient-Derived Colon Cancer Cell Model with Wild-Type RAS and PIK3CA Mutation. J Cancer 2017; 8(14): 2713-9.
[http://dx.doi.org/10.7150/jca.19458] [PMID: 28928860]
[69]
Zou H, Li L, Garcia Carcedo I, Xu ZP, Monteiro M, Gu W. Synergistic inhibition of colon cancer cell growth with nanoemulsion-loaded paclitaxel and PI3K/mTOR dual inhibitor BEZ235 through apoptosis. Int J Nanomedicine 2016; 11: 1947-58.
[PMID: 27226714]
[70]
Lien GS, Lin CH, Yang YL, Wu MS, Chen BC. Ghrelin induces colon cancer cell proliferation through the GHS-R, Ras, PI3K, Akt, and mTOR signaling pathways. Eur J Pharmacol 2016; 776: 124-31.
[http://dx.doi.org/10.1016/j.ejphar.2016.02.044] [PMID: 26879868]
[71]
Bhatia DR, Thiagarajan P. Combination effects of sorafenib with PI3K inhibitors under hypoxia in colorectal cancer. Hypoxia (Auckl) 2016; 4: 163-74.
[http://dx.doi.org/10.2147/HP.S115500] [PMID: 27995152]
[72]
Ma Q, Chang Z, Wang W, Wang B. Rapamycin-Mediated mTOR Inhibition Reverses Drug Resistance to Adriamycin in Colon Cancer Cells. Hepatogastroenterology 2015; 62(140): 880-6.
[PMID: 26902021]
[73]
Haagensen EJ, Thomas HD, Wilson I, et al. The enhanced in vivo activity of the combination of a MEK and a PI3K inhibitor correlates with [18F]-FLT PET in human colorectal cancer xenograft tumour-bearing mice. PLoS One 2013; 8(12)e81763
[http://dx.doi.org/10.1371/journal.pone.0081763] [PMID: 24339963]
[74]
Narayanankutty V, Narayanankutty A, Nair A. Heat Shock Proteins (HSPs): A Novel Target for Cancer Metastasis Prevention. Curr Drug Targets 2019; 20(7): 727-37.
[http://dx.doi.org/10.2174/1389450120666181211111815] [PMID: 30526455]
[75]
Narayanankutty A. Toll like receptors as a novel therapeutic target for natural products against chronic diseases. Curr Drug Targets 2019; 20: 1-13.
[http://dx.doi.org/10.2174/1389450120666190222181506] [PMID: 30806312]
[76]
Roy N, Narayanankutty A, Nazeem PA, Valsalan R, Babu TD, Mathew D. Plant Phenolics Ferulic Acid and P-Coumaric Acid Inhibit Colorectal Cancer Cell Proliferation through EGFR Down-Regulation. Asian Pac J Cancer Prev 2016; 17(8): 4019-23.
[PMID: 27644655]
[77]
Roy N, Nazeem PA, Babu TD, Abida PS, Narayanankutty A, Valsalan R, et al. EGFR gene regulation in colorectal cancer cells by garlic phytocompounds with special emphasis on S-Allyl-L-Cysteine Sulfoxide. Interdiscip Sci 2017.
[PMID: 28349439]
[78]
Li N, Zhang Z, Jiang G, Sun H, Yu D. Nobiletin sensitizes colorectal cancer cells to oxaliplatin by PI3K/Akt/MTOR pathway. Front Biosci 2019; 24: 303-12.
[http://dx.doi.org/10.2741/4719] [PMID: 30468657]
[79]
Kumar S, Agnihotri N. Piperlongumine, a piper alkaloid targets Ras/PI3K/Akt/mTOR signaling axis to inhibit tumor cell growth and proliferation in DMH/DSS induced experimental colon cancer. Biomed Pharmacother 2019; 109: 1462-77.
[http://dx.doi.org/10.1016/j.biopha.2018.10.182] [PMID: 30551398]
[80]
Zhang L, Chen C, Duanmu J, et al. Cryptotanshinone inhibits the growth and invasion of colon cancer by suppressing inflammation and tumor angiogenesis through modulating MMP/TIMP system, PI3K/Akt/mTOR signaling and HIF-1α nuclear translocation. Int Immunopharmacol 2018; 65: 429-37.
[http://dx.doi.org/10.1016/j.intimp.2018.10.035] [PMID: 30388517]
[81]
Wang D, Ge S, Bai J, Song Y. Boswellic acid exerts potent anticancer effects in HCT-116 human colon cancer cells mediated via induction of apoptosis, cell cycle arrest, cell migration inhibition and inhibition of PI3K/AKT signalling pathway. J BUON 2018; 23(2): 340-5.
[PMID: 29745074]
[82]
Tsai DH, Chung CH, Lee KT. Antrodia cinnamomea induces autophagic cell death via the CHOP/TRB3/Akt/mTOR pathway in colorectal cancer cells. Sci Rep 2018; 8(1): 17424.
[http://dx.doi.org/10.1038/s41598-018-35780-y] [PMID: 30479369]
[83]
Sun D, Zhang F, Qian J, et al. 4′-hydroxywogonin inhibits colorectal cancer angiogenesis by disrupting PI3K/AKT signaling. Chem Biol Interact 2018; 296: 26-33.
[http://dx.doi.org/10.1016/j.cbi.2018.09.003] [PMID: 30217479]
[84]
Liu M, Zhao G, Zhang D, et al. Active fraction of clove induces apoptosis via PI3K/Akt/mTOR-mediated autophagy in human colorectal cancer HCT-116 cells. Int J Oncol 2018; 53(3): 1363-73.
[http://dx.doi.org/10.3892/ijo.2018.4465] [PMID: 30015913]
[85]
Li Q, Lai Z, Yan Z, et al. Hedyotis diffusa Willd inhibits proliferation and induces apoptosis of 5-FU resistant colorectal cancer cells by regulating the PI3K/AKT signaling pathway. Mol Med Rep 2018; 17(1): 358-65.
[PMID: 29115462]
[86]
Han C, Xing G, Zhang M, et al. Wogonoside inhibits cell growth and induces mitochondrial-mediated autophagy-related apoptosis in human colon cancer cells through the PI3K/AKT/mTOR/p70S6K signaling pathway. Oncol Lett 2018; 15(4): 4463-70.
[http://dx.doi.org/10.3892/ol.2018.7852] [PMID: 29541215]
[87]
Sun Y, Zhao Y, Wang X, et al. Wogonoside prevents colitis-associated colorectal carcinogenesis and colon cancer progression in inflammation-related microenvironment via inhibiting NF-κB activation through PI3K/Akt pathway. Oncotarget 2016; 7(23): 34300-15.
[http://dx.doi.org/10.18632/oncotarget.8815] [PMID: 27102438]
[88]
Han B, Jiang P, Li Z, et al. Coptisine-induced apoptosis in human colon cancer cells (HCT-116) is mediated by PI3K/Akt and mitochondrial-associated apoptotic pathway. Phytomedicine 2018; 48: 152-60.
[http://dx.doi.org/10.1016/j.phymed.2017.12.027] [PMID: 30195873]
[89]
Bufu T, Di X, Yilin Z, Gege L, Xi C, Ling W. Celastrol inhibits colorectal cancer cell proliferation and migration through suppression of MMP3 and MMP7 by the PI3K/AKT signaling pathway. Anticancer Drugs 2018; 29(6): 530-8.
[http://dx.doi.org/10.1097/CAD.0000000000000621] [PMID: 29553945]
[90]
Attia YM, El-Kersh DM, Wagdy HA, Elmazar MM. Verbascoside: Identification, Quantification, and Potential Sensitization of Colorectal Cancer Cells to 5-FU by Targeting PI3K/AKT Pathway. Sci Rep 2018; 8(1): 16939.
[http://dx.doi.org/10.1038/s41598-018-35083-2] [PMID: 30446678]
[91]
Zeng YH, Zhou LY, Chen QZ, et al. Resveratrol inactivates PI3K/Akt signaling through upregulating BMP7 in human colon cancer cells. Oncol Rep 2017; 38(1): 456-64.
[http://dx.doi.org/10.3892/or.2017.5662] [PMID: 28534975]
[92]
Liu YZ, Wu K, Huang J, et al. The PTEN/PI3K/Akt and Wnt/β-catenin signaling pathways are involved in the inhibitory effect of resveratrol on human colon cancer cell proliferation. Int J Oncol 2014; 45(1): 104-12.
[http://dx.doi.org/10.3892/ijo.2014.2392] [PMID: 24756222]
[93]
Soo HC, Chung FF, Lim KH, et al. Cudraflavone C Induces Tumor-Specific Apoptosis in Colorectal Cancer Cells through Inhibition of the Phosphoinositide 3-Kinase (PI3K)-AKT Pathway. PLoS One 2017; 12(1)e0170551
[http://dx.doi.org/10.1371/journal.pone.0170551] [PMID: 28107519]
[94]
Mi C, Ma J, Wang KS, et al. Imperatorin suppresses proliferation and angiogenesis of human colon cancer cell by targeting HIF-1α via the mTOR/p70S6K/4E-BP1 and MAPK pathways. J Ethnopharmacol 2017; 203: 27-38.
[http://dx.doi.org/10.1016/j.jep.2017.03.033] [PMID: 28341244]
[95]
Lin J, Feng J, Yang H, et al. Scutellaria barbata D. Don inhibits 5-fluorouracil resistance in colorectal cancer by regulating PI3K/AKT pathway. Oncol Rep 2017; 38(4): 2293-300.
[http://dx.doi.org/10.3892/or.2017.5892] [PMID: 28849113]
[96]
Jin Y, Chen W, Yang H, et al. Scutellaria barbata D. Don inhibits migration and invasion of colorectal cancer cells via suppression of PI3K/AKT and TGF-β/Smad signaling pathways. Exp Ther Med 2017; 14(6): 5527-34.
[http://dx.doi.org/10.3892/etm.2017.5242] [PMID: 29285087]
[97]
Daaboul HE, Daher CF, Bodman-Smith K, et al. Antitumor activity of β-2-himachalen-6-ol in colon cancer is mediated through its inhibition of the PI3K and MAPK pathways. Chem Biol Interact 2017; 275: 162-70.
[http://dx.doi.org/10.1016/j.cbi.2017.08.003] [PMID: 28782499]
[98]
Cadoná FC, Rosa JL, Schneider T, et al. Guaraná, a Highly Caffeinated Food, Presents in vitro Antitumor Activity in Colorectal and Breast Cancer Cell Lines by Inhibiting AKT/mTOR/S6K and MAPKs Pathways. Nutr Cancer 2017; 69(5): 800-10.
[http://dx.doi.org/10.1080/01635581.2017.1324994] [PMID: 28569556]
[99]
Arun A, Patel OPS, Saini D, Yadav PP, Konwar R. Anti-colon cancer activity of Murraya koenigii leaves is due to constituent murrayazoline and O-methylmurrayamine A induced mTOR/AKT downregulation and mitochondrial apoptosis. Biomed Pharmacother 2017; 93: 510-21.
[http://dx.doi.org/10.1016/j.biopha.2017.06.065] [PMID: 28675857]
[100]
Zhao X, Li X, Ren Q, Tian J, Chen J. Calycosin induces apoptosis in colorectal cancer cells, through modulating the ERβ/MiR-95 and IGF-1R, PI3K/Akt signaling pathways. Gene 2016; 591(1): 123-8.
[http://dx.doi.org/10.1016/j.gene.2016.07.012] [PMID: 27393650]
[101]
Zhang J, Jiang H, Xie L, et al. Antitumor effect of manumycin on colorectal cancer cells by increasing the reactive oxygen species production and blocking PI3K-AKT pathway. OncoTargets Ther 2016; 9: 2885-95.
[http://dx.doi.org/10.2147/OTT.S102408] [PMID: 27307747]
[102]
Yang L, Liu Y, Wang M, et al. Celastrus orbiculatus extract triggers apoptosis and autophagy via PI3K/Akt/mTOR inhibition in human colorectal cancer cells. Oncol Lett 2016; 12(5): 3771-8.
[http://dx.doi.org/10.3892/ol.2016.5213] [PMID: 27895729]
[103]
Wani ZA, Guru SK, Rao AV, et al. A novel quinazolinone chalcone derivative induces mitochondrial dependent apoptosis and inhibits PI3K/Akt/mTOR signaling pathway in human colon cancer HCT-116 cells. Food Chem Toxicol 2016; 87: 1-11.
[http://dx.doi.org/10.1016/j.fct.2015.11.016] [PMID: 26615871]
[104]
Liu YQ, Wang SK, Xu QQ, Yuan HQ, Guo YX, Wang Q, et al. Acetyl-11-keto-beta-boswellic acid suppresses docetaxel-resistant prostate cancer cells in vitro and in vivo by blocking Akt and Stat3 signaling, thus suppressing chemoresistant stem cell-like properties. Acta Pharmacol Sin 2018; 31: 018-0157.
[105]
Li W, Liu J, Fu W, et al. 3-O-acetyl-11-keto-β-boswellic acid exerts anti-tumor effects in glioblastoma by arresting cell cycle at G2/M phase. J Exp Clin Cancer Res 2018; 37(1): 132.
[http://dx.doi.org/10.1186/s13046-018-0805-4] [PMID: 29970196]
[106]
Hu T, Li Z, Gao C-Y, Cho CH. Mechanisms of drug resistance in colon cancer and its therapeutic strategies. World J Gastroenterol 2016; 22(30): 6876-89.
[http://dx.doi.org/10.3748/wjg.v22.i30.6876] [PMID: 27570424]
[107]
Eduati F, Doldàn-Martelli V, Klinger B, et al. Drug Resistance Mechanisms in Colorectal Cancer Dissected with Cell Type-Specific Dynamic Logic Models. Cancer Res 2017; 77(12): 3364-75.
[http://dx.doi.org/10.1158/0008-5472.CAN-17-0078] [PMID: 28381545]
[108]
Kai W, Yating S, Lin M, et al. Natural product toosendanin reverses the resistance of human breast cancer cells to adriamycin as a novel PI3K inhibitor. Biochem Pharmacol 2018; 152: 153-64.
[http://dx.doi.org/10.1016/j.bcp.2018.03.022] [PMID: 29574068]
[109]
Hamed AR, Abdel-Azim NS, Shams KA, Hammouda FM. Targeting multidrug resistance in cancer by natural chemosensitizers. Bull Natl Res Cent 2019; 43: 8.
[http://dx.doi.org/10.1186/s42269-019-0043-8]

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