Bombesin marine toxin conjugates inhibit the growth of lung cancer cells.

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.

• 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)

Chemical References

• Antineoplastic Agents
• Marine Toxins
• Oligopeptides
• Prodrugs
• Receptors, Drug
• hemiasterlin
• Bombesin
• Calcium

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)