A DC-81-indole conjugate agent suppresses melanoma A375 cell migration partially via interrupting VEGF production and stromal cell-derived factor-1{alpha}-mediated signaling

Journal Article · Thu Sep 01 00:00:00 EDT 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2011.06.008· OSTI ID:21587833

Hsieh, Ming-Chu ^[1]; Hu, Wan-Ping ^[2]; Yu, Hsin-Su ^[3]; Wu, Wen-Chuan ^[4]; Chang, Long-Sen ^[5]; Kao, Ying-Hsien ^[6]; Wang, Jeh-Jeng ^[1]

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1. Graduate Institute of Pharmacy, Faculty of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan (China)
2. Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan (China)
3. Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan (China)
4. Department of Ophthalmology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan (China)
5. Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan (China)
6. Department of Medical Research, E-DA Hospital, I-Shou University, Kaohsiung, Taiwan (China)

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-1{alpha} (SDF-1{alpha}) stimulated A375 cell motility, while kinase inhibitors treatment confirmed that Rho/ROCK, Akt, ERK1/2, and p38 MAPK pathways were involved in SDF-1{alpha}-enhanced melanoma migration. IN4CPBD not only abolished the SDF-1{alpha}-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-1{alpha}-related signaling at cytostatic dose may partially constitute the rationale for its in vivo anti-metastatic potency. - Research Highlights: > A novel carboxylate-PBD hybrid as anti-melanoma drug. > IN4CPBD interrupts melanoma cell cycle progression and induces apoptosis. > IN4CPBD suppresses SDF-1{alpha}-enhanced signaling and melanoma migration. > IN4CPBD abolishes angiogenic factor production and chemotactic effect of SDF-1{alpha}. > This drug is clinically applicable to melanoma therapy.

• OSTI ID: 21587833
• Journal Information: Toxicology and Applied Pharmacology, Vol. 255, Issue 2; Other Information: DOI: 10.1016/j.taap.2011.06.008; PII: S0041-008X(11)00226-2; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
APOPTOSIS
CARBON
CELL CYCLE
DNA
GROWTH FACTORS
IN VIVO
INDOLES
LUNGS
MELANOMAS
METASTASES
MYOSIN
RECEPTORS
TETRAZOLIUM
TOXICITY
AROMATICS
AZAARENES
AZOLES
BODY
CARCINOMAS
CHLORIDES
CHLORINE COMPOUNDS
DISEASES
ELEMENTS
EPITHELIOMAS
GLOBULINS
HALIDES
HALOGEN COMPOUNDS
HETEROCYCLIC COMPOUNDS
MEMBRANE PROTEINS
MITOGENS
NEOPLASMS
NONMETALS
NUCLEIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
PROTEINS
PYRROLES
RESPIRATORY SYSTEM
TETRAZOLES