Secondary Metabolites from a Culture of the Fungus Neosartorya pseudofischeri and Their In Vitro Cytostatic Activity in Human Cancer Cells^[*]

 

 Buy Article Permissions and Reprints

Abstract

Four known (1, 2, 3, and 6) and three new compounds including a 1,4-diacetyl-2,5-dibenzylpiperazine derivative (4), a quinazolinone-containing indole derivative (5), and a new ester of 2,4-dihydroxy-6-methylbenzoic acid (7) were isolated from the fungus Neosartorya pseudofischeri S. W. Peterson. Compound 2 displayed in vitro growth inhibitory activity that ranged between the activities of etoposide and carboplatin, chosen as reference compounds, in six distinct cancer cell lines. Compound 1 displayed less activity than 2. Computer-assisted phase-contrast microscopy-related analysis revealed that 2 displayed cytostatic, not cytotoxic, effects in human U373 glioblastoma and A549 non-small cell lung cancer apoptosis-resistant cells with marked inhibition of mitotic rates. Cancer cells in the remaining phases of the cell cycle were unchanged. Flow cytometry analysis further confirmed that 2 does not induce apoptotic features in U373 or A549 cancer cells. Thus, 2 represents a novel chemical scaffold from which derivatives for anticancer cytostatic compounds can be derived.

^* Dedicated to the memory of Professor Werner Herz (12 February 1921 – 17 August 2012).

• References

• 1 Fujimoto H, Ikeda M, Yamamoto K, Yamazaki M. Structure of fischerin, a new toxic metabolite from an ascomicetes Neosartorya fischeri var. fischeri . J Nat Prod 1993; 56: 1268-1275
  CrossrefPubMedGoogle Scholar
• 2 Kijjoa AK, Santos S, Dethoup T, Manoch L, Almeida AP, Vasconcelos MH, Silva A, Gales L, Herz W. Sartoryglabrins, analogs of ardeemins from Neosartorya glabra . Nat Prod Commun 2011; 6: 807-812
  PubMedGoogle Scholar
• 3 Asami Y, Kakeya H, Onose R, Yoshida A, Matsuszaki H, Osada H. Azaspirene: a novel angiogenesis inhibitor containing a 1-oxa-7-azaspiro[4.4]non-2-ene-4,6-dione skeleton produced by the fungus Neosartorya sp. Org Lett 2002; 4: 2845-2848
  CrossrefPubMedGoogle Scholar
• 4 Jayasuriya H, Zink D, Basilio A, Vicente F, Collado J, Bills G, Goldman ML, Motyl M, Huber J, Dezeny G, Byrne K, Singh SM. Discovery and antibacterial activity of glabramycins A–C from Neosartorya glabra by an antisense strategy. J Antibiot 2009; 62: 265-269
  CrossrefPubMedGoogle Scholar
• 5 Yang SS, Wang GJ, Cheng KF, Ju CH, Tsau YJ, Lee TH. Bioactive γ-lactones from the fermented broth of Neosartorya sp. Planta Med 2010; 76: 1071-1075
  PubMedGoogle Scholar
• 6 Peterson SW. Neosartorya pseudofischeri sp. nov. and its relationship to other species in Aspergillus section Fumigati . Mycol Res 1992; 96: 547-554
  CrossrefPubMedGoogle Scholar
• 7 Padhye AA, Godfrey JH, Chandler FW, Peterson SW. Osteomyelitis caused by Neosartorya pseudofischeri . J Clin Microbiol 1994; 32: 2832-2836
  PubMedGoogle Scholar
• 8 Järv H, Lehtmaa J, Summerbell RC, Hoekstra ES, Samson RA, Naaber P. Isolation of Neosartorya pseudofischeri from blood: first hint of pulmonary aspergillosis. J Clin Microbiol 2004; 42: 925-928
  CrossrefPubMedGoogle Scholar
• 9 Ghebremedhin B, Bluemel A, Neumann KH, Koenig B, Koenig W. Peritonitis due to Neosartorya pseudofischeri in an elderly patient undergoing peritoneal dialysis successfully treated with voriconazole. J Med Microbiol 2009; 58: 678-682
  CrossrefPubMedGoogle Scholar
• 10 Larsen TO, Smedsgaard J, Nielsen KF, Hansen MAE, Samson RA, Frisvad JC. Production of mycotoxins by Aspergillus lentulus and other medically important and closely related species in section Fumigati . Med Mycol 2007; 45: 225-232
  CrossrefPubMedGoogle Scholar
• 11 Didier C, Critcher DJ, Walshe ND, Kojima Y, Yamauchi Y, Barret AGM. Full stereochemical assignment and synthesis of the potent anthelmintic pyrrolobenzoxazine natural product CJ-12662. J Org Chem 2004; 69: 7875-7879
  CrossrefPubMedGoogle Scholar
• 12 Kanokmedhakul K, Kanokmedhakul S, Suwannatrai R, Soytong K, Prabpai S, Kongsaeree P. Bioactive meroterpenoids and alkaloids from the fungus Eurotium chevalieri . Tetrahedron 2011; 67: 5461-5468
  CrossrefPubMedGoogle Scholar
• 13 Fujita T, Makishima D, Akiyama K, Hayashi H. New convulsive compounds, brasiliamides A and B from Penicillium brasilianum Batista JV-379. Biosci Biotechnol Biochem 2002; 66: 1697-1705
  CrossrefPubMedGoogle Scholar
• 14 Tomada H, Kim YK, Nishida H, Masuma R, Omura S. Pyripyropenes, novel inhibitors of acyl-CoA: cholesterol acyltransferase produced by Aspergillus fumigatus. I. Production, isolation, and biological properties. J Antibiot 1994; 47: 148-153
  CrossrefPubMedGoogle Scholar
• 15 Kim YK, Tomada H, Nishida H, Sunazuka T, Obata R, Omura S. Pyripyropenes, novel inhibitors of acyl-CoA: cholesterol acyltransferase produced by Aspergillus fumigates. II. Structure elucidation of pyripyropenes A, B, C, and D. J Antibiot 1994; 47: 144-162
  PubMedGoogle Scholar
• 16 Glass NL, Donaldson GC. Development of primer sets designed for use with the PCR to amplify conserved genes from filamentous ascomycetes. Appl Environ Microbiol 1995; 61: 1323-1330
  PubMedGoogle Scholar
• 17 Hayot C, Farinelle S, De Decker R, Decaestecker C, Darro F, Kiss R, Van Damme M. In vitro pharmacological characterizations of the antiangiogenic and anti-tumor cell migration properties mediated by microtubule affecting drugs, with special emphasis on the organization of the actin cytoskeleton. Int J Oncol 2002; 21: 417-425
  PubMedGoogle Scholar
• 18 Joseph B, Darro F, Béliard A, Lesur B, Collignon F, Decaestecker C, Frydman A, Guillaumet G, Kiss R. 3-Aryl-2-quinolone derivatives: synthesis and characterization of in vitro and in vivo antitumor effects with emphasis on a new therapeutical target connected with cell migration. J Med Chem 2002; 45: 2543-2555
  CrossrefPubMedGoogle Scholar
• 19 Delbrouck C, Doyen I, Belot N, Decaestecker C, Ghanooni R, de Lavareille A, Kaltner H, Choufani G, Danguy A, Vandenhoven G, Gabius HJ, Hassid S, Kiss R. Galectin-1 is overexpressed in nasal polyps under budesonide and inhibits eosinophil migration. Lab Invest 2002; 82: 147-158
  CrossrefPubMedGoogle Scholar
• 20 Balde SE, Andolfi A, Bruyère C, Cimmino A, Lamoral-Theys D, Vurro M, Van Damme M, Altomare C, Mathieu V, Kiss R, Evidente A. Investigations of fungal secondary metabolites with potential anticancer activity. J Nat Prod 2010; 73: 969-971
  CrossrefPubMedGoogle Scholar
• 21 Gao H, Zehl M, Kaehlig H, Schneider P, Stuppner H, Moreno y Banuls L, Kiss R, Kopp B. Rapid structural identification of cytotoxic bufadienolide sulfates in toad venom from Bufo melanosticus by LC-DAD-MS ⁿ and LC-SPE-NMR. J Nat Prod 2010; 73: 603-608
  CrossrefPubMedGoogle Scholar
• 22 Debeir O, Megalizzi V, Warzee N, Kiss R, Decaestecker C. Videomicroscopic extraction of specific information on cell proliferation and migration in vitro . Exp Cell Res 2008; 314: 2985-2998
  CrossrefPubMedGoogle Scholar
• 23 Mijatovic T, Mathieu V, Gaussin JF, De Neve N, Ribaucour F, Van Quaquebeke E, Dumont P, Darro F, Kiss R. Cardenolide-induced lysosomal membrane permeabilization contributes therapeutic benefits in experimental human non-small-cell-lung cancers. Neoplasia 2006; 8: 402-412
  CrossrefPubMedGoogle Scholar
• 24 Fujita T, Hayashi H. New brasiliamide congeners, brasiliamides C, D and E, from Pennicilium brasilianum Batista JV-379. Biosci Biotechnol Biochem 2004; 68: 820-826
  CrossrefPubMedGoogle Scholar
• 25 Jiao RH, Xu S, Liu JY, Ge HM, Ding H, Xu C, Zhu HL, Tan RX. Chaetominine, a cytotoxic alkaloid produced by endophytic Chaetomium sp. IFB-E015. Org Lett 2006; 8: 5709-5712
  CrossrefPubMedGoogle Scholar
• 26 Pommier Y, Leo E, Zhang H, Marchand C. DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem Biol 2010; 17: 421-433
  CrossrefPubMedGoogle Scholar
• 27 Stinchcombe TE, Bogart J, Wigle DA, Govindan R. Annual review of advances in lung cancer clinical research: a report for the year 2009. J Thorac Oncol 2010; 5: 935-939
  CrossrefPubMedGoogle Scholar
• 28 Lefranc F, James S, Camby I, Gaussin JF, Darro F, Brotchi J, Gabius HJ, Kiss R. Combined cimetidine and temozolomide, compared with temozolomide alone: significant increases in survival in nude mice bearing U373 human glioblastoma multiforme orthotopic xenografts. J Neurosurg 2005; 102: 706-714
  CrossrefPubMedGoogle Scholar
• 29 Lefranc F, Mijatovic T, Kondo Y, Sauvage S, Roland I, Krstic D, Vasic V, Gailly P, Kondo S, Blanco G, Kiss R. Targeting the [alpha] 1 subunit of the sodium pump to combat glioblastoma cells. Neurosurgery 2008; 62: 211-222
  CrossrefPubMedGoogle Scholar
• 30 Lefranc F, Brotchi J, Kiss R. Possible future issues in the treatment of glioblastomas, with a special emphasis on cell migration and the resistance of migrating glioblastoma cells to apoptosis (Review). J Clin Oncol 2005; 23: 2411-2422
  CrossrefPubMedGoogle Scholar
• 31 Mathieu A, Remmelink M, DʼHaene N, Penant S, Gaussin JF, Van Ginckel R, Darro F, Kiss R, Salmon I. Development of a chemoresistant orthotopic human nonsmall cell lung carcinoma model in nude mice: analyses of tumor heterogenity in relation to the immuno histochemical levels of expression of cyclooxygenase-2, omithine decarboxylase, lung-related resistance protein, prostaglandin E synthetase, and glutathione-S-transferase-alpha(GST)-alpha, GST-mu, and GST-pi. Cancer 2004; 101: 1908-1918
  CrossrefPubMedGoogle Scholar
• 32 Simpson CD, Anyiwe K, Schimmer AD. Anoikis resistance and tumor metastasis. Cancer Lett 2008; 272: 177-185
  CrossrefPubMedGoogle Scholar
• 33 Denlinger CE, Rundall BK, Jones DR. Modulation of anti-apoptotic cell signaling pathways in non-small cell lung cancer: the role of NF-κB. Semin Thorac Cardiovasc Surg 2004; 16: 28-39
  CrossrefPubMedGoogle Scholar
• 34 El Maalouf G, Le Tourneau C, Batty GN, Faivre S, Raymond E. Markers involved in resistance to cytotoxics and targeted therapeutics in pancreatic cancer. Cancer Treat Rev 2009; 35: 167-174
  CrossrefPubMedGoogle Scholar
• 35 Soengas MS, Lowe SW. Apoptosis and melanoma chemoresistance. Oncogene 2003; 22: 3138-3151
  CrossrefPubMedGoogle Scholar
• 36 DʼAmico TA, Harpole Jr. DH. Molecular biology of esophageal cancer. Chest Surg Clin N Am 2000; 10: 451-469
  PubMedGoogle Scholar
• 37 Dumont P, Ingrassia L, Rouzeau S, Ribaucour F, Thomas S, Roland I, Darro F, Lefranc F, Kiss R. The Amaryllidaceae isocarbostyril narciclasine induces apoptosis by activation of the death receptor and/or mitochondrial pathways in cancer cells but not in normal fibroblasts. Neoplasia 2007; 9: 766-776
  CrossrefPubMedGoogle Scholar
• 38 Krystof V, Uldrijan S. Cyclin-dependent kinase inhibitors as anticancer drugs. Curr Drug Targets 2010; 11: 291-302
  CrossrefPubMedGoogle Scholar

• Supplementary Material