Abstract
The mechanism by which vasoactive intestinal peptide (VIP)-ellipticine (E) conjugates are cytotoxic for human lung cancer cells was investigated. VIP-alanyl-leucyl-alanyl-leucyl-alanine (ALALA)-E and VIP-leucyl-alanyl-leucyl-alanine (LALA)-E inhibited (125)I-VIP binding to NCI-H1299 cells with an IC50 values of 0.5 and 0.1 microM, respectively. VIP-ALALA-E and VIP-LALA-E caused elevation of cAMP in NCI-H1299 cells with ED50 values of 0.7 and 0.1 microM. Radiolabeled VIP-LALA-E was internalized at 37 degrees C and delivered the cytotoxic E into NCI-H1299 cells. VIP-LALA-E inhibited the growth of NCI-H1299 cells in vitro. Three days after the addition of VIP-LALA-E to NCI-H1299 cells, cell viability decreased based on trypan blue exclusion and reduced 3H-thymidine uptake. These results suggest that VIP-E conjugates are internalized in lung cancer cells as a result of VPAC1 receptor-mediated endocytosis.
MeSH terms
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cyclic AMP / biosynthesis
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Drug Design
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Ellipticines / chemical synthesis*
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Ellipticines / chemistry
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Ellipticines / pharmacokinetics
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Ellipticines / pharmacology
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Endocytosis
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Humans
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Lung Neoplasms / drug therapy
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Receptors, Vasoactive Intestinal Peptide / agonists
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Receptors, Vasoactive Intestinal Peptide / metabolism
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Receptors, Vasoactive Intestinal Polypeptide, Type I
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Thymidine / metabolism
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Vasoactive Intestinal Peptide / chemical synthesis*
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Vasoactive Intestinal Peptide / chemistry
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Vasoactive Intestinal Peptide / pharmacokinetics
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Vasoactive Intestinal Peptide / pharmacology
Substances
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Antineoplastic Agents
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Ellipticines
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Receptors, Vasoactive Intestinal Peptide
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Receptors, Vasoactive Intestinal Polypeptide, Type I
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ellipticine
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Vasoactive Intestinal Peptide
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Cyclic AMP
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Thymidine