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Coibamide A, a natural lariat depsipeptide, inhibits VEGFA/VEGFR2 expression and suppresses tumor growth in glioblastoma xenografts

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Summary

Coibamide A is a cytotoxic lariat depsipeptide isolated from a rare cyanobacterium found within the marine reserve of Coiba National Park, Panama. Earlier testing of coibamide A in the National Cancer Institute in vitro 60 human tumor cell line panel (NCI-60) revealed potent anti-proliferative activity and a unique selectivity profile, potentially reflecting a new target or mechanism of action. In the present study we evaluated the antitumor activity of coibamide A in several functional cell-based assays and in vivo. U87-MG and SF-295 glioblastoma cells showed reduced migratory and invasive capacity and underwent G1 cell cycle arrest as, likely indirect, consequences of treatment. Coibamide A inhibited extracellular VEGFA secreted from U87-MG glioblastoma and MDA-MB-231 breast cancer cells with low nM potency, attenuated proliferation and migration of normal human umbilical vein endothelial cells (HUVECs) and selectively decreased expression of vascular endothelial growth factor receptor 2 (VEGFR2). We report that coibamide A retains potent antitumor properties in a nude mouse xenograft model of glioblastoma; established subcutaneous U87-MG tumors failed to grow for up to 28 days in response to 0.3 mg/Kg doses of coibamide A. However, the natural product was also associated with varied patterns of weight loss and thus targeted delivery and/or medicinal chemistry approaches will almost certainly be required to improve the toxicity profile of this unusual macrocycle. Finally, similarities between coibamide A- and apratoxin A-induced changes in cell morphology, decreases in VEGFR2 expression and macroautophagy signaling in HUVECs raise the possibility that both cyanobacterial natural products share a common mechanism of action.

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Notes

  1. The stereochemistry of natural coibamide A was recently revised by Yao and coauthors [21]. Yao, G., Pan, Z., Wu, C., Wang, W., Fang, L.Su, W. (2015) Efficient Synthesis and Stereochemical Revision of Coibamide A. J Am Chem Soc 137, 13,488–13,491.

References

  1. Newman DJ, Cragg GM (2012) Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod 75:311–335

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  2. Cragg GM, Newman DJ (2013) Natural products: a continuing source of novel drug leads. Biochim Biophys Acta 1830:3670–3695

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  3. Bouchard H, Viskov C, Garcia-Echeverria C (2014) Antibody-drug conjugates-a new wave of cancer drugs. Bioorg Med Chem Lett 24:5357–5363

    Article  PubMed  CAS  Google Scholar 

  4. Steichen SD, Caldorera-Moore M, Peppas NA (2013) A review of current nanoparticle and targeting moieties for the delivery of cancer therapeutics. Eur J Pharm Sci 48:416–427

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  5. Molinski TF, Dalisay DS, Lievens SL, Saludes JP (2009) Drug development from marine natural products. Nat Rev Drug Discov 8:69–85

    Article  PubMed  CAS  Google Scholar 

  6. Mayer AM, Glaser KB, Cuevas C, Jacobs RS, Kem W, Little RD, McIntosh JM, Newman DJ, Potts BC, Shuster DE (2010) The odyssey of marine pharmaceuticals: a current pipeline perspective. Trends Pharmacol Sci 31:255–265

    Article  PubMed  CAS  Google Scholar 

  7. Newman DJ, Cragg GM (2014) Marine-sourced anti-cancer and cancer pain control agents in clinical and late preclinical development. Mar Drugs 12:255–278

    Article  PubMed  PubMed Central  Google Scholar 

  8. Medina RA, Goeger DE, Hills P, Mooberry SL, Huang N, Romero LI, Ortega-Barria E, Gerwick WH, McPhail KL (2008) Coibamide a, a potent antiproliferative cyclic depsipeptide from the panamanian marine cyanobacterium leptolyngbya sp. J Am Chem Soc 130:6324–6325

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  9. Shoemaker RH (2006) The NCI60 human tumour cell line anticancer drug screen. Nat Rev Cancer 6:813–823

    Article  PubMed  CAS  Google Scholar 

  10. Hau AM, Greenwood JA, Lohr CV, Serrill JD, Proteau PJ, Ganley IG, McPhail KL, Ishmael JE (2013) Coibamide a induces mTOR-independent autophagy and cell death in human glioblastoma cells. PLoS One 8:e65250

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  11. Serrill JD, Tan M, Fotso S, Sikorska J, Kasanah N, Hau AM, McPhail KL, Santosa DA, Zabriskie TM, Mahmud T, Viollet B, Proteau PJ, Ishmael JE (2015) Apoptolidins a and C activate AMPK in metabolically sensitive cell types and are mechanistically distinct from oligomycin a. Biochem Pharmacol 93:251–265

    Article  PubMed  CAS  Google Scholar 

  12. Swinney DC, Anthony J (2011) How were new medicines discovered? Nat Rev Drug Discov 10:507–519

    Article  PubMed  CAS  Google Scholar 

  13. Gregori-Puigjane E, Setola V, Hert J, Crews BA, Irwin JJ, Lounkine E, Marnett L, Roth BL, Shoichet BK (2012) Identifying mechanism-of-action targets for drugs and probes. Proc Natl Acad Sci U S A 109:11178–11183

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  14. Thornburg CC, Cowley ES, Sikorska J, Shaala LA, Ishmael JE, Youssef DT, McPhail KL (2013) Apratoxin H and apratoxin a sulfoxide from the Red Sea cyanobacterium moorea producens. J Nat Prod 76:1781–1788

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  15. Ke N, Xi B, Ye P, Xu W, Zheng M, Mao L, Wu MJ, Zhu J, Wu J, Zhang W, Zhang J, Irelan J, Wang X, Xu X, Abassi YA (2010) Screening and identification of small molecule compounds perturbing mitosis using time-dependent cellular response profiles. Anal Chem 82:6495–6503

    Article  PubMed  CAS  Google Scholar 

  16. Makishima M, Honma Y, Hozumi M, Sampi K, Hattori M, Motoyoshi K (1991) Induction of differentiation of human leukemia cells by inhibitors of myosin light chain kinase. FEBS Lett 287:175–177

    Article  PubMed  CAS  Google Scholar 

  17. Kovacs M, Toth J, Hetenyi C, Malnasi-Csizmadia A, Sellers JR (2004) Mechanism of blebbistatin inhibition of myosin II. J Biol Chem 279:35557–35563

    Article  PubMed  CAS  Google Scholar 

  18. Hardee ME, Zagzag D (2012) Mechanisms of glioma-associated neovascularization. Am J Pathol 181:1126–1141

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Cebe-Suarez S, Zehnder-Fjallman A, Ballmer-Hofer K (2006) The role of VEGF receptors in angiogenesis; complex partnerships. Cell Mol Life Sci 63:601–615

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. Goel HL, Mercurio AM (2013) VEGF targets the tumour cell. Nat Rev Cancer 13:871–882

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Yao G, Pan Z, Wu C, Wang W, Fang L, Su W (2015) Efficient synthesis and stereochemical revision of coibamide a. J Am Chem Soc 137:13488–13491

    Article  PubMed  CAS  Google Scholar 

  22. Luesch H, Yoshida WY, Moore RE, Paul VJ (2002) New apratoxins of marine cyanobacterial origin from Guam and Palau. Bioorg Med Chem 10:1973–1978

    Article  PubMed  CAS  Google Scholar 

  23. Tidgewell K, Engene N, Byrum T, Media J, Doi T, Valeriote FA, Gerwick WH (2010) Evolved diversification of a modular natural product pathway: apratoxins F and G, two cytotoxic cyclic depsipeptides from a palmyra collection of lyngbya bouillonii. Chembiochem 11:1458–1466

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  24. Luesch H, Chanda SK, Raya RM, DeJesus PD, Orth AP, Walker JR, Izpisua Belmonte JC, Schultz PG (2006) A functional genomics approach to the mode of action of apratoxin a. Nat Chem Biol 2:158–167

    Article  PubMed  CAS  Google Scholar 

  25. Liu Y, Law BK, Luesch H (2009) Apratoxin a reversibly inhibits the secretory pathway by preventing cotranslational translocation. Mol Pharmacol 76:91–104

    Article  PubMed  CAS  Google Scholar 

  26. Shen S, Zhang P, Lovchik MA, Li Y, Tang L, Chen Z, Zeng R, Ma D, Yuan J, Yu Q (2009) Cyclodepsipeptide toxin promotes the degradation of Hsp90 client proteins through chaperone-mediated autophagy. J Cell Biol 185:629–639

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  27. Klionsky DJ et al. (2012) Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 8:445–544

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  28. Chen QY, Liu Y, Luesch H (2011) Systematic chemical mutagenesis identifies a potent novel apratoxin a/E hybrid with improved in vivo antitumor activity. ACS Med Chem Lett 2:861–865

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  29. Winiski AP, Foster CA (1992) ICAM-1 expression in a spontaneously transformed human keratinocyte cell line: characterization by a simple cell-ELISA assay. J Investig Dermatol 99:48–52

    Article  PubMed  CAS  Google Scholar 

  30. Hommel U, Weber HP, Oberer L, Naegeli HU, Oberhauser B, Foster CA (1996) The 3D-structure of a natural inhibitor of cell adhesion molecule expression. FEBS Lett 379:69–73

    Article  PubMed  CAS  Google Scholar 

  31. Garrison JL, Kunkel EJ, Hegde RS, Taunton J (2005) A substrate-specific inhibitor of protein translocation into the endoplasmic reticulum. Nature 436:285–289

    Article  PubMed  CAS  Google Scholar 

  32. Besemer J, Harant H, Wang S, Oberhauser B, Marquardt K, Foster CA, Schreiner EP, de Vries JE, Dascher-Nadel C, Lindley IJ (2005) Selective inhibition of cotranslational translocation of vascular cell adhesion molecule 1. Nature 436:290–293

    Article  PubMed  CAS  Google Scholar 

  33. Maifeld SV, MacKinnon AL, Garrison JL, Sharma A, Kunkel EJ, Hegde RS, Taunton J (2011) Secretory protein profiling reveals TNF-alpha inactivation by selective and promiscuous Sec61 modulators. Chem Biol 18:1082–1088

    Article  PubMed  CAS  Google Scholar 

  34. Klein W, Westendorf C, Schmidt A, Conill-Cortes M, Rutz C, Blohs M, Beyermann M, Protze J, Krause G, Krause E, Schulein R (2015) Defining a conformational consensus motif in cotransin-sensitive signal sequences: a proteomic and site-directed mutagenesis study. PLoS One 10:e0120886

    Article  PubMed  PubMed Central  Google Scholar 

  35. Fuchs Y, Steller H (2015) Live to die another way: modes of programmed cell death and the signals emanating from dying cells. Nat Rev Mol Cell Biol 16:329–344

    Article  PubMed  CAS  Google Scholar 

  36. Abassi YA, Xi B, Zhang W, Ye P, Kirstein SL, Gaylord MR, Feinstein SC, Wang X, Xu X (2009) Kinetic cell-based morphological screening: prediction of mechanism of compound action and off-target effects. Chem Biol 16:712–723

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  37. Khasraw M, Ameratunga MS, Grant R, Wheeler H, Pavlakis N (2014) Antiangiogenic therapy for high-grade glioma. The Cochrane Database of Systematic Reviews 9:CD008218

    PubMed  Google Scholar 

  38. Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJ, Mehta Jr MP (2014) A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 370:699–708

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  39. Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, Carpentier AF, Hoang-Xuan K, Kavan P, Cernea D, Brandes AA, Hilton M, Abrey L, Cloughesy T (2014) Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med 370:709–722

    Article  PubMed  CAS  Google Scholar 

  40. Baker GJ, Yadav VN, Motsch S, Koschmann C, Calinescu AA, Mineharu Y, Camelo-Piragua SI, Orringer D, Bannykh S, Nichols WS, deCarvalho AC, Mikkelsen T, Castro MG, Lowenstein PR (2014) Mechanisms of glioma formation: iterative perivascular glioma growth and invasion leads to tumor progression, VEGF-independent vascularization, and resistance to antiangiogenic therapy. Neoplasia 16:543–561

    Article  PubMed  PubMed Central  Google Scholar 

  41. Salvati M, D’Elia A, Frati A, Brogna C, Santoro A, Delfini R (2011) Safety and feasibility of the adjunct of local chemotherapy with biodegradable carmustine (BCNU) wafers to the standard multimodal approach to high grade gliomas at first diagnosis. J Neurosurg Sci 55:1–6

    PubMed  CAS  Google Scholar 

  42. Bregy A, Shah AH, Diaz MV, Pierce HE, Ames PL, Diaz D, Komotar RJ (2013) The role of gliadel wafers in the treatment of high-grade gliomas. Expert Rev Anticancer Ther 13:1453–1461

    Article  PubMed  CAS  Google Scholar 

  43. Ung TH, Malone H, Canoll P, Bruce JN (2015) Convection-enhanced delivery for glioblastoma: targeted delivery of antitumor therapeutics. CNS Oncology 4:225–234

    Article  PubMed  CAS  Google Scholar 

  44. Luesch H, Yoshida WY, Moore RE, Paul VJ, Corbett TH (2001) Total structure determination of apratoxin a, a potent novel cytotoxin from the marine cyanobacterium lyngbya majuscula. J Am Chem Soc 123:5418–5423

    Article  PubMed  CAS  Google Scholar 

  45. Chen QY, Liu Y, Cai W, Luesch H (2014) Improved total synthesis and biological evaluation of potent apratoxin S4 based anticancer agents with differential stability and further enhanced activity. J Med Chem 57:3011–3029

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  46. Bockus AT, McEwen CM, Lokey RS (2013) Form and function in cyclic peptide natural products: a pharmacokinetic perspective. Curr Top Med Chem 13:821–836

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank the Autoridad Nacional del Ambiente (ANAM), Panama for permission to make recollections (in 2012) of the coibamide A-producing cyanobacterium and funding from the NIH Fogarty International Center ICBG grant TW006634-06 (KLM) for collection and isolation. We also thank the Red Sea Protectorate for permission to make collections of the apratoxin-producing cyanobacterium (in 2007). This work was supported by an American Brain Tumor Association (ABTA) Discovery Grant (to JEI) and funding from the Oregon State University (OSU) General Research Fund. We are also grateful for the core facilities of the OSU Environmental Heath Sciences Center (P30-ES000210) and support from the American Foundation for Pharmaceutical Education (AFPE) in the form of an AFPE Pre-Doctoral Fellowship in the Pharmaceutical Sciences to JDS.

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  1. Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR, 97331, USA

    Jeffrey D. Serrill, Xuemei Wan, Andrew M. Hau, Hyo Sang Jang, Daniel J. Coleman, Arup K. Indra, Adam W. G. Alani, Kerry L. McPhail & Jane E. Ishmael

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Correspondence to Jane E. Ishmael.

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Serrill, J.D., Wan, X., Hau, A.M. et al. Coibamide A, a natural lariat depsipeptide, inhibits VEGFA/VEGFR2 expression and suppresses tumor growth in glioblastoma xenografts. Invest New Drugs 34, 24–40 (2016). https://doi.org/10.1007/s10637-015-0303-x

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