SR16388: chất chống tăng sinh mạch steroid với hiệu ứng ức chế mạnh mẽ đối với sự phát triển khối u trong cơ thể sống

Angiogenesis - Tập 14 - Trang 1-16 - 2010
Wan-Ru Chao1, Khalid Amin2, Yihui Shi1, Peter Hobbs1, Mas Tanabe1, Mary Tanga1, Ling Jong1, Nathan Collins1, Richard Peters1, Keith Laderoute1, Dominic Dinh1, Dawn Yean3, Carol Hou1, Barbara Sato1, Carsten Alt1, Lidia Sambucetti1
1Drug Discovery Department, Biosciences Division, SRI International, Menlo Park, USA
2Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, USA
3Applied StemCell, Inc., Sunnyvale, USA

Tóm tắt

Sự hình thành mạch là một trong những quá trình chủ yếu kiểm soát tăng trưởng và di căn của khối u. Các chất ức chế sự hình thành mạch đã được nhắm đến để điều trị nhiều loại ung thư trong hơn 2 thập kỷ qua. Chúng tôi đã phát triển một lớp hợp chất steroid mới nhằm mục tiêu ngăn chặn quá trình hình thành mạch trong các mô ung thư. Hợp chất chính của chúng tôi, SR16388, là một tác nhân chống hình thành mạch mạnh mẽ với độ gắn kết cao đến thụ thể estrogen-α (ER-α) và -β (ER-β) trong phạm vi nanomolar. Hợp chất này đã ức chế sự gia tăng của các tế bào nội mô vi mạch người (HMVEC) và nhiều loại tế bào ung thư người khác nhau trong môi trường nuôi cấy. SR16388 đã ức chế sự hình thành mạch thai kỳ như được đo bằng thử nghiệm màng niệu huyết (CAM) của phôi gà. Mật độ mạch máu trong CAM đã giảm đáng kể sau khi các phôi được điều trị với 3 μg/CAM SR16388 trong 24 giờ. SR16388 với liều 2 μM đã ngăn chặn sự hình thành ống trong Matrigel sau khi các tế bào HMVEC được điều trị trong 8 giờ. Trong thí nghiệm buồng Boyden điều chỉnh, SR16388 đã ức chế sự di cư của các tế bào HMVEC tới 80% tại nồng độ 500 nM. Sử dụng mô hình buồng Z-fibrin in vivo mới, chúng tôi đã chứng minh rằng SR16388 với liều uống 3 mg/kg một lần mỗi ngày trong 12 ngày đã ức chế một cách đáng kể độ dày của mô hạt (GT) và mật độ mạch máu của GT so với nhóm đối chứng. Quan trọng hơn, SR16388 đã giảm điều hòa các yếu tố phiên mã pro-angiogenic, yếu tố gây thiếu oxy 1α (HIF-1α) và yếu tố truyền tín hiệu và kích hoạt phiên mã 3 (STAT3) trong các tế bào ung thư phổi không nhỏ (NSCLC). Tất cả những tác động này của SR16388 có thể dẫn đến giảm vascularization và sự phát triển của khối u trong cơ thể sống.

Từ khóa

#angiogenesis #SR16388 #inhibitor #cancer #endothelial cells #HMVEC #NSCLC

Tài liệu tham khảo

Folkman J (1995) Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1:27–31 Folkman J, Shing Y (1992) Angiogenesis. J Bio Chem 267:10931–10934 Folkman J, Kalluri R (2004) Cancer without disease. Nature 427:787 Yancopoulos GD, Davis S, Gale NW et al (2000) Vascular-specific growth factors and blood vessel formation. Nature 407:242–248 Rosen LS (2005) VEGF-targeted therapy: therapeutic potential and recent advances. Oncologist 10:382–391 Ferrara N, Hillan KJ, Novotny W (2005) Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun 333:328–335 Takahashi Y, Kitadai Y, Bucana CD et al (1995) Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon Cancer. Cancer Res 55:3964–3968 Boocock CA, Charnock-Jones DS, Sharkey AM et al (1995) Expression of vascular endothelial growth factor and its receptor flt and KDR in ovarian carcinoma. J Natl Cancer Inst 87(7):506–516 Zeng G, Taylor SM, McColm JR et al (2007) Orientation of endothelial cell division is regulated by VEGF signaling during blood vessel formation. Blood 109:1345–1352 Kliche S, Waltenberger J (2001) VEGF receptor signaling and endothelial function. IUBMB Life 52:61–66 Claesson-Welch L (2003) Signal transduction by vascular endothelial growth factor receptors. Biochem Soc Trans 31:20–24 Shojaei F, Ferrara N (2007) Antiangiogensis to treat cancer and intraocular neovascular disorders. Lab Invest 87:227–230 Folkman J, Kalluri R (2003) Tumor angiogenesis. In: Kufe DW, Pollock RE, Weichselbaum RR et al (eds) Cancer medicine. B.C. Decker Inc., Hamilton, pp 161–194 Satchi-Fainaro R, Mamluk R, Wang L et al (2005) Inhibition of vessel permeability by TNP-470 and its polymer conjugate, caplostatin. Cancer Cell 7:251–261 Huang ZH, Fan YF, Xia H et al (2003) Effects of TNP-470 on proliferation and apoptosis in human colon cancer xenografts in nude mice. World J Gastroenterol 9(2):281–283 Huang JH, Fischer JS, New T et al (2004) TNP-470 promotes initial vascular sprouting in xenograft tumors. Mol Cancer Ther 3(3):335–343 Benny O, Fainaru O, Adini A et al (2008) An orally delivered small-molecule formulation with antiangiogenic and anticancer activity. Nat Biotechnol 26(7):799–807 Hockel M, Vaupel P (2001) Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 93(4):266–276 Jung JE, Kim HS, Lee CS et al (2007) Caffeic acid and its synthetic derivative CADPE suppress tumor angiogenesis by blocking STAT3-mediated VEGF expression in human renal carcinoma cells. Carcinogenesis 28(8):1780–1787 Semenza GL (2009) Regulation of cancer cell metabolism by hypoxia-induced factor-1. Semin Cancer Biol 19:12–16 Semenza GL (2007) Vasculogenesis, angiogenesis, and arteriogenesis: mechanisms of blood vessel formation and remodeling. J Cell Biochem 102:840–847 Simiantonaki N, Jayasinghe C, Michel-Schmidt R et al (2008) Hypoxia-induced epithelial VEGFD-C/VEGFR-3 upregulation in carcinoma cell lines. Int J Oncol 32:585–592 Byrne AM, Bouchier-Hayes DJ, Harmey JH (2005) Angiogenic and cell survival functions of vascular endothelial growth factor (VEGF). J Cell Mol Med 9(4):777–794 Niu G, Briggs J, Deng J et al (2008) Signal transducer and activator of transcription 3 is required for hypoxia-inducible factor-1α RNA expression in both tumor cells and tumor-associated myeloid cells. Mol Cancer Res 6(7):1099–1105 Kimbro KS, Simons JW (2006) Hypoxia-inducible factor-1 in human breast and prostate cancer. Endocr Relat Cancer 13:739–749 LaVallee TM, Burke PA, Swartz GM et al (2008) Significant antitumor activity in vivo following treatment with the microtubule agent ENMD-1198. Mol Cancer Ther 7(6):1472–1482 Moser C, Lang SA, Mori A et al (2008) ENMD-1198, a novel tubulin-binding agent reduces HIF-1 alpha and STAT3 activity in human hepatocellular carcinoma (HCC) cells, and inhibits growth and vascularization in vivo. BMC Cancer 8:206 Siddiquee KAZ, Turkson J (2008) STAT3 as a target for inducing apoptosis in solid and haematological tumors. Cell Res 18:254–267 Brantley EC, Nabors LB, Gillespie GY et al (2008) Loss of protein inhibitors of activated STAT3 expression in glioblatoma multiform tumors: implications for STAT3 activation and gene expression. Clin Cancer Res 14:4694–4704 Niu G, Wright KL, Huang M et al (2002) Constitutive STAT3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 21:2000–2008 Chen Z, Han ZC (2008) STAT3: a critical transcription activator in angiogenesis. Med Res Rev 28(2):185–200 Schaefer LK, Ren Z, Fuller GN et al (2002) Constitutive activation of STAT3α in brain tumors: localization to tumor endothelial cells and activation by the endothelial tyrosine kinase receptor 2 (VEGFR2). Oncogene 21:2058–2065 Kortylewski M, Yu H (2008) Role of STAT3 in suppressing anti-tumor immunity. Curr Opin Immunol 20(2):228–233 Kim ES, Hong SY, Lee HK et al (2008) Guggulsterone inhibits angiogenesis by blocking STAT3 and VEGF expression in colon cancer cells. Oncol Rep 20:1321–1327 Heimberger AB, Priebe W (2008) Small molecular inhibitors of p-STAT3: novel agents for treatment of primary and metastatic CNS cancers. Recent Pat CNS Drug Discov 3(3):179–188 Timofeeva OA, Gaponenko V, Lockett SJ et al (2007) Rationally designed inhibitors identify STAT3 N-domain as a promising anticancer drug target. ACS Chem Biol 2(12):799–809 Singh RP, Raina K, Deep G et al (2009) Silibinin suppress growth of human prostate carcinoma PC-3 orthotopic xenograft via activation of extracellular signal-regulated kinase ½ and inhibition of signal transducers and activators of transcription signaling. Clin Cancer Res 15(2):613–621 Tyagi A, Singh RP, Ramasamy K et al (2009) Growth inhibition and regression of lung tumors by silibinin: modulation of angiogenesis by macrophage-associated cytokines and nuclear factor-kB and signal transducers and activators of transcription 3. Cancer Prev Res 2(1):74–83 Leong H, Mathur PS, Greene GL (2009) Green tea catechins inhibit angiogenesis through suppression of STAT3 activation. Breast Cancer Res Treat 117:505–515 Nemenoff RA, Winn RA (2005) Role of nuclear receptors in lung tumourigenesis. Eur J Cancer 41:2561–2568 Sola B, Renoir JM (2006) Antiestrogenic therapies in solid cancers and multiple myeloma. Curr Mol Med 6:359–368 Hall JM, McDonnell DP (1999) The estrogen receptor beta-osiform (ERβ) of the human estrogen receptor modulates ERα transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens. Endocrinology 140:5566–5578 Harris HA (2007) Estrogen receptor-β: recent lessons from in vivo studies. Mol Endocrinol 21(1):1–13 Horvath LG, Henshall SM, Lee C-S et al (2001) Frequent loss of estrogen receptor-β expression in prostate cancer. Cancer Res 61:5331–5335 Stettner M, Kaulfub S, Burfeind P et al (2007) The relevance of estrogen receptor-β expression to the antiproliferative effects observed with histone deacetylase inhibitors and phytoestrogens in prostate cancer treatment. Mol Cancer Ther 6(10):2626–2633 Imamov O, Lopatkin NA, Gustafsson J-K (2004) Estrogen receptor β in prostate cancer. N Engl J Med 351(26):2773–2774 Pravettoni A, Mornai O, Martini PGV et al (2007) Estrogen receptor beta (ERbeta) and inhibition of prostate cancer cell proliferation: studies on the possible mechanism of action in DU145 cells. Mol Cell Endocrinol 263:46–54 Stabile LP, Davis AL, Gubish CT et al (2002) Human non-small cell lung tumors and cell derived from normal lung express both estrogen receptors (alpha) and (beta) and show biological response to estrogen. Cancer Res 62(7):2141–2150 Marquez-Garban DC, Chen HW, Fishbein MC et al (2007) Estrogen receptor signaling pathways in human non-small cell lung cancer. Steroids 72:135–143 Ali G, Donati V, Loggini B et al (2008) Different estrogen receptors expression in distinct histologic subtypes of lung adenocarcinoma. Human Pathol 39:1465–1473 Skov BG, Fisher BM, Pappot H (2008) Oestrogen receptor β over expression in males with non-small cell lung cancer is associated with better survival. Lung Cancer 59:88–94 Omoto Y, Kobayashi Y, Nishida K et al (2001) Expression, function, and clinical implications of the estrogen receptor beta in human lung cancers. Biochem Biophys Res Commun 285:340–347 Treon SP, Teoh G, Urashima M et al (1998) Anti-estrogens induce apoptosis of multiple myeloma cells. Blood 92:1749–1757 Otsuki T, Yamada O, Kurebayshi J et al (2000) Estrogen receptors in human myeloma cells. Cancer Res 60:1434–1441 Sola B, Renoir JM (2007) Estrogenic or anti estrogenic therapies for multiple myeloma? Mol Cancer 6:59. doi:10.1186/1476-4598-6-59 Gagliardi A, Collins DC (1993) Inhibition of angiogenesis by antiestrogens. Cancer Res 53:533–535 Lindner DJ, Borden EC (1997) Effects of tamoxifen and interferon-β or the combination on tumor-induced angiogenesis. Int J Cancer 71:456–461 Tanabe M, Peters R, Chao W-R et al (2000) Antiestrogenic steroids, and associated pharmaceutical compositions and methods of use. U.S. Patent 6,054,446 April 25 2000 Guo Y, Higazi AA, Arakelian A et al (2000) A peptide derived from the non-receptor-binding region of urokinase plasminogen activator (uPA) inhibits tumor progression and angiogenesis and induces tumor cell death in vivo. FASEB 14:1400–1410 Amin K, Li J, Chao W-R et al (2003) Dietary glycine inhibits angiogenesis during wound healing and tumor growth. Cancer Biol Ther 2(2):173–178 Ryan HE, Poloni M, McNulty W et al (2000) Hypoxia-inducible factor-1α is a positive factor in solid tumor growth. Cancer Res 60:4010–4015 Murphy BJ, Sato BG, Dalton TP et al (2005) The metal-responsive transcription factor-1 contributes to HIF-1 activation during hypoxia stress. Biochem Biophys Res Commun 337:860–867 Quesnelle KM, Boeham AL, Grandis JR (2007) STAT-mediated EGFR signaling in cancer. J Cell Biochem 102:311–319 Gao SP, Mark KG, Leslie K et al (2007) Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. J Clin Invest 117(12):3846–3856 Gridelli C, Bareschino MA, Schettino C et al (2007) Erlotinib in non-small cell lung cancer treatment: current status and future development. Oncologist 12:840–849 Renoir JM, Bouclier C, Seguin A et al (2008) Antiestrogen-mediated cell cycle arrest and apoptosis induction in breast and multiple myeloma cells. J Mol Endocrinol 40:101–112 Lonard DM, Smith CL (2002) Molecular perspectives on selective estrogen receptor modulators (SERM): progress in understanding their tissue-specific agonist and antagonist actions. Steroids 67:15024 Buzadar AU (2005) TAS-108: a novel steroidal antiestrogen. Clin Cancer Res 11:906s–908s Kumagai Y, Fujita T, Ozaki M et al (2009) Safety, tolerability and pharmacokinetics of TAS-108, a novel anti-estrogen, in healthy post menopausal Japanese women: a phase I single oral dose study. Basic Clin Pharmacol Toxicol 104:352–359 Eeullman SJ, Calaoagan JM, Sato BG et al (2010) A novel steroidal inhibitor of estrogen-related receptor alpha (ERR-alpha). Biochem Pharmacol 80:819–826 Giguere V (2008) Transcriptional control of energy homeostasis by the estrogen-related receptors. Endocrine Rev 29:677–696 Tremblay AM, Giguere V (2007) The NR3B subgroup: an overview. Nucl Recept Signal 5:e009 Ao A, Wang H, Kamarajugadda S et al (2008) Involvement of estrogen-related receptors in transcriptional response to hypoxia and growth of solid tumors. Proc Natl Acad Sci USA 105:7821–7826 Mak P, Leav I, Pursell B et al (2010) ER-β impedes prostate cancer EMT by destabilizing HIF-1α and inhibiting VEGF-mediated snail nuclear localization: implication for Gleason grading. Cancer Cell 17(4):319–332 Bookout AL, Jeong Y, Downes M et al (2006) Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell 126:789–799 Lai JS, Brown LG, True LD (2004) Metastases of prostate cancer express estrogen receptor = beta. Urology 64(4):814–820 Zhu X, Leave I, Leung YK et al (2004) Dynamic regulation of estrogen receptor-beta expression by DNA methylation during prostate cancer development and metastasis. Am J Pathol 164(6):2003–2012 Kuba K, Matsumoto K, Date K (2000) HGF/NK4, a four-kringle antagonist of hepatocyte growth factor, is an angiogenesis inhibitor that suppresses tumor growth and metastasis in mice. Cancer Res 60:6737–6743 Buettner R, Mora LB, Jove R (2002) Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res 8:945–954 Bromberg J, Darnell JE Jr (2000) The role of STATs in transcriptional control and their impact on cellular function. Oncogene 19:2468–2473 Bartoli M, Plantt D, Lemtalsi T et al (2003) VEGF differentially activates STAT3 in microvascular endothelial cells. FASEB J 17:1562–1564 Alas S, Bonavida B (2003) Inhibition of constitutive STAT3 activity sensitizes resistant non-Hodgkin’s lymphoma and multiple myeloma to chemotherapeutic drug-mediated apoptosis. Clin Cancer Res 9:316–326 Chen SH, Murphy DA, Lassoued W et al (2008) Activated STAT3 is a mediator and biomarker of VEGF endothelial activation. Cancer Biol Ther 7(12):1994–2003 Yahata Y, Shirakata Y, Tokumaru S et al (2003) Nuclear translocation of phosphorylated STAT3 is essential for vascular endothelial growth factor-induced human dermal microvascular endothelial cell migration and tube formation. J Biol Chem 278:40026–40031 Xu Q, Briggs J, Park S et al (2005) Targeting STAT3 blocks both HIF and VEGF expression induced by multiple oncogenic growth signaling pathways. Oncogene 24:5552–5560