Skip to main content
Erschienen in: Cancer Chemotherapy and Pharmacology 3/2019

05.12.2018 | Original Article

Targeted disruption of PI3K/Akt/mTOR signaling pathway, via PI3K inhibitors, promotes growth inhibitory effects in oral cancer cells

verfasst von: Sadhna Aggarwal, Sarah John, Leena Sapra, Suresh C. Sharma, Satya N. Das

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 3/2019

Einloggen, um Zugang zu erhalten

Abstract

Purpose

The phosphoinositide-3-kinase (PI3K) pathway is the frequently altered in human cancer. This has led to the development and study of novel PI3K inhibitors for targeted therapy and also to overcome resistance to radiotherapy.

Method

The anti-tumour effects of PI3K inhibitors (PI-828, PI-103 and PX-866) in terms of cell proliferation, colony formation, induction of apoptosis, cell cycle arrest, invasion, autophagy, and pNF-κB/p65 translocation in SCC-4, SCC-9 and SCC-25 cells were studied by performing MTT, clonogenic, DAPI staining, propidium iodide staining, annexin-V binding, matrigel invasion, acridine orange staining and immuno-fluorescence assay. Western blot assay was performed to assess the alteration in the expression of various proteins.

Result

PI-828 and PI-103 treatment exhibited dose-dependent inhibition of growth and proliferation of OSCC cells with a concomitant induction of apoptosis, altered cell cycle regulation and decreased invasiveness (p < 0.01). PX-866 induced apoptosis, cell cycle arrest, autophagy and a significant decrease in the invasiveness of oral cancer cells as compared to untreated cells (p < 0.01). These compounds significantly reduced expression of COX-2, cyclin-D1 and VEGF in the treated cells besides cytoplasmic accumulation of pNF-κB/p65 protein. In addition to PI3Kα, inactivation of downstream components, i.e. Akt and mTOR was seen.

Conclusion

PI3K inhibitors such as PI-103, PI-828 and PX-866 may be developed as potential therapeutic agents for effective treatment of oral squamous cell carcinoma (OSCC) patients, associated with activated PI3K/Akt pathway.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
1.
Zurück zum Zitat Elango JK, Gangadharan P, Sumithra S, Kuriakose MA (2006) Trends of head and neck cancers in urban and rural India. Asian Pac J Cancer Prev 7(1):108–112PubMed Elango JK, Gangadharan P, Sumithra S, Kuriakose MA (2006) Trends of head and neck cancers in urban and rural India. Asian Pac J Cancer Prev 7(1):108–112PubMed
2.
Zurück zum Zitat Sankaranarayanan R, Masuyer E, Swaminathan R, Ferlay J, Whelan S (1998) Head and neck cancer: a global perspective on epidemiology and prognosis. Anticancer Res 18(6B):4779–4786PubMed Sankaranarayanan R, Masuyer E, Swaminathan R, Ferlay J, Whelan S (1998) Head and neck cancer: a global perspective on epidemiology and prognosis. Anticancer Res 18(6B):4779–4786PubMed
3.
Zurück zum Zitat Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T et al (2008) Cancer statistics, 2008. CA Cancer J Clin 58(2):71–96CrossRefPubMed Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T et al (2008) Cancer statistics, 2008. CA Cancer J Clin 58(2):71–96CrossRefPubMed
4.
Zurück zum Zitat Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB (2005) Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov 4(12):988–1004CrossRefPubMed Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB (2005) Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov 4(12):988–1004CrossRefPubMed
5.
Zurück zum Zitat Scheid MP, Woodgett JR (2001) PKB/AKT: functional insights from genetic models. Nat Rev Mol Cell Biol 2(10):760–768CrossRefPubMed Scheid MP, Woodgett JR (2001) PKB/AKT: functional insights from genetic models. Nat Rev Mol Cell Biol 2(10):760–768CrossRefPubMed
7.
Zurück zum Zitat Lui VW, Hedberg ML, Li H et al (2013) Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers. Cancer Discov 3(7):761–769CrossRefPubMedPubMedCentral Lui VW, Hedberg ML, Li H et al (2013) Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers. Cancer Discov 3(7):761–769CrossRefPubMedPubMedCentral
9.
Zurück zum Zitat Sathiyamoorthy J, Sundar VS, Babu NA, Shanmugham S, Mani JG, Chinnaiyan P, Kalyanaraman A, Hari R (2018) Study on PIK3CA gene mutations in oral squamous cell carcinoma among South Indian populations. Biomed Pharmacol J. 11:2CrossRef Sathiyamoorthy J, Sundar VS, Babu NA, Shanmugham S, Mani JG, Chinnaiyan P, Kalyanaraman A, Hari R (2018) Study on PIK3CA gene mutations in oral squamous cell carcinoma among South Indian populations. Biomed Pharmacol J. 11:2CrossRef
10.
Zurück zum Zitat Giudice FS, Squarize CH (2013) The determinants of head and neck cancer: unmasking the PI3K pathway mutations. J Carcinogene Mutagene S5:003 Giudice FS, Squarize CH (2013) The determinants of head and neck cancer: unmasking the PI3K pathway mutations. J Carcinogene Mutagene S5:003
11.
Zurück zum Zitat Wan X, Li X, Yang J et al (2015) Genetic association between PIK3CA gene and oral squamous cell carcinoma: a case control study conducted in Chongqing, China. Int J Clin Exp Pathol 8(10):13360–13366PubMedPubMedCentral Wan X, Li X, Yang J et al (2015) Genetic association between PIK3CA gene and oral squamous cell carcinoma: a case control study conducted in Chongqing, China. Int J Clin Exp Pathol 8(10):13360–13366PubMedPubMedCentral
12.
Zurück zum Zitat Specenier P, Vermorken JB (2010) Advances in the systemic treatment of head and neck cancers. Curr Opin Oncol 22(3):200–205CrossRefPubMed Specenier P, Vermorken JB (2010) Advances in the systemic treatment of head and neck cancers. Curr Opin Oncol 22(3):200–205CrossRefPubMed
13.
Zurück zum Zitat da Silva SD, Hier M, Mlynarek A, Kowalski LP, Alaoui-Jamali MA (2012) Recurrent oral cancer: current and emerging therapeutic approaches. Front Pharmacol 3:149CrossRefPubMedPubMedCentral da Silva SD, Hier M, Mlynarek A, Kowalski LP, Alaoui-Jamali MA (2012) Recurrent oral cancer: current and emerging therapeutic approaches. Front Pharmacol 3:149CrossRefPubMedPubMedCentral
14.
Zurück zum Zitat Kioi M. Recent advances in molecular-targeted therapy for oral cancer (2017). Int J Oral Maxillofac Surg 46:27 Kioi M. Recent advances in molecular-targeted therapy for oral cancer (2017). Int J Oral Maxillofac Surg 46:27
15.
Zurück zum Zitat Jung K, Kang H, Mehra R (2018) Targeting phosphoinositide 3-kinase (PI3K) in head and neck squamous cell carcinoma (HNSCC). Cancers of the Head Neck 3:3CrossRefPubMedPubMedCentral Jung K, Kang H, Mehra R (2018) Targeting phosphoinositide 3-kinase (PI3K) in head and neck squamous cell carcinoma (HNSCC). Cancers of the Head Neck 3:3CrossRefPubMedPubMedCentral
16.
Zurück zum Zitat Bendell CJ, Varghese AM, Hyman DM, Bauer TM, Pant S, Callies S et al (2018) A first-in-human phase 1 study of LY3023414, an oral PI3K/mTOR dual inhibitor, in patients with advanced cancer. Clin Cancer Res 24(14):3253–3262CrossRefPubMed Bendell CJ, Varghese AM, Hyman DM, Bauer TM, Pant S, Callies S et al (2018) A first-in-human phase 1 study of LY3023414, an oral PI3K/mTOR dual inhibitor, in patients with advanced cancer. Clin Cancer Res 24(14):3253–3262CrossRefPubMed
17.
Zurück zum Zitat Janku F (2017) Phosphoinositide 3-kinase (PI3K) pathway inhibitors in solid tumors: from laboratory to patients. Cancer Treat Rev 59:93–101CrossRefPubMed Janku F (2017) Phosphoinositide 3-kinase (PI3K) pathway inhibitors in solid tumors: from laboratory to patients. Cancer Treat Rev 59:93–101CrossRefPubMed
18.
Zurück zum Zitat Fan Q-W, Knight ZA, Goldenberg DD, Yu W, Mostov KE, Stokoe D et al (2009) A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell 9(5):341–349CrossRef Fan Q-W, Knight ZA, Goldenberg DD, Yu W, Mostov KE, Stokoe D et al (2009) A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell 9(5):341–349CrossRef
19.
Zurück zum Zitat Ihle NT, Paine-Murrieta G, Berggren MI, Baker A, Tate WR, Wipf P et al (2005) The phosphatidylinositol-3-kinase inhibitor PX-866 overcomes resistance to the epidermal growth factor receptor inhibitor gefitinib in A-549 human non-small cell lung cancer xenografts. Mol Cancer Ther 4(9):1349–1357CrossRefPubMedPubMedCentral Ihle NT, Paine-Murrieta G, Berggren MI, Baker A, Tate WR, Wipf P et al (2005) The phosphatidylinositol-3-kinase inhibitor PX-866 overcomes resistance to the epidermal growth factor receptor inhibitor gefitinib in A-549 human non-small cell lung cancer xenografts. Mol Cancer Ther 4(9):1349–1357CrossRefPubMedPubMedCentral
20.
Zurück zum Zitat Aggarwal S, Sharma SC, Das SN (2015) Galectin-1 and galectin-3: plausible tumour markers for oral squamous cell carcinoma and suitable targets for screening high-risk population. Clin Chim Acta 442:13–21CrossRefPubMed Aggarwal S, Sharma SC, Das SN (2015) Galectin-1 and galectin-3: plausible tumour markers for oral squamous cell carcinoma and suitable targets for screening high-risk population. Clin Chim Acta 442:13–21CrossRefPubMed
21.
Zurück zum Zitat Aggarwal S, Das SN (2016) Garcinol inhibits tumour cell proliferation, angiogenesis, cell cycle progression and induces apoptosis via NF-κB inhibition in oral cancer. Tumour Biol 37(6):7175–7184CrossRefPubMed Aggarwal S, Das SN (2016) Garcinol inhibits tumour cell proliferation, angiogenesis, cell cycle progression and induces apoptosis via NF-κB inhibition in oral cancer. Tumour Biol 37(6):7175–7184CrossRefPubMed
22.
Zurück zum Zitat Aggarwal S, Sharma SC, Das N S (2017) Dynamics of regulatory T cells (Tregs) in patients with oral squamous cell carcinoma. J Surg Oncol 116(8):1103–1113CrossRefPubMed Aggarwal S, Sharma SC, Das N S (2017) Dynamics of regulatory T cells (Tregs) in patients with oral squamous cell carcinoma. J Surg Oncol 116(8):1103–1113CrossRefPubMed
23.
Zurück zum Zitat Arora R, Bharti V, Gaur P, Aggarwal S, Mittal M, Das SN (2017) Operculina turpethum extract inhibits growth and proliferation by inhibiting NF-kB, COX-2 and cyclin D1 and induces apoptosis by up regulating P53 in oral cancer cells. Arch Oral Biol 80:1–9CrossRefPubMed Arora R, Bharti V, Gaur P, Aggarwal S, Mittal M, Das SN (2017) Operculina turpethum extract inhibits growth and proliferation by inhibiting NF-kB, COX-2 and cyclin D1 and induces apoptosis by up regulating P53 in oral cancer cells. Arch Oral Biol 80:1–9CrossRefPubMed
24.
Zurück zum Zitat Koul D, Shen R, Kim Y-W, Kondo Y, Lu Y, Bankson J et al (2010) Cellular and in vivo activity of a novel PI3K inhibitor, PX-866, against human glioblastoma. Neuro-oncology 12(6):559–569CrossRefPubMedPubMedCentral Koul D, Shen R, Kim Y-W, Kondo Y, Lu Y, Bankson J et al (2010) Cellular and in vivo activity of a novel PI3K inhibitor, PX-866, against human glioblastoma. Neuro-oncology 12(6):559–569CrossRefPubMedPubMedCentral
25.
Zurück zum Zitat Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S et al (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304(5670):554CrossRefPubMed Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S et al (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304(5670):554CrossRefPubMed
26.
Zurück zum Zitat Trotman LC, Niki M, Dotan ZA, Koutcher JA, Di Cristofano A, Xiao A et al (2003) Pten dose dictates cancer progression in the prostate. PLoS Biol 1(3):E59CrossRefPubMedPubMedCentral Trotman LC, Niki M, Dotan ZA, Koutcher JA, Di Cristofano A, Xiao A et al (2003) Pten dose dictates cancer progression in the prostate. PLoS Biol 1(3):E59CrossRefPubMedPubMedCentral
27.
Zurück zum Zitat Wang S, Gao J, Lei Q, Rozengurt N, Pritchard C, Jiao J et al (2003) Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell 4(3):209–221CrossRefPubMed Wang S, Gao J, Lei Q, Rozengurt N, Pritchard C, Jiao J et al (2003) Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell 4(3):209–221CrossRefPubMed
28.
Zurück zum Zitat Nakatani K, Thompson DA, Barthel A, Sakaue H, Liu W, Weigel RJ et al (1999) Up-regulation of Akt3 in estrogen receptor-deficient breast cancers and androgen-independent prostate cancer lines. J Biol Chem 274(31):21528–21532CrossRefPubMed Nakatani K, Thompson DA, Barthel A, Sakaue H, Liu W, Weigel RJ et al (1999) Up-regulation of Akt3 in estrogen receptor-deficient breast cancers and androgen-independent prostate cancer lines. J Biol Chem 274(31):21528–21532CrossRefPubMed
29.
Zurück zum Zitat Li Q, Zhu G-D (2002) Targeting serine/threonine protein kinase B/Akt and cell-cycle checkpoint kinases for treating cancer. Curr Top Med Chem 2(9):939–971CrossRefPubMed Li Q, Zhu G-D (2002) Targeting serine/threonine protein kinase B/Akt and cell-cycle checkpoint kinases for treating cancer. Curr Top Med Chem 2(9):939–971CrossRefPubMed
30.
Zurück zum Zitat Bell HS, Ryan KM (2005) Intracellular signalling and cancer: complex pathways lead to multiple targets. Eur J Cancer 41(2):206–215CrossRefPubMed Bell HS, Ryan KM (2005) Intracellular signalling and cancer: complex pathways lead to multiple targets. Eur J Cancer 41(2):206–215CrossRefPubMed
31.
Zurück zum Zitat Serra V, Markman B, Scaltriti M, Eichhorn PJA, Valero V, Guzman M et al (2008) NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res 68(19):8022–8030CrossRefPubMed Serra V, Markman B, Scaltriti M, Eichhorn PJA, Valero V, Guzman M et al (2008) NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res 68(19):8022–8030CrossRefPubMed
32.
Zurück zum Zitat Eichhorn PJA, Gili M, Scaltriti M, Serra V, Guzman M, Nijkamp W et al (2008) Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res 68(22):9221–9230CrossRefPubMedPubMedCentral Eichhorn PJA, Gili M, Scaltriti M, Serra V, Guzman M, Nijkamp W et al (2008) Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res 68(22):9221–9230CrossRefPubMedPubMedCentral
33.
Zurück zum Zitat Wymann MP, Bulgarelli-Leva G, Zvelebil MJ, Pirola L, Vanhaesebroeck B, Waterfield MD et al (1996) Wortmannin inactivates phosphoinositide 3-kinase by covalent modification of Lys-802, a residue involved in the phosphate transfer reaction. Mol Cell Biol 16(4):1722–1733CrossRefPubMedPubMedCentral Wymann MP, Bulgarelli-Leva G, Zvelebil MJ, Pirola L, Vanhaesebroeck B, Waterfield MD et al (1996) Wortmannin inactivates phosphoinositide 3-kinase by covalent modification of Lys-802, a residue involved in the phosphate transfer reaction. Mol Cell Biol 16(4):1722–1733CrossRefPubMedPubMedCentral
34.
Zurück zum Zitat Walker EH, Pacold ME, Perisic O, Stephens L, Hawkins PT, Wymann MP et al (2000) Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol Cell 6(4):909–919CrossRefPubMed Walker EH, Pacold ME, Perisic O, Stephens L, Hawkins PT, Wymann MP et al (2000) Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol Cell 6(4):909–919CrossRefPubMed
35.
Zurück zum Zitat Chen JS, Zhou LJ, Entin-Meer M, Yang X, Donker M, Knight ZA et al (2008) Characterization of structurally distinct, isoform-selective phosphoinositide 3′-kinase inhibitors in combination with radiation in the treatment of glioblastoma. Mol Cancer Ther 7(4):841–850CrossRefPubMed Chen JS, Zhou LJ, Entin-Meer M, Yang X, Donker M, Knight ZA et al (2008) Characterization of structurally distinct, isoform-selective phosphoinositide 3′-kinase inhibitors in combination with radiation in the treatment of glioblastoma. Mol Cancer Ther 7(4):841–850CrossRefPubMed
36.
Zurück zum Zitat Chang L, Graham PH, Hao J, Ni J, Bucci J, Cozzi PJ et al (2014) PI3K/Akt/mTOR pathway inhibitors enhance radiosensitivity in radioresistant prostate cancer cells through inducing apoptosis, reducing autophagy, suppressing NHEJ and HR repair pathways. Cell Death Dis 5:e1437CrossRefPubMedPubMedCentral Chang L, Graham PH, Hao J, Ni J, Bucci J, Cozzi PJ et al (2014) PI3K/Akt/mTOR pathway inhibitors enhance radiosensitivity in radioresistant prostate cancer cells through inducing apoptosis, reducing autophagy, suppressing NHEJ and HR repair pathways. Cell Death Dis 5:e1437CrossRefPubMedPubMedCentral
37.
Zurück zum Zitat Fan Q-W, Cheng CK, Nicolaides TP, Hackett CS, Knight ZA, Shokat KM et al (2007) A dual phosphoinositide-3-kinase alpha/mTOR inhibitor cooperates with blockade of epidermal growth factor receptor in PTEN-mutant glioma. Cancer Res 67(17):7960–7965CrossRefPubMedPubMedCentral Fan Q-W, Cheng CK, Nicolaides TP, Hackett CS, Knight ZA, Shokat KM et al (2007) A dual phosphoinositide-3-kinase alpha/mTOR inhibitor cooperates with blockade of epidermal growth factor receptor in PTEN-mutant glioma. Cancer Res 67(17):7960–7965CrossRefPubMedPubMedCentral
38.
Zurück zum Zitat Park S, Chapuis N, Bardet V, Tamburini J, Gallay N, Willems L et al (2008) PI-103, a dual inhibitor of Class IA phosphatidylinositide 3-kinase and mTOR, has antileukemic activity in AML. Leukemia 22(9):1698–1706CrossRefPubMed Park S, Chapuis N, Bardet V, Tamburini J, Gallay N, Willems L et al (2008) PI-103, a dual inhibitor of Class IA phosphatidylinositide 3-kinase and mTOR, has antileukemic activity in AML. Leukemia 22(9):1698–1706CrossRefPubMed
39.
Zurück zum Zitat Gwak H-S, Shingu T, Chumbalkar V, Hwang Y-H, DeJournett R, Latha K et al (2011) Combined action of the dinuclear platinum compound BBR3610 with the PI3-K inhibitor PX-866 in glioblastoma. Int J Cancer 128(4):787–796CrossRefPubMedPubMedCentral Gwak H-S, Shingu T, Chumbalkar V, Hwang Y-H, DeJournett R, Latha K et al (2011) Combined action of the dinuclear platinum compound BBR3610 with the PI3-K inhibitor PX-866 in glioblastoma. Int J Cancer 128(4):787–796CrossRefPubMedPubMedCentral
40.
Zurück zum Zitat Eskes R, Desagher S, Antonsson B, Martinou JC (2000) Bid induces the oligomerization and insertion of Bax into the outer mitochondrial membrane. Mol Cell Biol 20(3):929–935CrossRefPubMedPubMedCentral Eskes R, Desagher S, Antonsson B, Martinou JC (2000) Bid induces the oligomerization and insertion of Bax into the outer mitochondrial membrane. Mol Cell Biol 20(3):929–935CrossRefPubMedPubMedCentral
41.
Zurück zum Zitat Morselli E, Galluzzi L, Kepp O, Criollo A, Maiuri MC, Tavernarakis N et al (2009) Autophagy mediates pharmacological lifespan extension by spermidine and resveratrol. Aging (Albany NY) 1(12):961–970CrossRef Morselli E, Galluzzi L, Kepp O, Criollo A, Maiuri MC, Tavernarakis N et al (2009) Autophagy mediates pharmacological lifespan extension by spermidine and resveratrol. Aging (Albany NY) 1(12):961–970CrossRef
42.
Zurück zum Zitat Guillard S, Clarke PA, Te Poele R, Mohri Z, Bjerke L, Valenti M et al (2009) Molecular pharmacology of phosphatidylinositol 3-kinase inhibition in human glioma. Cell Cycle 8(3):443–453CrossRefPubMed Guillard S, Clarke PA, Te Poele R, Mohri Z, Bjerke L, Valenti M et al (2009) Molecular pharmacology of phosphatidylinositol 3-kinase inhibition in human glioma. Cell Cycle 8(3):443–453CrossRefPubMed
43.
Zurück zum Zitat Hussain AR, Ahmed SO, Ahmed M et al (2016) Cross-talk between NFkB and the PI3-kinase/AKT pathway can be targeted in primary effusion lymphoma (PEL) cell lines for efficient apoptosis. PLoS One 7(6):e39945CrossRef Hussain AR, Ahmed SO, Ahmed M et al (2016) Cross-talk between NFkB and the PI3-kinase/AKT pathway can be targeted in primary effusion lymphoma (PEL) cell lines for efficient apoptosis. PLoS One 7(6):e39945CrossRef
44.
45.
Zurück zum Zitat Syed DN, Afaq F, Kweon M-H, Hadi N, Bhatia N, Spiegelman VS et al (2007) Green tea polyphenol EGCG suppresses cigarette smoke condensate-induced NF-kappaB activation in normal human bronchial epithelial cells. Oncogene 26(5):673–682CrossRefPubMed Syed DN, Afaq F, Kweon M-H, Hadi N, Bhatia N, Spiegelman VS et al (2007) Green tea polyphenol EGCG suppresses cigarette smoke condensate-induced NF-kappaB activation in normal human bronchial epithelial cells. Oncogene 26(5):673–682CrossRefPubMed
46.
Zurück zum Zitat Roskoski R (2007) Vascular endothelial growth factor (VEGF) signaling in tumor progression. Crit Rev Oncol Hematol 62(3):179–213CrossRefPubMed Roskoski R (2007) Vascular endothelial growth factor (VEGF) signaling in tumor progression. Crit Rev Oncol Hematol 62(3):179–213CrossRefPubMed
47.
Zurück zum Zitat Ferrara N, Houck KA, Jakeman LB, Winer J, Leung DW (1991) The vascular endothelial growth factor family of polypeptides. J Cell Biochem 47(3):211–218CrossRefPubMed Ferrara N, Houck KA, Jakeman LB, Winer J, Leung DW (1991) The vascular endothelial growth factor family of polypeptides. J Cell Biochem 47(3):211–218CrossRefPubMed
48.
Zurück zum Zitat Dvorak HF, Brown LF, Detmar M, Dvorak AM (1995) Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 146(5):1029–1039PubMedPubMedCentral Dvorak HF, Brown LF, Detmar M, Dvorak AM (1995) Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 146(5):1029–1039PubMedPubMedCentral
49.
Zurück zum Zitat Aggarwal S, Devaraja K, Sharma SC, Das SN (2014) Expression of vascular endothelial growth factor (VEGF) in patients with oral squamous cell carcinoma and its clinical significance. Clin Chim Acta 436:35–40CrossRefPubMed Aggarwal S, Devaraja K, Sharma SC, Das SN (2014) Expression of vascular endothelial growth factor (VEGF) in patients with oral squamous cell carcinoma and its clinical significance. Clin Chim Acta 436:35–40CrossRefPubMed
50.
Zurück zum Zitat Chan G, Boyle JO, Yang EK, Zhang F, Sacks PG, Shah JP et al (1999) Cyclooxygenase-2 expression is up-regulated in squamous cell carcinoma of the head and neck. Cancer Res 59(5):991–994PubMed Chan G, Boyle JO, Yang EK, Zhang F, Sacks PG, Shah JP et al (1999) Cyclooxygenase-2 expression is up-regulated in squamous cell carcinoma of the head and neck. Cancer Res 59(5):991–994PubMed
51.
Zurück zum Zitat Kapoor V, Singh AK, Dey S, Sharma SC, Das SN (2010) Circulating cycloxygenase-2 in patients with tobacco-related intraoral squamous cell carcinoma and evaluation of its peptide inhibitors as potential antitumor agent. J Cancer Res Clin Oncol 136(12):1795–1804CrossRefPubMed Kapoor V, Singh AK, Dey S, Sharma SC, Das SN (2010) Circulating cycloxygenase-2 in patients with tobacco-related intraoral squamous cell carcinoma and evaluation of its peptide inhibitors as potential antitumor agent. J Cancer Res Clin Oncol 136(12):1795–1804CrossRefPubMed
52.
Zurück zum Zitat Garg R, Kapoor V, Mittal M, Singh MK, Shukla NK, Das SN (2013) Abnormal expression of PI3K isoforms in patients with tobacco-related oral squamous cell carcinoma. Clin Chim Acta 416:100–106CrossRefPubMed Garg R, Kapoor V, Mittal M, Singh MK, Shukla NK, Das SN (2013) Abnormal expression of PI3K isoforms in patients with tobacco-related oral squamous cell carcinoma. Clin Chim Acta 416:100–106CrossRefPubMed
53.
Zurück zum Zitat Martin KA, Blenis J (2002) Coordinate regulation of translation by the PI 3-kinase and mTOR pathways. Adv Cancer Res 86:1–39CrossRefPubMed Martin KA, Blenis J (2002) Coordinate regulation of translation by the PI 3-kinase and mTOR pathways. Adv Cancer Res 86:1–39CrossRefPubMed
Metadaten
Titel
Targeted disruption of PI3K/Akt/mTOR signaling pathway, via PI3K inhibitors, promotes growth inhibitory effects in oral cancer cells
verfasst von
Sadhna Aggarwal
Sarah John
Leena Sapra
Suresh C. Sharma
Satya N. Das
Publikationsdatum
05.12.2018
Verlag
Springer Berlin Heidelberg
Erschienen in
Cancer Chemotherapy and Pharmacology / Ausgabe 3/2019
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-018-3746-x

Weitere Artikel der Ausgabe 3/2019

Cancer Chemotherapy and Pharmacology 3/2019 Zur Ausgabe

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.