Meme Kanser Kök Hücrelerinde Notch Sinyal Yolağının İnhibisyonunda Güncel Yaklaşımlar

Öz

Dünyada kadınlarda kanser sebepli ölümlerde meme kanseri en üst sıralarda yer almaktadır. Kemoterapi, radyoterapi, hormonal tedavi gibi yöntemler meme kanserinin tedavisi için kullanılmasına rağmen metastaz ve nüks sıkça karşılaşılan durumlardır. Meme kanseri tedavisinin etkin olarak sağlanamamasında en çarpıcı etken tümör dokusundaki ufak bir popülasyonu oluşturan kanser kök hücreleridir. Meme kanser kök hücrelerinin eliminasyonu konusundaki çalışmalar kök hücre özelliklerinin ortaya çıkmasında kritik rol oynayan gelişimsel sinyal yolakları üzerinde etkili olabilecek yaklaşımları içermektedir. Gelişimsel sinyal yolaklarından en önemlilerinden biri olan Notch sinyal yolağı meme kanser kök hücrelerinde apoptoz, proliferasyon, anjiyojenez ve farklılaşma mekanizmaları üzerinde oldukça etkilidir. Güncel çalışmalar kanser kök hücrelerinin karakteristiğinde kritik rol oynayan Notch sinyal yolağının inhibisyonun etkili tedavi yaklaşımları için önemli olduğunu göstermektedir. Bu derlemede meme kanserinin tedavisinde Notch sinyal yolağının inhibisyonu için getirilmiş farklı yaklaşımlar ele alınacak ve gelecekte etkin kanser tedavisinin geliştirilmesinde faydalı olabilecek yöntemler tartışılacaktır.

Anahtar Kelimeler

• Meme kanseri,Notch,Kanser Kök Hücre

Recent Applications in Inhibition of Notch Signalling Pathway on Breast Cancer Stem Cell

Öz

In the world, breast cancer is at the top of the list in deaths due to cancer in women. Although treatments such as chemotherapy, radiotherapy, hormonal therapy are used for the treatment of breast cancer, metastasis and recurrence are frequent cases. The most striking factor in the inability to effectively breast cancer treatment is cancer stem cells, which form a small population of tumor tissue. Studies on the elimination of breast cancer stem cells involve approaches that may be effective on developmental signaling pathways that play a critical role in the forming of stem cell characteristics. One of the most important developmental signaling pathways, the Notch signaling pathway is highly effective on apoptosis, proliferation, angiogenesis and differentiation mechanisms in breast cancer stem cells. Recent studies indicate that inhibition of the Notch signaling pathway, which plays a critical role in the characterization of cancer stem cells, is important for effective treatment approaches. In this review, different approaches will be discussed for inhibition of Notch signalling pathway in breast cancer treatment and methods that may be useful for efficient cancer treatment.

Anahtar Kelimeler

• Breast cancer,Notch,Cancer stem cell

Kaynakça

1. American Cancer Society. (2016). Cancer Facts & Figures. Retrieved from https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2016.html
2. Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J., & Clarke, M. F. (2003). Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A, 100(7), 3983-3988. doi:10.1073/pnas.0530291100
3. Charafe-Jauffret, E., Ginestier, C., Iovino, F., Wicinski, J., Cervera, N., Finetti, P., Hur, M.H., Diebel, M.E., Monville, F., Dutcher, J., Brown, M., Viens, P., Xerri, L., Bertucci, F., Stassi, G., Dontu, G., Birnbaum, D.,. Wicha, M. S. (2009). Breast Cancer Cell Lines Contain Functional Cancer Stem Cells with Metastatic Capacity and a Distinct Molecular Signature. Cancer Res, 69(4), 1302.
4. Croker, A. K., Goodale, D., Chu, J., Postenka, C., Hedley, B. D., Hess, D. A., & Allan, A. L. (2009). High aldehyde dehydrogenase and expression of cancer stem cell markers selects for breast cancer cells with enhanced malignant and metastatic ability. J Cell Mol Med, 13(8b), 2236-2252. doi:10.1111/j.1582-4934.2008.00455.x
5. Fillmore, C. M., & Kuperwasser, C. (2008). Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy. Breast Cancer Res, 10(2), R25-R25. doi:10.1186/bcr1982
6. McCubrey, J. A., Davis, N. M., Abrams, S. L., Montalto, G., Cervello, M., Libra, M., Nicoletti, F., D'Assoro, A.B., Cocco, L., Martelli, A.M., Steelman, L. S. (2014). Targeting breast cancer initiating cells: advances in breast cancer research and therapy. Adv Biol Regul, 56, 81-107. doi:10.1016/j.jbior.2014.05.003
7. Wang, R., Lv, Q., Meng, W., Tan, Q., Zhang, S., Mo, X., & Yang, X. (2014). Comparison of mammosphere formation from breast cancer cell lines and primary breast tumors. J Thorac Dis, 6(6), 829-837. doi:10.3978/j.issn.2072-1439.2014.03.38
8. Takebe, N., Warren, R. Q., & Ivy, S. P. (2011). Breast cancer growth and metastasis: interplay between cancer stem cells, embryonic signaling pathways and epithelial-to-mesenchymal transition. Breast Cancer Res, 13(3), 211. doi:10.1186/bcr2876

9. Yu, Z., Pestell, T. G., Lisanti, M. P., & Pestell, R. G. (2012). Cancer stem cells. Int J Biochem Cell Biol, 44(12), 2144-2151. doi:10.1016/j.biocel.2012.08.022
10. Dragu, D. L., Necula, L. G., Bleotu, C., Diaconu, C. C., & Chivu-Economescu, M. (2015). Therapies targeting cancer stem cells: Current trends and future challenges. World J Stem Cells, 7(9), 1185-1201. doi:10.4252/wjsc.v7.i9.1185
11. Reya, T., & Clevers, H. (2005). Wnt signalling in stem cells and cancer. Nature, 434(7035), 843-850.
12. Iqbal, W., Alkarim, S., AlHejin, A., Mukhtar, H., & Saini, K. S. (2016). Targeting signal transduction pathways of cancer stem cells for therapeutic opportunities of metastasis. Oncotarget, 7(46), 76337-76353. doi:10.18632/oncotarget.10942
13. Espinoza, I., Pochampally, R., Xing, F., Watabe, K., & Miele, L. (2013). Notch signaling: targeting cancer stem cells and epithelial-to-mesenchymal transition. OncoTargets & Therapy, 6.
14. Dontu, G., Jackson, K. W., McNicholas, E., Kawamura, M. J., Abdallah, W. M., & Wicha, M. S. (2004). Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Research, 6(6), R605. doi:10.1186/bcr920
15. Pannuti, A., Foreman, K., Rizzo, P., Osipo, C., Golde, T., Osborne, B., & Miele, L. (2010). Targeting Notch to target cancer stem cells. Clin Cancer Res, 16(12), 3141-3152. doi:10.1158/1078-0432.CCR-09-2823
16. Bray, S. J. (2006). Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol, 7(9), 678-689. doi:10.1038/nrm2009
17. Yang, F., Xu, J., Tang, L., & Guan, X. (2017). Breast cancer stem cell: the roles and therapeutic implications. Cell Mol Life Sci, 74(6), 951-966. doi:10.1007/s00018-016-2334-7
18. Dufraine, J., Funahashi, Y., & Kitajewski, J. (2008). Notch signaling regulates tumor angiogenesis by diverse mechanisms. Oncogene, 27(38), 5132-5137. doi:10.1038/onc.2008.227
19. Harrison, H., Simões, B. M., Rogerson, L., Howell, S. J., Landberg, G., & Clarke, R. B. (2013). Oestrogen increases the activity of oestrogen receptor negative breast cancer stem cells through paracrine EGFR and Notch signalling. Breast Cancer Research, 15(2), R21. doi:10.1186/bcr3396
20. Liu, J., Shen, J. X., Wen, X. F., Guo, Y. X., & Zhang, G. J. (2016). Targeting Notch degradation system provides promise for breast cancer therapeutics. Crit Rev Oncol Hematol, 104, 21-29. doi:10.1016/j.critrevonc.2016.05.010
21. Atapattu, L., Saha, N., Chheang, C., Eissman, M. F., Xu, K., Vail, M. E., Hii, L., Llerena, C., Liu, Z., Horvay, K., Abud, H.E., Kusebauch, U., Moritz, R.L., Ding, B.S., Cao, Z., Rafii, S., Ernst, M., Scott, A.M., Nikolov, D.B., Lackmann, M., Janes, P. W. (2016). An activated form of ADAM10 is tumor selective and regulates cancer stem-like cells and tumor growth. J Exp Med, 213(9), 1741-1757. doi:10.1084/jem.2015109
22. Al-Hussaini, H., Subramanyam, D., Reedijk, M., & Sridhar, S. S. (2011). Notch signaling pathway as a therapeutic target in breast cancer. Mol Cancer Ther, 10(1), 9-15. doi:10.1158/1535-7163.MCT-10-0677
23. Andersson, E. R., & Lendahl, U. (2014). Therapeutic modulation of Notch signalling--are we there yet? Nat Rev Drug Discov, 13(5), 357-378. doi:10.1038/nrd4252
24. Takebe, N., Miele, L., Harris, P. J., Jeong, W., Bando, H., Kahn, M., Yang, S. X., Ivy, S. P. (2015). Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol, 12(8), 445-464. doi:10.1038/nrclinonc.2015.61
25. Zhang, J., Kuang, Y., Wang, Y., Xu, Q., & Ren, Q. (2017). Notch-4 silencing inhibits prostate cancer growth and EMT via the NF-κB pathway. Apoptosis, 22(6), 877-884. doi:10.1007/s10495-017-1368-0
26. Harrison, H., Farnie, G., Howell, S. J., Rock, R. E., Stylianou, S., Brennan, K. R., Brundred, N.J., Clarke, R. B. (2010). Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor. Cancer Res, 70(2), 709-718. doi:10.1158/0008-5472.CAN-09-1681
27. Clarke, R. B., Spence, K., Anderson, E., Howell, A., Okano, H., & Potten, C. S. (2005). A putative human breast stem cell population is enriched for steroid receptor-positive cells. Dev Biol, 277(2), 443-456. doi:10.1016/j.ydbio.2004.07.044
28. Andrieu, G., Tran, A. H., Strissel, K. J., & Denis, G. V. (2016). BRD4 Regulates Breast Cancer Dissemination through Jagged1/Notch1 Signaling. Cancer Res, 76(22), 6555-6567. doi:10.1158/0008-5472.can-16-0559
29. Li, Y., Burns, J. A., Cheney, C. A., Zhang, N., Vitelli, S., Wang, F., Bett, A., Chastain, M., Audoly, L.P., Zhang, Z.-Q. (2010). Distinct expression profiles of Notch-1 protein in human solid tumors: Implications for development of targeted therapeutic monoclonal antibodies. Biologics : Targets & Therapy, 4, 163-171.
30. Polyak, K., & Weinberg, R. A. (2009). Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer, 9(4), 265-273.
31. Sethi, N., Dai, X., Winter, C. G., & Kang, Y. (2011). Tumor-derived JAGGED1 promotes osteolytic bone metastasis of breast cancer by engaging notch signaling in bone cells. Cancer Cell, 19(2), 192-205. doi:10.1016/j.ccr.2010.12.022
32. Kwon, C., Cheng, P., King, I. N., Andersen, P., Shenje, L., Nigam, V., & Srivastava, D. (2011). Notch Post-Translationally Regulates β-Catenin Protein in Stem and Progenitor Cells. Nature cell biology, 13(10), 1244-1251. doi:10.1038/ncb2313
33. Won, H. Y., Lee, J. Y., Shin, D. H., Park, J. H., Nam, J. S., Kim, H. C., & Kong, G. (2012). Loss of Mel-18 enhances breast cancer stem cell activity and tumorigenicity through activating Notch signaling mediated by the Wnt/TCF pathway. Faseb j, 26(12), 5002-5013. doi:10.1096/fj.12-209247
34. Steg, A. D., Burke, M. R., Amm, H. M., Katre, A. A., Dobbin, Z. C., Jeong, D. H., & Landen, C. N. (2014). Proteasome inhibition reverses hedgehog inhibitor and taxane resistance in ovarian cancer. Oncotarget, 5(16), 7065-7080.
35. Kondratyev, M., Kreso, A., Hallett, R. M., Girgis-Gabardo, A., Barcelon, M. E., Ilieva, D., Ilieva, D., Ware, C., Majumder, P.K., Hassell, J. A. (2012). Gamma-secretase inhibitors target tumor-initiating cells in a mouse model of ERBB2 breast cancer. Oncogene, 31(1), 93-103. doi:http://www.nature.com/onc/journal/v31/n1/suppinfo/onc2011212s1.html
36. Li, S., & Li, Q. (2014). Cancer stem cells and tumor metastasis (Review). Int J Oncol, 44(6), 1806-1812. doi:10.3892/ijo.2014.2362
37. Zhang, P., He, D., Chen, Z., Pan, Q., Du, F., Zang, X., Wang, Y., Tang, C., Li, H., Lu, H., Yao, X., Jin, J. Ma, X. (2016). Chemotherapy enhances tumor vascularization via Notch signaling-mediated formation of tumor-derived endothelium in breast cancer. Biochem Pharmacol, 118, 18-30. doi:10.1016/j.bcp.2016.08.008
38. Collignon, J., Lousberg, L., Schroeder, H., & Jerusalem, G. (2016). Triple-negative breast cancer: treatment challenges and solutions. Breast Cancer : Targets and Therapy, 8, 93-107. doi:10.2147/BCTT.S69488
39. Guestini, F., McNamara, K. M., Ishida, T., & Sasano, H. (2016). Triple negative breast cancer chemosensitivity and chemoresistance: current advances in biomarkers indentification. Expert Opin Ther Targets, 20(6), 705-720. doi:10.1517/14728222.2016.1125469
40. Pant, S., Jones, S. F., Kurkjian, C. D., Infante, J. R., Moore, K. N., Burris, H. A., McMeekin, D.S., Benhadji, K.A., Patel, B.K., Frenzel, M.J., Kursar, J.D., Zamek-Gliszczynski, M.J., Yuen, E.S., Chan, E.M., Bendell, J. C. (2016). A first-in-human phase I study of the oral Notch inhibitor, LY900009, in patients with advanced cancer. Eur J Cancer, 56, 1-9. doi:10.1016/j.ejca.2015.11.021
41. Locatelli, M. A., Aftimos, P., Dees, E. C., LoRusso, P. M., Pegram, M. D., Awada, A., Huang, B., Cesari, R., Jiang, Y., Shaik, M.N., Kern, K.A., Curigliano, G. (2017). Phase I study of the gamma secretase inhibitor PF-03084014 in combination with docetaxel in patients with advanced triple-negative breast cancer. Oncotarget, 8(2), 2320-2328. doi:10.18632/oncotarget.13727
42. Nickoloff, B. J., Osborne, B. A., & Miele, L. (2003). Notch signaling as a therapeutic target in cancer: a new approach to the development of cell fate modifying agents. Oncogene, 22(42), 6598-6608. doi:10.1038/sj.onc.1206758
43. Shih Ie, M., & Wang, T. L. (2007). Notch signaling, gamma-secretase inhibitors, and cancer therapy. Cancer Res, 67(5), 1879-1882. doi:10.1158/0008-5472.CAN-06-3958
44. Wu, Y., Cain-Hom, C., Choy, L., Hagenbeek, T. J., de Leon, G. P., Chen, Y., Finkle, D., Venook, R., u, X., Fidgway, J., Schahin-Reed, D., Dow, G.J., Shelton, A., Stawicki, S., Watts, R.J., Zhang, J., Choy, R., Howard, P., Kadyk, L., Yan, M., Zha, J., Callahan, C. A., Hymowitz, S. G., Siebel, C. W. (2010). Therapeutic antibody targeting of individual Notch receptors. Nature, 464(7291), 1052-1057. doi:http://www.nature.com/nature/journal/v464/n7291/suppinfo/nature08878_S1.html
45. Sharma, A., Paranjape, A. N., Rangarajan, A., & Dighe, R. R. (2012). A monoclonal antibody against human Notch1 ligand-binding domain depletes subpopulation of putative breast cancer stem-like cells. Mol Cancer Ther, 11(1), 77-86. doi:10.1158/1535-7163.mct-11-0508
46. Ridgway, J., Zhang, G., Wu, Y., Stawicki, S., Liang, W.-C., Chanthery, Y., Kowalski, J., Watts, R.J., Callahan, C., Kasman, I., Singh, M., Chien, M., Tan, C., Hongo, J.S., de Sauvage, F., Plowman, G., Yan, M. (2006). Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature, 444(7122), 1083-1087. doi:http://www.nature.com/nature/journal/v444/n7122/suppinfo/nature05313_S1.html
47. Chiorean, E. G., LoRusso, P., Strother, R. M., Diamond, J. R., Younger, A., Messersmith, W. A., Adriaens, L., Liu, L., Kao, R.J., DiCioccio, A.T., Kostic, A., Leek, R., Harris, A., Jimeno, A. (2015). A Phase I First-in-Human Study of Enoticumab (REGN421), a Fully Human Delta-like Ligand 4 (Dll4) Monoclonal Antibody in Patients with Advanced Solid Tumors. Clin Cancer Res, 21(12), 2695-2703. doi:10.1158/1078-0432.ccr-14-2797
48. Xu, Z., Wang, Z., Jia, X., Wang, L., Chen, Z., Wang, S., . . . Wu, M. (2016). MMGZ01, an anti-DLL4 monoclonal antibody, promotes nonfunctional vessels and inhibits breast tumor growth. Cancer Lett, 372(1), 118-127. doi:10.1016/j.canlet.2015.12.025
49. Purow, B. (2012). Notch inhibition as a promising new approach to cancer therapy. Adv Exp Med Biol, 727, 305-319. doi:10.1007/978-1-4614-0899-4_23
50. Smalley, M. J., Reis-Filho, J. S., & Ashworth, A. (2008). BRCA1 and stem cells: tumour typecasting. Nat Cell Biol, 10(4), 377-379.
51. Buckley, N. E., Nic An tSaoir, C. B., Blayney, J. K., Oram, L. C., Crawford, N. T., D'Costa, Z. C., Quinn, J.E., Kennedy, R.D., Harkin, D.P., Mullan, P. B. (2013). BRCA1 is a key regulator of breast differentiation through activation of Notch signalling with implications for anti-endocrine treatment of breast cancers. Nucleic Acids Res, 41(18), 8601-8614. doi:10.1093/nar/gkt626
52. Chang, S., & Sharan, S. K. (2012). BRCA1 and MicroRNAs: Emerging Networks and Potential Therapeutic Targets. Molecules and Cells, 34(5), 425-432. doi:10.1007/s10059-012-0118-y
53. Moskwa, P., Buffa, F. M., Pan, Y., Panchakshari, R., Gottipati, P., Muschel, R. J., Beech, J., Kulshrestha, R., Abdelmohsen, K., Weinstock, D.M., Gorospe, M., Harris, A.L., Helleday, T., Chowdhury, D. (2011). miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors. Mol Cell, 41(2), 210-220. doi:10.1016/j.molcel.2010.12.005
54. Wang, Z., Li, Y., Kong, D., Ahmad, A., Banerjee, S., & Sarkar, F. H. (2010). Cross-talk between miRNA and Notch signaling pathways in tumor development and progression. Cancer Lett, 292(2), 141-148. doi:10.1016/j.canlet.2009.11.012
55. Brabletz, S., Bajdak, K., Meidhof, S., Burk, U., Niedermann, G., Firat, E., Wellner, U., Dimmler, A., Faller, G., Schubert, J., Brabletz, T. (2011). The ZEB1/miR-200 feedback loop controls Notch signalling in cancer cells. Embo j, 30(4), 770-782. doi:10.1038/emboj.2010.349
56. Li, X.-j., Ji, M.-h., Zhong, S.-l., Zha, Q.-b., Xu, J.-j., Zhao, J.-h., & Tang, J.-h. (2012). MicroRNA-34a Modulates Chemosensitivity of Breast Cancer Cells to Adriamycin by Targeting Notch1. Archives of Medical Research, 43(7), 514-521. doi:http://dx.doi.org/10.1016/j.arcmed.2012.09.007
57. Garzon, R., Marcucci, G., & Croce, C. M. (2010). Targeting microRNAs in cancer: rationale, strategies and challenges. Nat Rev Drug Discov, 9(10), 775-789. doi:10.1038/nrd3179
58. Suman, S., Das, T. P., & Damodaran, C. (2013). Silencing NOTCH signaling causes growth arrest in both breast cancer stem cells and breast cancer cells. Br J Cancer, 109(10), 2587-2596. doi:10.1038/bjc.2013.642
59. Pal, D., Kolluru, V., Chandrasekaran, B., Baby, B. V., Aman, M., Suman, S., Sirimulla, S., Sanders, M.A., Alatassi, H., Ankem, M.K., Damodaran, C. (2017). Targeting aberrant expression of Notch-1 in ALDH+ cancer stem cells in breast cancer. Mol Carcinog, 56(3), 1127-1136. doi:10.1002/mc.22579
60. So, J. Y., Wahler, J., Das Gupta, S., Salerno, D. M., Maehr, H., Uskokovic, M., & Suh, N. (2015). HES1-mediated inhibition of Notch1 signaling by a Gemini vitamin D analog leads to decreased CD44(+)/CD24(-/low) tumor-initiating subpopulation in basal-like breast cancer. J Steroid Biochem Mol Biol, 148, 111-121. doi:10.1016/j.jsbmb.2014.12.013
61. Shan, N. L., Wahler, J., Lee, H. J., Bak, M. J., Gupta, S. D., Maehr, H., & Suh, N. (2016). Vitamin D compounds inhibit cancer stem-like cells and induce differentiation in triple negative breast cancer. J Steroid Biochem Mol Biol. doi:10.1016/j.jsbmb.2016.12.001
62. Shim, Y., & Song, J. M. (2015). Quantum dot nanoprobe-based high-content monitoring of notch pathway inhibition of breast cancer stem cell by capsaicin. Mol Cell Probes, 29(6), 376-381. doi:10.1016/j.mcp.2015.09.004
63. Sun, D. W., Zhang, H. D., Mao, L., Mao, C. F., Chen, W., Cui, M., Ma, R., Cao, H.X., Jing, C.W., Wang, Z., Wu, J.Z., Tang, J. H. (2015). Luteolin Inhibits Breast Cancer Development and Progression In Vitro and In Vivo by Suppressing Notch Signaling and Regulating MiRNAs. Cell Physiol Biochem, 37(5), 1693-1711. doi:10.1159/000438535
64. Moselhy, J., Srinivasan, S., Ankem, M. K., & Damodaran, C. (2015). Natural Products That Target Cancer Stem Cells. Anticancer Res, 35(11), 5773-5788.
65. Brannon-Peppas, L., & Blanchette, J. O. (2012). Nanoparticle and targeted systems for cancer therapy. Advanced drug delivery reviews, 64, 206-212.
66. Hartmann, L. C., Keeney, G. L., Lingle, W. L., Christianson, T. J., Varghese, B., Hillman, D., Oberg, A. L., Low, P. S. (2007). Folate receptor overexpression is associated with poor outcome in breast cancer. Int J Cancer, 121(5), 938-942.
67. Wittig, R., Rosenholm, J. M., von Haartman, E., Hemming, J., Genze, F., Bergman, L., Simmet, T., Lindén, M., Sahlgren, C. (2014). Active targeting of mesoporous silica drug carriers enhances gamma-secretase inhibitor efficacy in an in vivo model for breast cancer. Nanomedicine (Lond), 9(7), 971-987. doi:10.2217/nnm.13.62
68. Mamaeva, V., Rosenholm, J. M., Bate-Eya, L. T., Bergman, L., Peuhu, E., Duchanoy, A., Fortelius, L.E., Landor, S., Toivola, D.M., Lindén, M. (2011). Mesoporous silica nanoparticles as drug delivery systems for targeted inhibition of Notch signaling in cancer. Molecular Therapy, 19(8), 1538-1546.
69. Mamaeva, V., Niemi, R., Beck, M., Ozliseli, E., Desai, D., Landor, S., Gronroos, T., Kroqvist, P., Pettersen, I.K.N., McCormack, E., Rosenholm, J.M., Linden, M., Sahlgren, C. (2016). Inhibiting Notch Activity in Breast Cancer Stem Cells by Glucose Functionalized Nanoparticles Carrying gamma-secretase Inhibitors. Mol Ther, 24(5), 926-936. doi:10.1038/mt.2016.42
70. Yang, H., Li, Y., Li, T., Xu, M., Chen, Y., Wu, C., Dang, X., Liu, Y. (2014). Multifunctional core/shell nanoparticles cross-linked polyetherimide-folic acid as efficient Notch-1 siRNA carrier for targeted killing of breast cancer. Sci Rep, 4, 7072. doi:10.1038/srep07072