Phytochemicals as PI3K/ Akt/ mTOR Inhibitors and Their Role in Breast Cancer Treatment

Author(s): Arunaksharan Narayanankutty*

Journal Name: Recent Patents on Anti-Cancer Drug Discovery

Volume 15 , Issue 3 , 2020


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Abstract:

Background: Breast cancer is the predominant form of cancer in women; various cellular pathways are involved in the initiation and progression of breast cancer. Among the various types of breast cancer that differ in their growth factor receptor status, PI3K/Akt signaling is a common pathway where all these converge. Thus, the PI3K signaling is of great interest as a target for breast cancer prevention; however, it is less explored.

Objective: The present review is aimed to provide a concise outline of the role of PI3K/Akt/mTOR pathway in breast carcinogenesis and its progression events, including metastasis, drug resistance and stemness. The review emphasizes the role of natural and synthetic inhibitors of PI3K/Akt/m- TOR pathway in breast cancer prevention.

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

Results: PI3K/Akt/mTOR signaling plays an important role in human breast carcinogenesis; it acts on the initiation and progression events associated with it. Numerous molecules have been isolated and identified as promising drug candidates by targeting the signaling pathway. Results from clinical studies confirm their application in the treatment of human breast cancer alone and in combination with classical chemotherapeutics as well as monoclonal antibodies.

Conclusion: PI3K/mTOR signaling blockers have evolved as promising anticancer agents by interfering breast cancer development and progression at various stages. Natural products and bioactive components are emerging as novel inhibitors of PI3K signaling and more research in this area may yield numerous drug candidates.

Keywords: Breast cancer, carcinogenesis, curcumin, drug development, metastasis, natural products, PI3K/Akt/mTOR pathway.

[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 Peer J 2018; 6: e5092-e.
[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]
Yang J, Nie J, Ma X, Wei Y, Peng Y, Wei X. Targeting PI3K in cancer: Mechanisms and advances in clinical trials. Mol Cancer 2019; 18(1): 26.
[http://dx.doi.org/10.1186/s12943-019-0954-x] [PMID: 30782187]
[8]
Mukohara T. PI3K mutations in breast cancer: Prognostic and therapeutic implications. Breast Cancer (Dove Med Press) 2015; 7: 111-23.
[http://dx.doi.org/10.2147/BCTT.S60696] [PMID: 26028978]
[9]
Guerrero-Zotano A, Mayer IA, Arteaga CL. PI3K/AKT/mTOR: Role in breast cancer progression, drug resistance, and treatment. Cancer Metastasis Rev 2016; 35(4): 515-24.
[http://dx.doi.org/10.1007/s10555-016-9637-x] [PMID: 27896521]
[10]
Roy N, Nazeem PA, Babu TD, et al. EGFR gene regulation in colorectal cancer cells by garlic phytocompounds with special emphasis on S-Allyl-L-Cysteine Sulfoxide. Interdiscip Sci 2018; 10(4): 686-93.
[http://dx.doi.org/10.1007/s12539-017-0227-6] [PMID: 28349439]
[11]
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]
[12]
Roy N, Davis S, Narayanankutty A, et al. Garlic phytocompounds possess anticancer activity by specifically targeting breast cancer biomarkers - an in silico study. Asian Pac J Cancer Prev 2016; 17(6): 2883-8.
[PMID: 27356707]
[13]
Lima ZS, Ghadamzadeh M, Arashloo FT, Amjad G, Ebadi MR, Younesi L. Recent advances of therapeutic targets based on the molecular signature in breast cancer: Genetic mutations and implications for current treatment paradigms. J Hematol Oncol 2019; 12(1): 38.
[http://dx.doi.org/10.1186/s13045-019-0725-6] [PMID: 30975222]
[14]
Momenimovahed Z, Salehiniya H. Epidemiological characteristics of and risk factors for breast cancer in the world. Breast Cancer 2019; 11: 151-64.
[http://dx.doi.org/10.2147/BCTT.S176070] [PMID: 31040712]
[15]
Arthur RS, Wang T, Xue X, Kamensky V, Rohan TE. Genetic factors, adherence to healthy lifestyle behavior, and risk of invasive breast cancer among women in the UK Biobank. J Natl Cancer Inst 2020; 3(10): djz241.
[http://dx.doi.org/10.1093/jnci/djz241] [PMID: 31899501]
[16]
Semmler L, Reiter-Brennan C, Klein A. BRCA1 and breast cancer: A review of the underlying mechanisms resulting in the tissue-specific tumorigenesis in mutation carriers. J Breast Cancer 2019; 22(1): 1-14.
[http://dx.doi.org/10.4048/jbc.2019.22.e6] [PMID: 30941229]
[17]
Roy R, Chun J, Powell SN. BRCA1 and BRCA2: Different roles in a common pathway of genome protection. Nat Rev Cancer 2011; 12(1): 68-78.
[http://dx.doi.org/10.1038/nrc3181] [PMID: 22193408]
[18]
Mehrgou A, Akouchekian M. The importance of BRCA1 and BRCA2 genes mutations in breast cancer development. Med J Islam Repub Iran 2016; 30: 369.
[PMID: 27493913]
[19]
Godet I, Gilkes DM. BRCA1 and BRCA2 mutations and treatment strategies for breast cancer. Integr Cancer Sci Ther 2017; 4 (1).
[http://dx.doi.org/10.15761/ICST.1000228] [PMID: 28706734]
[20]
Moasser MM. The oncogene HER2: Its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene 2007; 26(45): 6469-87.
[http://dx.doi.org/10.1038/sj.onc.1210477] [PMID: 17471238]
[21]
Aman NA, Doukoure B, Koffi KD, et al. HER2 overexpression and correlation with other significant clinicopathologic parameters in Ivorian breast cancer women. BMC Clin Pathol 2019; 19(1): 1.
[http://dx.doi.org/10.1186/s12907-018-0081-4] [PMID: 30675127]
[22]
Cesca MG, Vian L, Cristóvão-Ferreira S, Pondé N, de Azambuja E. HER2-positive advanced breast cancer treatment in 2020. Cancer Treat Rev 2020; 88: 102033.
[http://dx.doi.org/10.1016/j.ctrv.2020.102033] [PMID: 32534233]
[23]
Rexer BN, Arteaga CL. Intrinsic and acquired resistance to HER2-targeted therapies in HER2 gene-amplified breast cancer: Mechanisms and clinical implications. Crit Rev Oncog 2012; 17(1): 1-16.
[http://dx.doi.org/10.1615/CritRevOncog.v17.i1.20] [PMID: 22471661]
[24]
Rouanet P, Roger P, Rousseau E, et al. HER2 overexpression a major risk factor for recurrence in pT1a-bN0M0 breast cancer: Results from a French regional cohort. Cancer Med 2014; 3(1): 134-42.
[http://dx.doi.org/10.1002/cam4.167] [PMID: 24407937]
[25]
Viale G. The current state of breast cancer classification. Ann Oncol 2012; 23(Suppl. 10): 207-10.
[http://dx.doi.org/10.1093/annonc/mds326] [PMID: 22987963]
[26]
Effi AB, Aman NA, Koui BS, Koffi KD, Traore ZC, Kouyate M. Breast cancer molecular subtypes defined by ER/PR and HER2 status: Association with clinicopathologic parameters in Ivorian patients. Asian Pac J Cancer Prev 2016; 17(4): 1973-8.
[http://dx.doi.org/10.7314/APJCP.2016.17.4.1973] [PMID: 27221883]
[27]
Bouchal P, Schubert OT, Faktor J, et al. Breast cancer classification based on proteotypes obtained by swath mass spectrometry. Cell Rep 2019; 28(3): 832-43.
[http://dx.doi.org/10.1016/j.celrep.2019.06.046] [PMID: 31315058]
[28]
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]
[29]
Park J-Y, Kang S-E, Ahn KS, et al. Inhibition of the PI3K-AKT-mTOR pathway suppresses the adipocyte-mediated proliferation and migration of breast cancer cells. J Cancer 2020; 11(9): 2552-9.
[http://dx.doi.org/10.7150/jca.37975] [PMID: 32201525]
[30]
Huang F, Shi Q, Li Y, et al. HER2/EGFR-AKT signaling switches TGFβ from inhibiting cell proliferation to promoting cell migration in breast cancer. Cancer Res 2018; 78(21): 6073-85.
[http://dx.doi.org/10.1158/0008-5472.CAN-18-0136] [PMID: 30171053]
[31]
Yang W, Hosford SR, Dillon LM, et al. Strategically timing inhibition of phosphatidylinositol 3-kinase to maximize therapeutic index in estrogen receptor alpha-positive, PIK3CA-mutant breast cancer. Clin Cancer Res 2016; 22(9): 2250-60.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-2276] [PMID: 26733612]
[32]
Qu Y, Hao C, Xu J, Cheng Z, Wang W, Liu H. ILK promotes cell proliferation in breast cancer cells by activating the PI3K/Akt pathway. Mol Med Rep 2017; 16(4): 5036-42.
[http://dx.doi.org/10.3892/mmr.2017.7180] [PMID: 28791358]
[33]
Gonzalez-Angulo AM, Ferrer-Lozano J, Stemke-Hale K, et al. PI3K pathway mutations and PTEN levels in primary and metastatic breast cancer. Mol Cancer Ther 2011; 10(6): 1093-101.
[http://dx.doi.org/10.1158/1535-7163.MCT-10-1089] [PMID: 21490305]
[34]
Lopez-Knowles E, Toole S, McNeil C, et al. PI3K pathway activation in breast cancer is associated with the basal-like phenotype and cancer-specific mortality. Cancer Res 2009; 69(24): 2123.
[35]
Christowitz C, Davis T, Isaacs A, van Niekerk G, Hattingh S, Engelbrecht A-M. Mechanisms of doxorubicin-induced drug resistance and drug resistant tumour growth in a murine breast tumour model. BMC Cancer 2019; 19(1): 757.
[http://dx.doi.org/10.1186/s12885-019-5939-z] [PMID: 31370818]
[36]
Dong C, Chen Y, Ma J, et al. Econazole nitrate reversed the resistance of breast cancer cells to Adriamycin through inhibiting the PI3K/AKT signaling pathway. Am J Cancer Res 2020; 10(1): 263-74.
[PMID: 32064166]
[37]
Narayanankutty A. Toll-like receptors as a novel therapeutic target for natural products against chronic diseases. Curr Drug Targets 2019; 20(10): 1068-80.
[http://dx.doi.org/10.2174/1389450120666190222181506] [PMID: 30806312]
[38]
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]
[39]
Narayanankutty A, Job JT, Narayanankutty V. Glutathione, an antioxidant tripeptide: Dual roles in carcinogenesis and chemoprevention. Curr Protein Pept Sci 2019; 20(9): 907-17.
[http://dx.doi.org/10.2174/1389203720666190206130003] [PMID: 30727890]
[40]
Narayanankutty A. PI3K/Akt/mTOR pathway as a therapeutic target for colorectal cancer: A review of preclinical and clinical evidence. Curr Drug Targets 2019; 20(12): 1217-26.
[http://dx.doi.org/10.2174/1389450120666190618123846] [PMID: 31215384]
[41]
Mirza-Aghazadeh-Attari M, Ekrami EM, Aghdas SAM, et al. Targeting PI3K/Akt/mTOR signaling pathway by polyphenols: Implication for cancer therapy. Life Sci 2020; 255: 117481.
[http://dx.doi.org/10.1016/j.lfs.2020.117481] [PMID: 32135183]
[42]
Santi SA, Douglas AC, Lee H. The Akt isoforms, their unique functions and potential as anticancer therapeutic targets. Biomol Concepts 2010; 1(5-6): 389-401.
[http://dx.doi.org/10.1515/bmc.2010.035] [PMID: 25962012]
[43]
Xie Y, Shi X, Sheng K, et al. PI3K/Akt signaling transduction pathway, erythropoiesis and glycolysis in hypoxia. Mol Med Rep 2019; 19(2): 783-91.
[PMID: 30535469]
[44]
Manning BD, Toker A. AKT/PKB signaling: Navigating the network. Cell 2017; 169(3): 381-405.
[http://dx.doi.org/10.1016/j.cell.2017.04.001] [PMID: 28431241]
[45]
Alberto MM, Giovanna T, Roberta B, et al. The Phosphoinositide 3-Kinase (PI3K)/AKT signaling pathway as a therapeutic target for the treatment of human Acute Myeloid Leukemia (AML). Curr Signal Transduct Ther 2007; 2(3): 246-56.
[http://dx.doi.org/10.2174/157436207781745373]
[46]
Matsuda S, Nakanishi A, Wada Y, Kitagishi Y. Roles of PI3K/AKT/PTEN pathway as a target for pharmaceutical therapy. Open Med Chem J 2013; 7: 23-9.
[http://dx.doi.org/10.2174/1874104501307010023] [PMID: 24222802]
[47]
Gonzalez E, McGraw TE. The Akt kinases: Isoform specificity in metabolism and cancer. Cell Cycle 2009; 8(16): 2502-8.
[http://dx.doi.org/10.4161/cc.8.16.9335] [PMID: 19597332]
[48]
Lahlou H, Müller T, Sanguin-Gendreau V, Birchmeier C, Muller WJ. Uncoupling of PI3K from ErbB3 impairs mammary gland development but does not impact on ErbB2-induced mammary tumorigenesis. Cancer Res 2012; 72(12): 3080-90.
[http://dx.doi.org/10.1158/0008-5472.CAN-11-3513] [PMID: 22665265]
[49]
Williams MM, Vaught DB, Joly MM, et al. ErbB3 drives mammary epithelial survival and differentiation during pregnancy and lactation. Breast Cancer Res 2017; 19(1): 17-893.
[http://dx.doi.org/10.1186/s13058-017-0893-7]
[50]
Maroulakou IG, Oemler W, Naber SP, Klebba I, Kuperwasser C, Tsichlis PN. Distinct roles of the three Akt isoforms in lactogenic differentiation and involution. J Cell Physiol 2008; 217(2): 468-77.
[http://dx.doi.org/10.1002/jcp.21518] [PMID: 18561256]
[51]
Chen CC, Stairs DB, Boxer RB, et al. Autocrine prolactin induced by the Pten-Akt pathway is required for lactation initiation and provides a direct link between the Akt and Stat5 pathways. Genes Dev 2012; 26(19): 2154-68.
[http://dx.doi.org/10.1101/gad.197343.112] [PMID: 23028142]
[52]
Chen CC, Boxer RB, Stairs DB, et al. Akt is required for Stat5 activation and mammary differentiation. Breast Cancer Res 2010; 12(5): R72.
[http://dx.doi.org/10.1186/bcr2640] [PMID: 20849614]
[53]
Wang Z, Hou X, Qu B, Wang J, Gao X, Li Q. Pten regulates development and lactation in the mammary glands of dairy cows. PLoS One 2014; 9(7): e102118.
[54]
Meng Y, Zhang J, Yuan C, et al. Oleic acid stimulates HC11 mammary epithelial cells proliferation and mammary gland development in peripubertal mice through activation of CD36-Ca2+ and PI3K/Akt signaling pathway. Oncotarget 2018; 9(16): 12982-94.
[http://dx.doi.org/10.18632/oncotarget.24204] [PMID: 29560125]
[55]
Yang L, Yang Q, Li F, et al. Effects of dietary supplementation of lauric acid on lactation function, mammary gland development, and serum lipid metabolites in lactating mice. Animals (Basel) 2020; 10(3): E529.
[http://dx.doi.org/10.3390/ani10030529] [PMID: 32235692]
[56]
Meng Y, Yuan C, Zhang J, et al. Stearic acid suppresses mammary gland development by inhibiting PI3K/Akt signaling pathway through GPR120 in pubertal mice. Biochem Biophys Res Commun 2017; 491(1): 192-7.
[http://dx.doi.org/10.1016/j.bbrc.2017.07.075] [PMID: 28712865]
[57]
Miller TW, Rexer BN, Garrett JT, Arteaga CL. Mutations in the phosphatidylinositol 3-kinase pathway: Role in tumor progression and therapeutic implications in breast cancer. Breast Cancer Res 2011; 13(6): 224.
[http://dx.doi.org/10.1186/bcr3039] [PMID: 22114931]
[58]
Lyu H, Huang J, Edgerton SM, Thor AD, He Z, Liu B. Increased ErbB3 promotes ErbB2/neu-driven mammary tumor proliferation and co-targeting of ErbB2/ErbB3 receptors exhibits potent inhibitory effects on breast cancer cells. Int J Clin Exp Pathol 2015; 8(6): 6143-56.
[PMID: 26261492]
[59]
Cook RS, Garrett JT, Sánchez V, et al. ErbB3 ablation impairs PI3K/Akt-dependent mammary tumorigenesis. Cancer Res 2011; 71(11): 3941-51.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-3775] [PMID: 21482676]
[60]
Young CD, Pfefferle AD, Owens P, et al. Conditional loss of ErbB3 delays mammary gland hyperplasia induced by mutant PIK3CA without affecting mammary tumor latency, gene expression, or signaling. Cancer Res 2013; 73(13): 4075-85.
[http://dx.doi.org/10.1158/0008-5472.CAN-12-4579] [PMID: 23633485]
[61]
Illam SP, Narayanankutty A, Mathew SE, Valsalakumari R, Jacob RM, Raghavamenon AC. Epithelial mesenchymal transition in cancer progression: Preventive phytochemicals. Recent Patents Anticancer Drug Discov 2017; 12(3): 234-46.
[http://dx.doi.org/10.2174/1574892812666170424150407] [PMID: 28440207]
[62]
Hao Y, Baker D, Ten Dijke P. TGF-β-mediated epithelial-mesenchymal transition and cancer metastasis. Int J Mol Sci 2019; 20(11): 2767.
[http://dx.doi.org/10.3390/ijms20112767] [PMID: 31195692]
[63]
Liu S, Huang J, Zhang Y, Liu Y, Zuo S, Li R. MAP2K4 interacts with Vimentin to activate the PI3K/AKT pathway and promotes breast cancer pathogenesis. Aging (Albany NY) 2019; 11(22): 10697-710.
[http://dx.doi.org/10.18632/aging.102485] [PMID: 31761784]
[64]
Chen L, Fu H, Luo Y, et al. cPLA2α mediates TGF-β-induced epithelial-mesenchymal transition in breast cancer through PI3k/Akt signaling. Cell Death Dis 2017; 8(4): e2728.
[http://dx.doi.org/10.1038/cddis.2017.152] [PMID: 28383549]
[65]
Tokunaga E, Kimura Y, Mashino K, et al. Activation of PI3K/Akt signaling and hormone resistance in breast cancer. Breast Cancer 2006; 13(2): 137-44.
[http://dx.doi.org/10.2325/jbcs.13.137] [PMID: 16755107]
[66]
Wallin JJ, Guan J, Edgar KA, et al. Active PI3K pathway causes an invasive phenotype which can be reversed or promoted by blocking the pathway at divergent nodes. PLoS One 2012; 7(5): e36402.
[http://dx.doi.org/10.1371/journal.pone.0036402] [PMID: 22570710]
[67]
Ikink GJ, Boer M, Bakker ERM, Hilkens J. IRS4 induces mammary tumorigenesis and confers resistance to HER2-targeted therapy through constitutive PI3K/AKT-pathway hyperactivation. Nat Commun 2016; 7(1): 13567.
[http://dx.doi.org/10.1038/ncomms13567] [PMID: 27876799]
[68]
Clark AS, West K, Streicher S, Dennis PA. Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol Cancer Ther 2002; 1(9): 707-17.
[PMID: 12479367]
[69]
Liu T, Guo J, Zhang X. MiR-202-5p/PTEN mediates doxorubicin-resistance of breast cancer cells via PI3K/Akt signaling pathway. Cancer Biol Ther 2019; 20(7): 989-98.
[http://dx.doi.org/10.1080/15384047.2019.1591674] [PMID: 30983514]
[70]
Mei Y, Liao X, Zhu L, Yang H. Overexpression of RSK4 reverses doxorubicin resistance in human breast cancer cells via PI3K/AKT signalling pathway. J Biochem 2020; 167(6): 603-11.
[http://dx.doi.org/10.1093/jb/mvaa009] [PMID: 31960922]
[71]
Gohr K, Hamacher A, Engelke LH, Kassack MU. Inhibition of PI3K/Akt/mTOR overcomes cisplatin resistance in the triple negative breast cancer cell line HCC38. BMC Cancer 2017; 17(1): 17-3695.
[72]
Cerliani J, Gargini R, Calvo J, Lanari C, Izquierdo M. PI3K/Akt and stem cells in two breast cancer cell lines. Cancer Res 2008; 68(9): 2019.
[73]
Majumder M, Xin X, Liu L, et al. COX-2 induces breast cancer stem cells via EP4/PI3K/AKT/NOTCH/WNT axis. Stem Cells 2016; 34(9): 2290-305.
[http://dx.doi.org/10.1002/stem.2426] [PMID: 27301070]
[74]
Kim Y, Rouse M, González-Mariscal I, Egan JM, O’Connell JF. Dietary curcumin enhances insulin clearance in diet-induced obese mice via regulation of hepatic PI3K-AKT axis and IDE, and preservation of islet integrity. Nutr Metab (Lond) 2019; 16: 48.
[http://dx.doi.org/10.1186/s12986-019-0377-0] [PMID: 31372175]
[75]
Cheng F, Han L, Xiao Y, et al. d-Chiro-inositol ameliorates high fat diet-induced hepatic steatosis and insulin resistance via PKCE-PI3K/Akt pathway. J Agric Food Chem 2019; 67(21): 5957-67.
[http://dx.doi.org/10.1021/acs.jafc.9b01253] [PMID: 31066268]
[76]
Ali MY, Zaib S, Rahman MM, et al. Didymin, a dietary citrus flavonoid exhibits anti-diabetic complications and promotes glucose uptake through the activation of PI3K/Akt signaling pathway in insulin-resistant HepG2 cells. Chem Biol Interact 2019; 305: 180-94.
[http://dx.doi.org/10.1016/j.cbi.2019.03.018] [PMID: 30928401]
[77]
Liu TY, Shi CX, Gao R, et al. Irisin inhibits hepatic gluconeogenesis and increases glycogen synthesis via the PI3K/Akt pathway in type 2 diabetic mice and hepatocytes. Clin Sci (Lond) 2015; 129(10): 839-50.
[http://dx.doi.org/10.1042/CS20150009] [PMID: 26201094]
[78]
Wang LY, Wang Y, Xu DS, Ruan KF, Feng Y, Wang S. MDG-1, a polysaccharide from Ophiopogon japonicus exerts hypoglycemic effects through the PI3K/Akt pathway in a diabetic KKAy mouse model. J Ethnopharmacol 2012; 143(1): 347-54.
[http://dx.doi.org/10.1016/j.jep.2012.06.050] [PMID: 22776833]
[79]
Yan F, Dai G, Zheng X. Mulberry anthocyanin extract ameliorates insulin resistance by regulating PI3K/AKT pathway in HepG2 cells and db/db mice. J Nutr Biochem 2016; 36: 68-80.
[http://dx.doi.org/10.1016/j.jnutbio.2016.07.004] [PMID: 27580020]
[80]
Tang D, Chen QB, Xin XL, Aisa HA. Anti-diabetic effect of three new norditerpenoid alkaloids in vitro and potential mechanism via PI3K/Akt signaling pathway. Biomed Pharmacother 2017; 87: 145-52.
[http://dx.doi.org/10.1016/j.biopha.2016.12.058] [PMID: 28049096]
[81]
Pisonero-Vaquero S, Martínez-Ferreras Á, García-Mediavilla MV, et al. Quercetin ameliorates dysregulation of lipid metabolism genes via the PI3K/AKT pathway in a diet-induced mouse model of nonalcoholic fatty liver disease. Mol Nutr Food Res 2015; 59(5): 879-93.
[http://dx.doi.org/10.1002/mnfr.201400913] [PMID: 25712622]
[82]
Xu X, Liu X, Yang Y, et al. Resveratrol inhibits the development of obesity-related osteoarthritis via the TLR4 and PI3K/Akt signaling pathways. Connect Tissue Res 2019; 60(6): 571-82.
[http://dx.doi.org/10.1080/03008207.2019.1601187] [PMID: 30922122]
[83]
Brito PM, Devillard R, Nègre-Salvayre A, et al. Resveratrol inhibits the mTOR mitogenic signaling evoked by oxidized LDL in smooth muscle cells. Atherosclerosis 2009; 205(1): 126-34.
[http://dx.doi.org/10.1016/j.atherosclerosis.2008.11.011] [PMID: 19108833]
[84]
Abdel-Aleem GA, Khaleel EF, Mostafa DG, Elberier LK. Neuroprotective effect of resveratrol against brain ischemia reperfusion injury in rats entails reduction of DJ-1 protein expression and activation of PI3K/Akt/GSK3b survival pathway. Arch Physiol Biochem 2016; 122(4): 200-13.
[http://dx.doi.org/10.1080/13813455.2016.1182190] [PMID: 27109835]
[85]
Zhang B, Wang Y, Li H, et al. Neuroprotective effects of salidroside through PI3K/Akt pathway activation in Alzheimer’s disease models. Drug Des Devel Ther 2016; 10: 1335-43.
[PMID: 27103787]
[86]
Li J, Zhu L, Zhang YM, et al. Sheng-Jiang powder ameliorates high fat diet induced nonalcoholic fatty liver disease via inhibiting activation of Akt/mTOR/S6 pathway in rats. Evid Based Complement Alternat Med 2018; 2018: 6190254.
[http://dx.doi.org/10.1155/2018/6190254] [PMID: 30402130]
[87]
Jung HJ, Seong SH, Ali MY, Min BS, Jung HA, Choi JS. α-Methyl artoflavanocoumarin from Juniperus chinensis exerts anti-diabetic effects by inhibiting PTP1B and activating the PI3K/Akt signaling pathway in insulin-resistant HepG2 cells. Arch Pharm Res 2017; 40(12): 1403-13.
[http://dx.doi.org/10.1007/s12272-017-0992-0] [PMID: 29177868]
[88]
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]
[89]
Pan H, Liu F, Wang J, et al. Dihydromethysticin, a natural molecule from Kava, suppresses the growth of colorectal cancer via the NLRC3/PI3K pathway. Mol Carcinog 2020; 59(6): 575-89.
[http://dx.doi.org/10.1002/mc.23182] [PMID: 32187756]
[90]
Pan R-R, Zhang C-Y, Li Y, et al. Daphnane diterpenoids from Daphne genkwa inhibit PI3K/Akt/mTOR signaling and induce cell cycle arrest and apoptosis in human colon cancer cells. J Nat Prod 2020; 83(4): 1238-48.
[http://dx.doi.org/10.1021/acs.jnatprod.0c00003] [PMID: 32223193]
[91]
Huang Y-L, Wei F, Zhao K, Zhang Y, Wang D, Li X-H. Isoliquiritigenin inhibits colorectal cancer cells HCT-116 growth by suppressing the PI3K/AKT pathway. Open Life Sci 2017; 12(1): 300.
[http://dx.doi.org/10.1515/biol-2017-0035]
[92]
Liu Y, Liu C, Tan T, Li S, Tang S, Chen X. Sinomenine sensitizes human gastric cancer cells to cisplatin through negative regulation of PI3K/AKT/Wnt signaling pathway. Anticancer Drugs 2019; 30(10): 983-90.
[http://dx.doi.org/10.1097/CAD.0000000000000834] [PMID: 31609766]
[93]
Wen C, Wang H, Wu X, et al. ROS-mediated inactivation of the PI3K/AKT pathway is involved in the antigastric cancer effects of thioredoxin reductase-1 inhibitor chaetocin. Cell Death Dis 2019; 10(11): 809.
[http://dx.doi.org/10.1038/s41419-019-2035-x] [PMID: 31649256]
[94]
Jia L, Zhu Z, Li H, Li Y. Shikonin inhibits proliferation, migration, invasion and promotes apoptosis in NCI-N87 cells via inhibition of PI3K/AKT signal pathway. Artif Cells Nanomed Biotechnol 2019; 47(1): 2662-9.
[http://dx.doi.org/10.1080/21691401.2019.1632870] [PMID: 31257936]
[95]
Rong L, Li Z, Leng X, et al. Salidroside induces apoptosis and protective autophagy in human gastric cancer AGS cells through the PI3K/Akt/mTOR pathway. Biomed Pharmacother 2020; 122109726.
[http://dx.doi.org/10.1016/j.biopha.2019.109726] [PMID: 31918283]
[96]
Won Y-S, Seo K-I, Sanggenol L. Induces apoptosis and cell cycle arrest via activation of p53 and suppression of PI3K/Akt/mTOR signaling in human prostate cancer cells. Nutrients 2020; 12(2): 488.
[http://dx.doi.org/10.3390/nu12020488] [PMID: 32075054]
[97]
Wang Z, Wang Y, Zhu S, et al. DT-13 inhibits proliferation and metastasis of human prostate cancer cells through blocking PI3K/Akt pathway. Front Pharmacol 2018; 9(1450): 1450.
[http://dx.doi.org/10.3389/fphar.2018.01450] [PMID: 30581390]
[98]
Cai F, Zhang Y, Li J, Huang S, Gao R. Isorhamnetin inhibited the proliferation and metastasis of androgen-independent prostate cancer cells by targeting the mitochondrion-dependent intrinsic apoptotic and PI3K/Akt/mTOR pathway. Biosci Rep 2020; 40(3): BSR20192826.
[http://dx.doi.org/10.1042/BSR20192826] [PMID: 32039440]
[99]
Lu X, Yang F, Chen D, et al. Quercetin reverses docetaxel resistance in prostate cancer via androgen receptor and PI3K/Akt signaling pathways. Int J Biol Sci 2020; 16(7): 1121-34.
[http://dx.doi.org/10.7150/ijbs.41686] [PMID: 32174789]
[100]
Lu K, Wei W, Hu J, et al. Apoptosis activation in thyroid cancer cells by jatrorrhizine-platinum(II) complex via downregulation of PI3K/AKT/mammalian Target Of Rapamycin (mTOR). Pathway Med Sci Monit 2020; 26: e922518.
[101]
Bian P, Hu W, Liu C, Li L. Resveratrol potentiates the anti-tumor effects of rapamycin in papillary thyroid cancer: PI3K/AKT/mTOR pathway involved. Arch Biochem Biophys 2020; 689: 108461.
[http://dx.doi.org/10.1016/j.abb.2020.108461] [PMID: 32531316]
[102]
Yang J, Ren X, Zhang L, Li Y, Cheng B, Xia J. Oridonin inhibits oral cancer growth and PI3K/Akt signaling pathway. Biomed Pharmacother 2018; 100: 226-32.
[http://dx.doi.org/10.1016/j.biopha.2018.02.011] [PMID: 29432993]
[103]
Ye M, Wu Q, Zhang M, Huang J. Lycopene inhibits the cell proliferation and invasion of human head and neck squamous cell carcinoma. Mol Med Rep 2016; 14(4): 2953-8.
[http://dx.doi.org/10.3892/mmr.2016.5597] [PMID: 27510325]
[104]
Bratton MR, Martin EC, Elliott S, et al. Glyceollin, a novel regulator of mTOR/p70S6 in estrogen receptor positive breast cancer. J Steroid Biochem Mol Biol 2015; 150: 17-23.
[http://dx.doi.org/10.1016/j.jsbmb.2014.12.014] [PMID: 25771071]
[105]
Fultang N, Illendula A, Chen B, et al. Strictinin, a novel ROR1-inhibitor, represses triple negative breast cancer survival and migration via modulation of PI3K/AKT/GSK3ß activity. PLoS One 2019; 14(5): e0217789.
[http://dx.doi.org/10.1371/journal.pone.0217789] [PMID: 31150511]
[106]
Guo Y, Pei X. Tetrandrine-Induced Autophagy in MDA-MB-231 Triple-negative breast cancer cell through the inhibition of PI3K/AKT/mTOR signaling. Evid Based Complement Alternat Med 2019; 2019: 7517431.
[http://dx.doi.org/10.1155/2019/7517431] [PMID: 30713576]
[107]
Chiang CT, Way TD, Tsai SJ, Lin JK. Diosgenin, a naturally occurring steroid, suppresses fatty acid synthase expression in HER2-overexpressing breast cancer cells through modulating Akt, mTOR and JNK phosphorylation. FEBS Lett 2007; 581(30): 5735-42.
[http://dx.doi.org/10.1016/j.febslet.2007.11.021] [PMID: 18022396]
[108]
Pan MH, Lin CC, Lin JK, Chen WJ. Tea polyphenol (-)-epigallocatechin 3-gallate suppresses heregulin-beta1-induced fatty acid synthase expression in human breast cancer cells by inhibiting phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase cascade signaling. J Agric Food Chem 2007; 55(13): 5030-7.
[http://dx.doi.org/10.1021/jf070316r] [PMID: 17539658]
[109]
Lin VC, Chou CH, Lin YC, et al. Osthole suppresses fatty acid synthase expression in HER2-overexpressing breast cancer cells through modulating Akt/mTOR pathway. J Agric Food Chem 2010; 58(8): 4786-93.
[http://dx.doi.org/10.1021/jf100352c] [PMID: 20218616]
[110]
Zhang N, Ayral-Kaloustian S, Anderson JT, et al. 5-ureidobenzofuranone indoles as potent and efficacious inhibitors of PI3 kinase-alpha and mTOR for the treatment of breast cancer. Bioorg Med Chem Lett 2010; 20(12): 3526-9.
[http://dx.doi.org/10.1016/j.bmcl.2010.04.139] [PMID: 20483602]
[111]
He X, Wang Y, Zhu J, Orloff M, Eng C. Resveratrol enhances the anti-tumor activity of the mTOR inhibitor rapamycin in multiple breast cancer cell lines mainly by suppressing rapamycin-induced AKT signaling. Cancer Lett 2011; 301(2): 168-76.
[http://dx.doi.org/10.1016/j.canlet.2010.11.012] [PMID: 21168265]
[112]
Rao YK, Wu AT, Geethangili M, et al. Identification of antrocin from Antrodia camphorata as a selective and novel class of small molecule inhibitor of Akt/mTOR signaling in metastatic breast cancer MDA-MB-231 cells. Chem Res Toxicol 2011; 24(2): 238-45.
[http://dx.doi.org/10.1021/tx100318m] [PMID: 21158420]
[113]
Chen JH. TH Wu A, TW Tzeng D, Huang CC, Tzeng YM, Chao TY. Antrocin, a bioactive component from Antrodia cinnamomea, suppresses breast carcinogenesis and stemness via downregulation of β-catenin/Notch1/Akt signaling. Phytomedicine 2019; 52: 70-8.
[http://dx.doi.org/10.1016/j.phymed.2018.09.213] [PMID: 30599914]
[114]
Jeong YJ, Cho HJ, Magae J, Lee IK, Park KG, Chang YC. Ascofuranone suppresses EGF-induced HIF-1α protein synthesis by inhibition of the Akt/mTOR/p70S6K pathway in MDA-MB-231 breast cancer cells. Toxicol Appl Pharmacol 2013; 273(3): 542-50.
[http://dx.doi.org/10.1016/j.taap.2013.09.027] [PMID: 24096035]
[115]
Jung CH, Kim H, Ahn J, et al. Anthricin isolated from Anthriscus sylvestris (L.) Hoffm. inhibits the growth of breast cancer cells by inhibiting Akt/mTOR signaling, and its apoptotic effects are enhanced by autophagy inhibition. Evid Based Complement Alternat Med 2013; 2013: 385219.
[http://dx.doi.org/10.1155/2013/385219] [PMID: 23818925]
[116]
Rivera Rivera A, Castillo-Pichardo L, Gerena Y, Dharmawardhane S. Anti-breast cancer potential of quercetin via the Akt/AMPK/mammalian target of rapamycin (mTOR) signaling cascade. PLoS One 2016; 11(6): e0157251.
[http://dx.doi.org/10.1371/journal.pone.0157251] [PMID: 27285995]
[117]
Jia L, Huang S, Yin X, Zan Y, Guo Y, Han L. Quercetin suppresses the mobility of breast cancer by suppressing glycolysis through Akt-mTOR pathway mediated autophagy induction. Life Sci 2018; 208: 123-30.
[http://dx.doi.org/10.1016/j.lfs.2018.07.027] [PMID: 30025823]
[118]
Jeong YJ, Choi Y, Shin JM, et al. Melittin suppresses EGF-induced cell motility and invasion by inhibiting PI3K/Akt/mTOR signaling pathway in breast cancer cells. Food Chem Toxicol 2014; 68: 218-25.
[http://dx.doi.org/10.1016/j.fct.2014.03.022] [PMID: 24675423]
[119]
Zhang Y, Nicolau A, Lima CF, Rodrigues LR. Bovine lactoferrin induces cell cycle arrest and inhibits mTOR signaling in breast cancer cells. Nutr Cancer 2014; 66(8): 1371-85.
[http://dx.doi.org/10.1080/01635581.2014.956260] [PMID: 25356800]
[120]
Tsai CH, Shen YC, Chen HW, Liu KL, Chang JW, Chen PY, et al. Docosahexaenoic acid increases the expression of oxidative stress-induced growth inhibitor 1 through the PI3K/Akt/Nrf2 signaling pathway in breast cancer cells. Food Chem Toxicol 2017; 108 (Pt A): 276-88.
[121]
Adams LS, Phung S, Yee N, Seeram NP, Li L, Chen S. Blueberry phytochemicals inhibit growth and metastatic potential of MDA-MB-231 breast cancer cells through modulation of the phosphatidylinositol 3-kinase pathway. Cancer Res 2010; 70(9): 3594-605.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-3565] [PMID: 20388778]
[122]
Meng LY, Liu HR, Shen Y, Yu YQ, Tao X. Cochinchina momordica seed extract induces G2/M arrest and apoptosis in human breast cancer MDA-MB-231 cells by modulating the PI3K/Akt pathway. Asian Pac J Cancer Prev 2011; 12(12): 3483-8.
[PMID: 22471502]
[123]
Sun JQ, Zhang GL, Zhang Y, et al. Spatholobus suberectus column extract inhibits estrogen receptor positive breast cancer via suppressing ER MAPK PI3K/AKT Pathway. Evid Based Complement Alternat Med 2016; 2016: 2934340.
[http://dx.doi.org/10.1155/2016/2934340] [PMID: 28096885]
[124]
Nassan MA, Soliman MM, Ismail SA, El-Shazly S. Effect of Taraxacum officinale extract on PI3K/Akt pathway in DMBA-induced breast cancer in albino rats. Biosci Rep 2018; 38(6): BSR20180334.
[http://dx.doi.org/10.1042/BSR20180334] [PMID: 30126855]
[125]
Hsieh CJ, Kuo PL, Hou MF, et al. Wedelolactone inhibits breast cancer-induced osteoclastogenesis by decreasing Akt/mTOR signaling. Int J Oncol 2015; 46(2): 555-62.
[http://dx.doi.org/10.3892/ijo.2014.2769] [PMID: 25421824]
[126]
Li G, Shan C, Liu L, et al. Tanshinone IIA inhibits HIF-1α and VEGF expression in breast cancer cells via mTOR/p70S6K/RPS6/4E-BP1 signaling pathway. PLoS One 2015; 10(2): e0117440.
[http://dx.doi.org/10.1371/journal.pone.0117440] [PMID: 25659153]
[127]
Lu J, Sun D, Gao S, Gao Y, Ye J, Liu P. Cyclovirobuxine D induces autophagy-associated cell death via the Akt/mTOR pathway in MCF-7 human breast cancer cells. J Pharmacol Sci 2014; 125(1): 74-82.
[http://dx.doi.org/10.1254/jphs.14013FP] [PMID: 24758922]
[128]
Shrivastava S, Kulkarni P, Thummuri D, et al. Piperlongumine, an alkaloid causes inhibition of PI3 K/Akt/mTOR signaling axis to induce caspase-dependent apoptosis in human triple-negative breast cancer cells. Apoptosis 2014; 19(7): 1148-64.
[http://dx.doi.org/10.1007/s10495-014-0991-2] [PMID: 24729100]
[129]
Wang Y, Liu Y, Du X, Ma H, Yao J. Berberine reverses doxorubicin resistance by inhibiting autophagy through the PTEN/Akt/mTOR signaling pathway in breast cancer. OncoTargets Ther 2020; 13: 1909-19.
[http://dx.doi.org/10.2147/OTT.S241632] [PMID: 32184626]
[130]
Stern HM, Kutok JL. Treatment of cancers using PI3 kinase isoform modulators. WO2014071109, 2013.
[131]
Jean M, Fouque A, Legembre P, Weghe PVD. New pi3k/Akt/mTOR inhibitors and pharmaceutical uses thereof. EP3049400, 2018.
[132]
Banno H, Hirose M, Kurasawa O, et al. Heteroaryl as PI3K inhibitor and use thereof. JP2015147804, 2015.
[133]
Caravatti G, Fairhurst RA, Furet P, et al. Oxazolidin-2-one compounds and their use as PI3K inhibitors. JP6154404, 2017.
[134]
Do S, Goldsmith R, Heffron T, et al. Benzopyran and benzoxepin PI3K inhibitor compounds and methods of use. US9309265, 2016.
[135]
Dotson J, Heffron T, Olivero A, et al. Pyrazolopyrimidine PI3k inhibitor compounds and methods of use. WO2009097446, 2009.
[136]
Fairhurst RA, Gerspacher M, Mah R. 2-Carboxamide cycloamino ureas useful as PI3K inhibitors. AU2010268058, 2012.
[137]
Hamdy A, Rothbaum W, Izumi R, et al. Therapeutic combinations of a BTK inhibitor, a PI3K inhibitor, a JAK-2 inhibitor, a PD-1 inhibitor, and/or a PD-L1 inhibitor. US20200069796, 2019.
[138]
Kutok JL, Palombella VJ, Winkler DG. Heterocyclic compounds for use in the treatment of PI3K-gamma mediated disorders. AU2015231413, 2020.
[139]
Kutok JL, Winkler DG, Palombella VJ. Heterocyclic compounds for use in the treatment of PI3K-gamma mediated disorders. EP3119397, 2017.
[140]
Scherle PA, Liu X. Treatment of b-cell malignancies by a combination JAK and PI3K inhibitor. WO2015157257, 2015.
[141]
Jagt DV, Abcouwer LD, Bobrovnikova-Marjon E, Weber W. Cancer treatment using curcumin derivatives. US20060276536, 2006.
[142]
Kwon BM, Dae-seop S, Jin LY, Cho HD, Han Y. Novel 2-hydroxy curcuminoid derivatives, a method for preparing the same and pharmaceutical compositions for anticancer property comprising the same. KR20120041816, 2010.
[143]
Xiaoping L, Lingling Z, Lan C, Yu H, Huijuan C. Application of curcumin in preparation of drug used for resisting colitis. CN103908444, 2014.
[144]
Zhang C. Nutritional phytonutrient compositions and methods of use. WO2020027859, 2018.
[145]
Rangnekar VM. Chloroquine induction of par-4 and treatment of cancer. WO2016196614, 2016.
[146]
Rangnekar VM. Chloroquine induction of par-4 and treatment of cancer. US10512641, 2016.
[147]
Patricia GM, Jesus M. Composition including silbinin and an inhibitor of the P13k / Akt via for the treatment of cancer. ES2345587, 2008.
[148]
Patricia GM, Jesus M. Composition comprising silibinin at determined concentrations and combined preparation comprising silibinin and a PI3K/Akt pathway inhibitor for the treatment of cancer. WO2010037892, 2010.
[149]
Grant RS, Braidy N, Guillemin G, Smythe G. Pharmaceutical formulations of resveratrol and methods of use thereof for treating cell disorders. WO2009108999, 2009.
[150]
Konda V, Desai A, Tripp ML, et al. Protein kinase-regulated cancer therapy based on hexahydro-isoalpha acid. JP2009541329, 2007.
[151]
Tripp ML, Babish JG, Bland JS, et al. Hexahydro-isoalpha acid based protein kinase modulation cancer treatment. TW200819121, 2007.
[152]
Tripp ML, Babish JG, Bland J, et al. Isoalpha acid based protein kinase modulation cancer treatment. WO2007149504, 2007.
[153]
Tripp ML, Bbish JG, Bland J, et al. Xanthohumol based protein kinase modulation cancer treatment. WO2007149482, 2007.
[154]
Matthew T, John B, Jeffrey B, et al. Xanthohumol based protein kinase modulation cancer treatment. US20080033056, 2007.
[155]
Roy NK, Bordoloi D, Monisha J, et al. Specific targeting of Akt kinase isoforms: Taking the precise path for prevention and treatment of cancer. Curr Drug Targets 2017; 18(4): 421-35.
[http://dx.doi.org/10.2174/1389450117666160307145236] [PMID: 26953242]
[156]
Kada F, Saji M, Ringel MD. Akt: A potential target for thyroid cancer therapy. Curr Drug Targets Immune Endocr Metabol Disord 2004; 4(3): 181-5.
[http://dx.doi.org/10.2174/1568008043339857] [PMID: 15379721]
[157]
Hua S, Vignarajan S, Yao M, Xie C, Sved P, Dong Q. AKT and cytosolic phospholipase A2α form a positive loop in prostate cancer cells. Curr Cancer Drug Targets 2015; 15(9): 781-91.
[http://dx.doi.org/10.2174/1568009615666150706103234] [PMID: 26143945]
[158]
Jiang BH. PI3K/AKT and mTOR/p70S6K1 signaling pathways in human cancer. Curr Cancer Drug Targets 2013; 13(3): 233.
[http://dx.doi.org/10.2174/1568009611313030001] [PMID: 23621679]
[159]
Carpenter RL, Jiang BH. Roles of EGFR, PI3K, AKT, and mTOR in heavy metal-induced cancer. Curr Cancer Drug Targets 2013; 13(3): 252-66.
[http://dx.doi.org/10.2174/1568009611313030004] [PMID: 23297824]
[160]
Cheng GZ, Park S, Shu S, et al. Advances of AKT pathway in human oncogenesis and as a target for anti-cancer drug discovery. Curr Cancer Drug Targets 2008; 8(1): 2-6.
[http://dx.doi.org/10.2174/156800908783497159] [PMID: 18288938]
[161]
Carnero A, Blanco-Aparicio C, Renner O, Link W, Leal JF. The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications. Curr Cancer Drug Targets 2008; 8(3): 187-98.
[http://dx.doi.org/10.2174/156800908784293659] [PMID: 18473732]
[162]
Grunt TW, Mariani GL. Novel approaches for molecular targeted therapy of breast cancer: Interfering with PI3K/AKT/mTOR signaling. Curr Cancer Drug Targets 2013; 13(2): 188-204.
[http://dx.doi.org/10.2174/1568009611313020008] [PMID: 23215720]
[163]
Mitsiades CS, Mitsiades N, Koutsilieris M. The Akt pathway: Molecular targets for anti-cancer drug development. Curr Cancer Drug Targets 2004; 4(3): 235-56.
[http://dx.doi.org/10.2174/1568009043333032] [PMID: 15134532]
[164]
Zhang X, Li XR, Zhang J. Current status and future perspectives of PI3K and mTOR inhibitor as anticancer drugs in breast cancer. Curr Cancer Drug Targets 2013; 13(2): 175-87.
[http://dx.doi.org/10.2174/1568009611313020007] [PMID: 23215724]
[165]
Borah A, Pillai SC, Rochani AK, et al. GANT61 and curcumin-loaded PLGA nanoparticles for GLI1 and PI3K/Akt-mediated inhibition in breast adenocarcinoma. Nanotechnology 2020; 31(18): 185102.
[http://dx.doi.org/10.1088/1361-6528/ab6d20] [PMID: 31952056]
[166]
Neufeld MJ, DuRoss AN, Landry MR, Winter H, Goforth AM, Sun C. Co-delivery of PARP and PI3K inhibitors by nanoscale metal-organic frameworks for enhanced tumor chemoradiation. Nano Res 2019; 12(12): 3003-17.
[http://dx.doi.org/10.1007/s12274-019-2544-z]
[167]
Pandey A, Kulkarni A, Roy B, et al. Sequential application of a cytotoxic nanoparticle and a PI3K inhibitor enhances antitumor efficacy. Cancer Res 2014; 74(3): 675-85.
[http://dx.doi.org/10.1158/0008-5472.CAN-12-3783] [PMID: 24121494]
[168]
Harfouche R, Basu S, Soni S, Hentschel DM, Mashelkar RA, Sengupta S. Nanoparticle-mediated targeting of phosphatidylinositol-3-kinase signaling inhibits angiogenesis. Angiogenesis 2009; 12(4): 325-38.
[http://dx.doi.org/10.1007/s10456-009-9154-4] [PMID: 19685150]
[169]
Narayanankutty A, Sasidharan A, Job JT. Targeting toll like receptors in cancer: Role of TLR natural and synthetic modulators. Curr Pharm Des 2020; 26: 1-16.
[http://dx.doi.org/10.2174/1381612826666200720235058] [PMID: 32693759]


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