| A DC-81-indole conjugate agent suppresses melanoma A375 cell migration partially via interrupting VEGF production and stromal cell-derived factor-1α-mediated signaling. | |
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MedLine Citation:
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PMID: 21708181 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Pyrrolo[2,1-c][1,4]benzodiazepine (PBD) chemicals are antitumor antibiotics inhibiting nucleic acid synthesis. An indole carboxylate-PBD hybrid with six-carbon spacer structure (IN6CPBD) has been previously demonstrated to induce melanoma cell apoptosis and reduce metastasis in mouse lungs. This study aimed at investigating the efficacy of the other hybrid compound with four-carbon spacer (IN4CPBD) and elucidating its anti-metastatic mechanism. Human melanoma A375 cells with IN4CPBD treatment underwent cytotoxicity and apoptosis-associated assays. Transwell migration assay, Western blotting, and ELISA were used for mechanistic study. IN4CPBD exhibited potent melanoma cytotoxicity through interrupting G1/S cell cycle progression, increasing DNA fragmentation and hypodipoidic DNA contents, and reducing mitochondrial membrane potential. Caspase activity elevation suggested that both intrinsic and extrinsic pathways were involved in IN4CPBD-induced melanoma apoptosis. IN4CPBD up-regulated p53 and p21, thereby concomitantly derailing the equilibrium between Bcl-2 and Bax levels. Transwell migration assay demonstrated that stromal cell-derived factor-1α (SDF-1α) stimulated A375 cell motility, while kinase inhibitors treatment confirmed that Rho/ROCK, Akt, ERK1/2, and p38 MAPK pathways were involved in SDF-1α-enhanced melanoma migration. IN4CPBD not only abolished the SDF-1α-enhanced chemotactic motility but also suppressed constitutive MMP-9 and VEGF expression. Mechanistically, IN4CPBD down-regulated Akt, ERK1/2, and p38 MAPK total proteins and MYPT1 phosphorylation. In conclusion, beyond the fact that IN4CPBD induces melanoma cell apoptosis at cytotoxic dose, the interruption in the VEGF expression and the SDF-1α-related signaling at cytostatic dose may partially constitute the rationale for its in vivo anti-metastatic potency. |
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Authors:
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Ming-Chu Hsieh; Wan-Ping Hu; Hsin-Su Yu; Wen-Chuan Wu; Long-Sen Chang; Ying-Hsien Kao; Jeh-Jeng Wang |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2011-06-25 |
Journal Detail:
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Title: Toxicology and applied pharmacology Volume: 255 ISSN: 1096-0333 ISO Abbreviation: Toxicol. Appl. Pharmacol. Publication Date: 2011 Sep |
Date Detail:
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Created Date: 2011-08-15 Completed Date: 2011-10-26 Revised Date: 2012-02-29 |
Medline Journal Info:
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Nlm Unique ID: 0416575 Medline TA: Toxicol Appl Pharmacol Country: United States |
Other Details:
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Languages: eng Pagination: 150-9 Citation Subset: IM |
Copyright Information:
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Copyright © 2011 Elsevier Inc. All rights reserved. |
Affiliation:
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Graduate Institute of Pharmacy, Faculty of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Agents
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pharmacology* Apoptosis / drug effects Benzodiazepines / pharmacology* Blotting, Western Caspases / metabolism Cell Cycle / drug effects Cell Line, Tumor Cell Movement / drug effects* Chemokine CXCL12 / metabolism* Flow Cytometry Humans Indoles / pharmacology* Melanoma / drug therapy*, pathology Organophosphorus Compounds / pharmacology* Protein Kinase Inhibitors / pharmacology Pyrroles / pharmacology*, therapeutic use Signal Transduction / drug effects Vascular Endothelial Growth Factor A / biosynthesis |
| Chemical | |
Reg. No./Substance:
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0/(11aS)-8-hydroxy-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo(2,1-c)(1,4)benzodiazepin-5-one; 0/Antineoplastic Agents; 0/Chemokine CXCL12; 0/Indoles; 0/Organophosphorus Compounds; 0/Protein Kinase Inhibitors; 0/Pyrroles; 0/VEGFA protein, human; 0/Vascular Endothelial Growth Factor A; 12794-10-4/Benzodiazepines; EC 3.4.22.-/Caspases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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