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Angiogenesis
Published in: Angiogenesis 4/2009

01-12-2009

Nanoparticle-mediated targeting of phosphatidylinositol-3-kinase signaling inhibits angiogenesis

Authors: Rania Harfouche, Sudipta Basu, Shivani Soni, Dirk M. Hentschel, Raghunath A. Mashelkar, Shiladitya Sengupta

Published in: Angiogenesis | Issue 4/2009

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Abstract

Objective

Dysregulation of the phosphatidylinositol-3-kinase (PI3K) signaling pathway is a hallmark of human cancer, occurring in a majority of tumors. Activation of this pathway is critical for transformation and also for the angiogenic switch, which is a key step for tumor progression. The objective of this study was to engineer a PI3K inhibitor-loaded biodegradable nanoparticle and to evaluate its efficacy.

Methods and results

Here we report that a nanoparticle-enabled targeting of the PI3K pathway results in inhibition of downstream Akt phosphorylation, leading to inhibition of proliferation and induction of apoptosis of B16/F10 melanoma. It, however, failed to exert a similar activity on MDA-MB-231 breast cancer cells, resulting from reduced internalization and processing of nanoparticles in this cell line. Excitingly, the nanoparticle-enabled targeting of the PI3K pathway resulted in inhibition of endothelial cell proliferation and tubulogenesis, two key steps in tumor angiogenesis. Furthermore, it inhibited both B16/F10- and MDA-MB-231-induced angiogenesis in a zebrafish tumor xenotransplant model.

Conclusion

Our study, for the first time, shows that targeting of the PI3K pathway using nanoparticles can offer an attractive strategy for inhibiting tumor angiogenesis.
Appendix
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Literature
1.
Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2:489–501CrossRefPubMed
2.
Datta SR, Brunet A, Greenberg ME (1999) Cellular survival: a play in three Akts. Genes Dev 13:2905–2927CrossRefPubMed
3.
Shayesteh L, Lu Y, Kuo WL, Baldocchi R, Godfrey T, Collins C, Pinkel D, Powell B, Mills GB, Gray JW (1999) PIK3CA is implicated as an oncogene in ovarian cancer. Nat Genet 21:99–102CrossRefPubMed
4.
Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, Maira M, McNamara K, Perera SA, Song Y, Chirieac LR, Kaur R, Lightbown A, Simendinger J, Li T, Padera RF, García-Echeverría C, Weissleder R, Mahmood U, Cantley LC, Wong KK (2008) Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 14:1351–1356CrossRefPubMed
5.
Koul D (2008) PTEN signaling pathways in glioblastoma. Cancer Biol Ther 7:1321–1325PubMed
6.
Petrocelli T, Slingerland JM (2001) PTEN deficiency: a role in mammary carcinogenesis. Breast Cancer Res 3:356–360CrossRefPubMed
7.
Steelman LS, Stadelman KM, Chappell WH, Horn S, Bäsecke J, Cervello M, Nicoletti F, Libra M, Stivala F, Martelli AM, McCubrey JA (2008) Akt as a therapeutic target in cancer. Expert Opin Ther Targets 12:1139–1165CrossRefPubMed
8.
Iwanaga K, Yang Y, Raso MG, Ma L, Hanna AE, Thilaganathan N, Moghaddam S, Evans CM, Li H, Cai WW, Sato M, Minna JD, Wu H, Creighton CJ, Demayo FJ, Wistuba II, Kurie JM (2008) Pten inactivation accelerates oncogenic K-ras-initiated tumorigenesis in a mouse model of lung cancer. Cancer Res 68:1119–1127CrossRefPubMed
9.
Horie Y, Suzuki A, Kataoka E, Sasaki T, Hamada K, Sasaki J, Mizuno K, Hasegawa G, Kishimoto H, Iizuka M, Naito M, Enomoto K, Watanabe S, Mak TW, Nakano T (2004) Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. J Clin Invest 113:1774–1783PubMed
10.
Yuan TL, Choi HS, Matsui A, Benes C, Lifshits E, Luo J, Frangioni JV, Cantley LC (2008) Class 1A PI3K regulates vessel integrity during development and tumorigenesis. Proc Natl Acad Sci U S A 105:9739–9744CrossRefPubMed
11.
Sengupta S, Sellers LA, Li RC, Gherardi E, Zhao G, Watson N, Sasisekharan R, Fan TP (2003) Targeting of mitogen-activated protein kinases and phosphatidylinositol 3 kinase inhibits hepatocyte growth factor/scatter factor-induced angiogenesis. Circulation 107:2955–2961CrossRefPubMed
12.
Sengupta S, Sasisekharan R (2007) Exploiting nanotechnology to target cancer. Br J Cancer 96(9):1315–1319PubMed
13.
Yuan F, Leunig M, Huang SK, Berk DA, Papahadjopoulos D, Jain RK (1994) Microvascular permeability and interstitial penetration of sterically stabilized (stealth) liposomes in a human tumor xenograft. Cancer Res 54:3352PubMed
14.
Ibrahim NK, Desai N, Legha S, Soon-Shiong P, Theriault RL, Rivera E, Esmaeli B, Ring SE, Bedikian A, Hortobagyi GN, Ellerhorst JA (2002) Phase I and pharmacokinetic study of ABI-007, a Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel. Clin Cancer Res 8:1038–1044PubMed
15.
Stavridi F, Palmieri C (2008) Efficacy and toxicity of nonpegylated liposomal doxorubicin in breast cancer. Expert Rev Anticancer Ther 8:1859–1869CrossRefPubMed
16.
Basu S, Harfouche R, Soni S, Chimote G, Mashelkar RA, Sengupta S (2009) Nanoparticle-mediated targeting of MAPK signaling predisposes tumor to chemotherapy. Proc Natl Acad Sci U S A 106(19):7957–7961CrossRefPubMed
17.
Vlahos CJ, Matter WF, Hui KY, Brown RF (1994) A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem 269:5241–5248PubMed
18.
Nicoli S, Presta M (2007) The zebrafish/tumor xenograft angiogenesis assay. Nat Protoc 2:2918–2923CrossRefPubMed
19.
Ferrari M (2005) Cancer nanotechnology: opportunities and challenges. Nature Rev Cancer 5:161–171CrossRef
20.
Peer D, Karp JM, Hong S, Farokhzad OC, Margalit R, Langer R (2007) Nanocarriers as an emerging platform for cancer therapy. Nature Nanotech 2:751–760CrossRef
21.
Moghimi SM, Hunter AC, Murray JC (2005) Nanomedicine: current status and future prospects. FASEB J 19(3):311–330CrossRefPubMed
22.
Soppimath KS, Aminabhavi T, Kulkarni AR, Rudzinski WE (2001) Biodegradable polymeric nanoparticles as drug delivery devices. J Controlled Release 70:1–260CrossRef
23.
Honorat M, Mesnier A, Di Pietro A, Lin V, Cohen P, Dumontet C, Payen L (2008) Dexamethasone down-regulates ABCG2 expression levels in breast cancer cells. Biochem Biophys Res Commun 375:308–314CrossRefPubMed
24.
Stokoe D, Stephens LR, Copeland T, Gaffney PR, Reese CB, Painter GF, Holmes AB, McCormick F, Hawkins PT (1997) Dual role of phosphatidylinositol-3, 4, 5-trisphosphate in the activation of protein kinase B. Science 277:567–570CrossRefPubMed
25.
Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91:231–241CrossRefPubMed
26.
Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S, Reed JC (1998) Regulation of cell death protease caspase-9 by phosphorylation. Science 282:1318–1321CrossRefPubMed
27.
Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96:857–868CrossRefPubMed
28.
Buck E, Eyzaguirre A, Rosenfeld-Franklin M, Thomson S, Mulvihill M, Barr S, Brown E, O’Connor M, Yao Y, Pachter J, Miglarese M, Epstein D, Iwata KK, Haley JD, Gibson NW, Ji QS (2008) Feedback mechanisms promote cooperativity for small molecule inhibitors of epidermal and insulin-like growth factor receptors. Cancer Res 68:8322–8332CrossRefPubMed
29.
30.
She QB, Solit DB, Ye Q, O’Reilly KE, Lobo J, Rosen N (2005) Nanocarriers as an emerging platform for cancer therapy. Cancer Cell 8:287–297CrossRefPubMed
31.
Kinkade CW, Castillo-Martin M, Puzio-Kuter A, Yan J, Foster TH, Gao H, Sun Y, Ouyang X, Gerald WL, Cordon-Cardo C, Abate-Shen C (2008) Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model. J Clin Invest 118:3051–3064PubMed
32.
Folkman J (2007) Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov 6:273–286CrossRefPubMed
33.
Folkman J (2002) Role of angiogenesis in tumor growth and metastasis. Semin Oncol 29:15–18PubMed
34.
Gasparini G, Longo R, Toi M, Ferrara N (2005) Nanocarriers as an emerging platform for cancer therapy. Nat Clin Pract Oncol 2:562–577CrossRefPubMed
35.
Sengupta S, Sellers LA, Cindrova T, Skepper J, Gherardi E, Sasisekharan R, Fan TP (2003) Cyclooxygenase-2-selective nonsteroidal anti-inflammatory drugs inhibit hepatocyte growth factor/scatter factor-induced angiogenesis. Cancer Res 63:8351–8359PubMed
36.
Schnell CR, Stauffer F, Allegrini PR, O’Reilly T, McSheehy PM, Dartois C, Stumm M, Cozens R, Littlewood-Evans A, García-Echeverría C, Maira SM (2008) Effects of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 on the tumor vasculature: implications for clinical imaging. Cancer Res 68:6598–6607CrossRefPubMed
37.
Stoletov K, Montel V, Lester RD, Gonias SL, Klemke R (2007) High-resolution imaging of the dynamic tumor cell vascular interface in transparent zebrafish. Proc Natl Acad Sci U S A 104:17406–17411CrossRefPubMed
38.
Sengupta S, Eavarone D, Capila I, Zhao G, Watson N, Kiziltepe T, Sasisekharan R (2005) Temporal targeting of tumour cells and neovasculature with a nanoscale delivery system. Nature 436:568–572CrossRefPubMed
39.
Kaul G, Amiji M (2004) Biodistribution and targeting potential of poly(ethylene glycol)-modified gelatin nanoparticles in subcutaneous murine tumor model. J Drug Target 12:585–591CrossRefPubMed
40.
Hood JD, Bednarski M, Frausto R, Guccione S, Reisfeld RA, Xiang R, Cheresh DA (2002) Tumor regression by targeted gene delivery to the neovasculature. Science 296:2404CrossRefPubMed
Metadata
Title
Nanoparticle-mediated targeting of phosphatidylinositol-3-kinase signaling inhibits angiogenesis
Authors
Rania Harfouche
Sudipta Basu
Shivani Soni
Dirk M. Hentschel
Raghunath A. Mashelkar
Shiladitya Sengupta
Publication date
01-12-2009
Publisher
Springer Netherlands
Published in
Angiogenesis / Issue 4/2009
Print ISSN: 0969-6970
Electronic ISSN: 1573-7209
DOI
https://doi.org/10.1007/s10456-009-9154-4

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WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

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