title: Secalonic Acid-D Represses HIF1α/VEGF-Mediated Angiogenesis by Regulating the Akt/mTOR/p70S6K Signaling Cascade.
abstract: Tumor angiogenesis is a validated target for therapeutic intervention, but agents that are more disease selective are needed. Here, we report the isolation of secalonic acid-D (SAD), a mycotoxin from a novel source that exhibits potent antiangiogenic antitumor activity. SAD inhibited multiple HIF1α/VEGF-arbitrated angiogenesis dynamics as scored in human umbilical vascular endothelial cells and human MCF-7 breast tumor xenografts. Similarly, SAD suppressed VEGF-induced microvessel sprouting from rat aortic ring and blood vessel formation in the Matrigel plug assay in C57/BL6J mice. Under normoxic or hypoxic conditions, SAD inhibited cell survival through the Akt/mTOR/p70S6K pathway, with attendant effects on key proangiogenesis factors, including HIF1α, VEGFR, and MMP-2/MMP-9. These effects were reversed by cotreatment with the Akt inhibitors perifosine and GSK69069 or by the addition of neutralizing VEGF antibodies. The apoptotic properties of SAD were determined to be both extrinsic and intrinsic in nature, whereas the cell-cycle inhibitory effects were mediated by altering the level of key G1-S transition-phase proteins. In experimental mouse models of breast cancer, SAD dosing produced no apparent toxicities (either orally or intraperitoneal) at levels that yielded antitumor effects. Taken together, our findings offered a preclinical validation and mechanistic definition of the antiangiogenic activity of a novel mycotoxin, with potential application as a cancer-selective therapeutic agent.
authors.affiliation: Division of Cancer Pharmacology, Indian Institute of Integrative Medicine, CSIR, Jammu, India.
authors.forename: Santosh Kumar
authors.initials: SK
authors.lastname: Guru
authors.affiliation: Division of Cancer Pharmacology, Indian Institute of Integrative Medicine, CSIR, Jammu, India. Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.
authors.forename: Anup Singh
authors.initials: AS
authors.lastname: Pathania
authors.affiliation: Division of Cancer Pharmacology, Indian Institute of Integrative Medicine, CSIR, Jammu, India. Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.
authors.forename: Suresh
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Academy of Scientific and Innovative Research (AcSIR), New Delhi, India. Natural Product Chemistry (Microbes), Indian Institute of Integrative Medicine, CSIR, Jammu, India.
authors.forename: Deshidi
authors.initials: D
authors.lastname: Ramesh
authors.affiliation: Natural Product Chemistry (Microbes), Indian Institute of Integrative Medicine, CSIR, Jammu, India.
authors.forename: Manjeet
authors.initials: M
authors.lastname: Kumar
authors.affiliation: Plant Biotechnology, Indian Institute of Integrative Medicine, CSIR, Jammu, India.
authors.forename: Satiander
authors.initials: S
authors.lastname: Rana
authors.affiliation: Division of Cancer Pharmacology, Indian Institute of Integrative Medicine, CSIR, Jammu, India.
authors.forename: Ajay
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Division of Cancer Pharmacology, Indian Institute of Integrative Medicine, CSIR, Jammu, India. Academy of Scientific and Innovative Research (AcSIR), New Delhi, India. Experimental Breast Cancer Research Laboratory, University of Michigan North Campus Research Complex, Ann Arbor, Michigan.
authors.forename: Fayaz
authors.initials: F
authors.lastname: Malik
authors.affiliation: Division of Cancer Pharmacology, Indian Institute of Integrative Medicine, CSIR, Jammu, India.
authors.forename: P R
authors.initials: PR
authors.lastname: Sharma
authors.affiliation: PK-PD-Toxicology Division, Indian Institute of Integrative Medicine, CSIR, Jammu, India.
authors.forename: B K
authors.initials: BK
authors.lastname: Chandan
authors.affiliation: Division of QCQA&CMC, Indian Institute of Integrative Medicine, CSIR, Jammu, India.
authors.forename: Sundeep
authors.initials: S
authors.lastname: Jaglan
authors.affiliation: Division of QCQA&CMC, Indian Institute of Integrative Medicine, CSIR, Jammu, India.
authors.forename: J P
authors.initials: JP
authors.lastname: Sharma
authors.affiliation: Natural Product Chemistry (Microbes), Indian Institute of Integrative Medicine, CSIR, Jammu, India.
authors.forename: Bhahwal Ali
authors.initials: BA
authors.lastname: Shah
authors.affiliation: Division of Cancer Pharmacology, Indian Institute of Integrative Medicine, CSIR, Jammu, India. PK-PD-Toxicology Division, Indian Institute of Integrative Medicine, CSIR, Jammu, India.
authors.forename: Sheikh Abdullah
authors.initials: SA
authors.lastname: Tasduq
authors.affiliation: Plant Biotechnology, Indian Institute of Integrative Medicine, CSIR, Jammu, India.
authors.forename: Surrinder K
authors.initials: SK
authors.lastname: Lattoo
authors.affiliation: Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, India.
authors.forename: Abdul
authors.initials: A
authors.lastname: Faruk
authors.affiliation: Division of Cancer Pharmacology, Indian Institute of Integrative Medicine, CSIR, Jammu, India. Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.
authors.forename: A K
authors.initials: AK
authors.lastname: Saxena
authors.affiliation: Academy of Scientific and Innovative Research (AcSIR), New Delhi, India. Division of Medicinal Chemistry, Indian Institute of Integrative Medicine, CSIR, Jammu, India.
authors.forename: R A
authors.initials: RA
authors.lastname: Vishwakarma
authors.affiliation: Division of Cancer Pharmacology, Indian Institute of Integrative Medicine, CSIR, Jammu, India. Academy of Scientific and Innovative Research (AcSIR), New Delhi, India. sbhushan@iiim.ac.in.
authors.forename: Shashi
authors.initials: S
authors.lastname: Bhushan
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D061986:MCF-7 Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*; D044004:Xanthones / Q000494:pharmacology*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D044004:Xanthones; C009218:secalonic acid; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases