title: 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.affiliation: Department of Health and Human Services, NCI Office of the Director, CCR, Bethesda, MD 20892 USA. moodyt@mail.nih.gov
authors.forename: Terry W
authors.initials: TW
authors.lastname: Moody
authors.forename: Tapas
authors.initials: T
authors.lastname: Pradhan
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Mantey
authors.forename: Robert T
authors.initials: RT
authors.lastname: Jensen
authors.forename: Marcin
authors.initials: M
authors.lastname: Dyba
authors.forename: Deborah
authors.initials: D
authors.lastname: Moody
authors.forename: Nadya I
authors.initials: NI
authors.lastname: Tarasova
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Michejda
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001839:Bombesin / Q000737:chemistry / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008387:Marine Toxins / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D009842:Oligopeptides / Q000494:pharmacology*; D011355:Prodrugs / Q000494:pharmacology; D011485:Protein Binding; D011955:Receptors, Drug / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D008387:Marine Toxins; D009842:Oligopeptides; D011355:Prodrugs; D011955:Receptors, Drug; C467070:hemiasterlin; D001839:Bombesin; D002118:Calcium