Your browser doesn't support javascript.
loading
Secalonic Acid-D Represses HIF1α/VEGF-Mediated Angiogenesis by Regulating the Akt/mTOR/p70S6K Signaling Cascade.
Guru, Santosh Kumar; Pathania, Anup Singh; Kumar, Suresh; Ramesh, Deshidi; Kumar, Manjeet; Rana, Satiander; Kumar, Ajay; Malik, Fayaz; Sharma, P R; Chandan, B K; Jaglan, Sundeep; Sharma, J P; Shah, Bhahwal Ali; Tasduq, Sheikh Abdullah; Lattoo, Surrinder K; Faruk, Abdul; Saxena, A K; Vishwakarma, R A; Bhushan, Shashi.
Afiliação
  • Guru SK; Division of Cancer Pharmacology, Indian Institute of Integrative Medicine, CSIR, Jammu, India.
  • Pathania AS; Division of Cancer Pharmacology, Indian Institute of Integrative Medicine, CSIR, Jammu, India. Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.
  • Kumar S; Division of Cancer Pharmacology, Indian Institute of Integrative Medicine, CSIR, Jammu, India. Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.
  • Ramesh D; Academy of Scientific and Innovative Research (AcSIR), New Delhi, India. Natural Product Chemistry (Microbes), Indian Institute of Integrative Medicine, CSIR, Jammu, India.
  • Kumar M; Natural Product Chemistry (Microbes), Indian Institute of Integrative Medicine, CSIR, Jammu, India.
  • Rana S; Plant Biotechnology, Indian Institute of Integrative Medicine, CSIR, Jammu, India.
  • Kumar A; Division of Cancer Pharmacology, Indian Institute of Integrative Medicine, CSIR, Jammu, India.
  • Malik F; 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.
  • Sharma PR; Division of Cancer Pharmacology, Indian Institute of Integrative Medicine, CSIR, Jammu, India.
  • Chandan BK; PK-PD-Toxicology Division, Indian Institute of Integrative Medicine, CSIR, Jammu, India.
  • Jaglan S; Division of QCQA&CMC, Indian Institute of Integrative Medicine, CSIR, Jammu, India.
  • Sharma JP; Division of QCQA&CMC, Indian Institute of Integrative Medicine, CSIR, Jammu, India.
  • Shah BA; Natural Product Chemistry (Microbes), Indian Institute of Integrative Medicine, CSIR, Jammu, India.
  • Tasduq SA; Division of Cancer Pharmacology, Indian Institute of Integrative Medicine, CSIR, Jammu, India. PK-PD-Toxicology Division, Indian Institute of Integrative Medicine, CSIR, Jammu, India.
  • Lattoo SK; Plant Biotechnology, Indian Institute of Integrative Medicine, CSIR, Jammu, India.
  • Faruk A; Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, India.
  • Saxena AK; Division of Cancer Pharmacology, Indian Institute of Integrative Medicine, CSIR, Jammu, India. Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.
  • Vishwakarma RA; Academy of Scientific and Innovative Research (AcSIR), New Delhi, India. Division of Medicinal Chemistry, Indian Institute of Integrative Medicine, CSIR, Jammu, India.
  • Bhushan S; 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.
Cancer Res ; 75(14): 2886-96, 2015 Jul 15.
Article em En | MEDLINE | ID: mdl-25977334
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas Quinases S6 Ribossômicas 70-kDa / Xantonas / Fator A de Crescimento do Endotélio Vascular / Proteínas Proto-Oncogênicas c-akt / Subunidade alfa do Fator 1 Induzível por Hipóxia / Serina-Treonina Quinases TOR / Neovascularização Patológica Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Cancer Res Ano de publicação: 2015 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas Quinases S6 Ribossômicas 70-kDa / Xantonas / Fator A de Crescimento do Endotélio Vascular / Proteínas Proto-Oncogênicas c-akt / Subunidade alfa do Fator 1 Induzível por Hipóxia / Serina-Treonina Quinases TOR / Neovascularização Patológica Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Cancer Res Ano de publicação: 2015 Tipo de documento: Article