PARProceedings of Anticancer Research2208-35452208-3553Bio-Byword Scientific Publishing Pty. Ltd.10.26689/par.v2i3.358ArticleNigrospora sphaerica products from the flowering dogwood exhibit antitumorigenic effects via the translational regulator, pS6 ribosomal proteinhttps://artdesignp.com/journal/PAR/2/3/10.26689/par.v2i3.358MaheshwariAsha,MmbagaMargaret,QuickQuincy2018232018-12-12The utility of diverse species of endophytic fungi as a viable source for drug agents with clinical applicability for the treatment of human diseases continues to expand. In this study we examined secondary metabolites of Nigrospora sphaerica isolated from the flowering dogwood, Cornus florida L., for their anticancer properties on lung cancer and glioblastoma.  Molecular identification of N. sphaerica was determined using ITS-rDNA sequence.  The expression of translational pathway proteins were examined after exposure to various crude extract concentrations (2µg/ml, 4µg/ml, 8µg/ml) using immunoblotting procedures, while tumor cell migration analysis was performed using boyden chamber assays.  Crude N. sphaerica extracts exhibited antiproliferative and antimigratory effects on solid tumors as determined by cell proliferation and cell migration assays, respectively.  The antitumorigenic effects of N. sphaerica were as a consequence of negatively regulating the PI3K/Akt/mTOR translational control signaling pathway, a canonical mechanistic axis that contributes to the maintenance and progression of several human cancers.  To our knowledge this is the first evidence that demonstrates N. sphaerica from C. florida inhibits tumor cell migration, and thus disease recurrence a major factor in the therapeutic resistance of cancers to chemotherapeutic agents.

Petrini O. Fungal Endophytes of Tree Leaves. In: Andrews JH, Hirano SS editors Microbial Ecology of Leaves. New York (NY): Springer Verlag; 1991.

Strobel GA. Rainforest endophytes and bioactive products. Crit Rev Biotechnol. 2002, 22:315–33.

Nair DN, Padmavathy S. Impact of Endophytic Microorganisms on Plants, Environment and Humans. The Scientific World Journal. 2014.

Venugopalan A, Srivastava S. Endophytes as in vitro production platforms of high value plant secondary metabolites. Biotechnology Advances. 2015, 33:873–887.

Graziose R, Rojas-Silva P, Rathinasabapathy T, et al. Antiparasitic compounds from Cornus florida L. with activities against Plasmodium falciparum and Leishmania tarentolae. J Ethnopharmacol. 2012, 142:456-61.

Vareed SK, Reddy MK, Schutzki RE, et al. Anthocyanins in Cornus alternifolia, Cornus controversa, Cornus kousa and Cornus florida fruits with health benefits. Life Sci. 2006, 78:777-84.

Yang KL, Wei MY, Shao CH, et al. Antibacterial anthraquinone derivatives from a Sea Anemone derived fungus Nigrospora sp. J. Nat. Prod. 2012, 75:935−941.

Ibrahim D, Lee CC, Yenn TW, et al. Effect of the extract of endophytic fungus, Nigrospora sphaerica CL-OP 30, against the growth of methicillin- resistant Staphylococcus aureus (MRSA) and Klebsiella pneumonia cells. Tropical Journal of Pharmaceutical Research. 2015, 11:2091-2097.

Zhang SP, Huang R, Li FF, et al. Antiviral anthraquinones and azaphilones produced by an endophytic fungus Nigrospora sp. from Aconitum carmichaeli. Fitoterapia. 2016, 112:85-9.

Zhao JH, Zhang YL, Wang LW, et al. Bioactive secondary metabolites from Nigrospora sp. LLGLM003, an endophytic fungus of the medicinal plant Moringa oleifera Lam. World J Microbiol Biotechnol. 2012, 28: 2107-12.

Ayob FW, Simarani K, Zainal Abidin N, et al. First report on a novel Nigrospora sphaerica isolated from Catharanthus roseus plant with anticarcinogenic properties. Microb Biotechnol. 2017, 10:926-32.

Schulz B, Wanke U, Draeger S, et al. Endophytes from herbaceous plants and shrubs: effectiveness of surface sterilization methods. Mycol Res. 1993, 97:1447-1450.

White TJ, Bruns T, Lee S, et al. Amplification and direct sequencing of fungal ribosomal RNA genes for phylogenetics. PCR Protocols: A Guide to Methods and Applications, New York (NY): Academic Press, Inc.;1990.

Kumar S, Stecher G, Tamura K. MEGA7: Molecular Evolutionary Genetics Analysis version 7.0 for bigger datasets. Molecular Biology and Evolution. 2016, 33:1870-1874.

Saitou N, Nei M. The neighbor-joining method: A new method for reconstructing phylogenetic trees. Molecular Biology and Evolution. 1987, 4:406-425.

Nei M, Kumar S. Molecular Evolution and Phylogenetics. New York (NY): Oxford University Press; 2000.

Felsenstein J. Confidence limits on phylogenies: An approach using the bootstrap. Evolution. 1985, 39:783-791.

Gallo MB, Chagas FO, Almeida MO, et al. Endophytic fungi found in association with Smallanthus sonchifolius (Asteraceae) as resourceful producers of cytotoxic bioactive natural products. J Basic Microbiol. 2009, 49:142-51.

Metwaly AM, Kadryb HA, El-Helab AA, et al. Nigrosphaerin A a new isochromene derivative from the endophytic fungus Nigrospora sphaerica. Phytochem Lett. 2014, 7:1–5.

Santos IP, Silva LCN, Silva MV, et al. Antibacterial activity of endophytic fungi from leaves of Indigofera suffruticosa Miller (Fabaceae). Front. Microbiol. 2015, 6:35.

Gallo MBC, Falso MJS, Balem F, et al. The Anti-Promyelocytic leukemia mode of action of two endophytic secondary metabolites unveiled by a proteomic approach. Planta Med. 2014, 80(06):473-481.

Mady MS, Mohyeldin MM, Ebrahim HY, et al. The indole alkaloid Meleagrin, from the olive tree endophytic fungus Penicillium chrysogenum, as a novel lead for the control of c-Met-dependent breast cancer proliferation, migration and invasion. Bioorg Med Chem. 2016, 24:113-22.

Liu Y, Wan WZ, Li Y, et al. Recent development of ATP-competitive small molecule phosphatidylinostitol-3-kinase inhibitors as anticancer agents. Oncotarget. 2017, 8:7181-7200.

Kim SH, Jang YH, Chau GC, Pyo S, Um SH. Prognostic significance and function of phosphorylated ribosomal protein S6 in esophageal squamous cell carcinoma. Mod Pathol. 2013, 26:327-35.

Chen B, Tan Z, Gao J, Wu W, Liu L, Jin W, Cao Y, Zhao S, Zhang W, Qiu Z, et al. Hyperphosphorylation of ribosomal protein S6 predicts unfavorable clinical survival in non-small cell lung cancer. J Exp Clin Cancer Res. 2015, 34:126.