Abstract |
Hemiasterlin (Hem) and dolastatin (Dol) are marine natural products which are cytotoxic for cancer cells. Hem, a tripeptide, and Dol, a hexapeptide, were conjugated with linkers (L) to the universal BB agonist DPhe-Gln-Trp-Ala-Val-betaAla-His-Phe-Nle-NH2(BA1) and the effects of the Hem-BB and Dol-BB conjugates investigated on NCI-H1299 lung cancer cells. Hem-LA-BA1 and Hem-LB-BA1 inhibited specific (125I-Tyr4)BB binding to NCI-H1299 cells, which have BB2 receptors (R), with IC50 values of 15 and 25 nM, respectively. Addition of Hem-LA-BA1 and Hem-LB-BA1 to Fura-2 AM loaded cells containing BB2R, caused elevated cytosolic Ca2+. In a growth assay, Hem-LA-BA1 and Hem-LB-BA1 inhibited the proliferation of NCI-H1299 cells. Dol- succinamide (Dols)-LD-BA1 and Dols-LE-BA1 bound with high affinity to NCI-H1299 cells and elevated cytosolic Ca2+, but did not inhibit the proliferation of NCI-H1299 cells. Also, Hem-LA-BA1 inhibited 125I-DTyr-Gln-Trp-Ala-Val-betaAla-His-Phe-Nle-NH2 (BA2) binding to Balb/3T3 cells transfected with BB1R or BB2R as well as with BRS-3 with IC50 values of 130, 8, and 540 nM, respectively. These results show that Hem-BB conjugates are cytotoxic for cancer cells containing BB2R.
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Authors | Terry W Moody, Tapas Pradhan, Samuel A Mantey, Robert T Jensen, Marcin Dyba, Deborah Moody, Nadya I Tarasova, Christopher J Michejda |
Journal | Life sciences
(Life Sci)
Vol. 82
Issue 15-16
Pg. 855-61
(Apr 09 2008)
ISSN: 0024-3205 [Print] Netherlands |
PMID | 18336841
(Publication Type: Journal Article, Research Support, N.I.H., Intramural)
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Chemical References |
- Antineoplastic Agents
- Marine Toxins
- Oligopeptides
- Prodrugs
- Receptors, Drug
- hemiasterlin
- Bombesin
- Calcium
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Topics |
- 3T3 Cells
- Animals
- Antineoplastic Agents
(chemistry, pharmacology)
- Bombesin
(chemistry, pharmacology)
- Calcium
(metabolism)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Cell Survival
(drug effects)
- Cytosol
(metabolism)
- Humans
- Lung Neoplasms
(drug therapy, pathology)
- Marine Toxins
(chemistry, pharmacology)
- Mice
- Oligopeptides
(pharmacology)
- Prodrugs
(pharmacology)
- Protein Binding
- Receptors, Drug
(drug effects)
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