Moody Terry W, Pradhan Tapas, Mantey Samuel A, Jensen Robert T, Dyba Marcin, Moody Deborah, Tarasova Nadya I, Michejda Christopher J
Department of Health and Human Services, NCI Office of the Director, CCR, Bethesda, MD 20892 USA.
Life Sci. 2008 Apr 9;82(15-16):855-61. doi: 10.1016/j.lfs.2008.01.019. Epub 2008 Feb 14.
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.
海鞘素(Hem)和多拉司他汀(Dol)是对癌细胞具有细胞毒性的海洋天然产物。Hem是一种三肽,Dol是一种六肽,它们通过连接子(L)与通用的BB激动剂DPhe-Gln-Trp-Ala-Val-βAla-His-Phe-Nle-NH2(BA1)偶联,并研究了Hem-BB和Dol-BB偶联物对NCI-H1299肺癌细胞的作用。Hem-LA-BA1和Hem-LB-BA1抑制特异性(125I-Tyr4)BB与具有BB2受体(R)的NCI-H1299细胞的结合,IC50值分别为15和25 nM。将Hem-LA-BA1和Hem-LB-BA1添加到含有BB2R的Fura-2 AM负载细胞中,导致胞质Ca2+升高。在生长试验中,Hem-LA-BA1和Hem-LB-BA1抑制NCI-H1299细胞的增殖。多拉司他汀琥珀酰胺(Dols)-LD-BA1和Dols-LE-BA1与NCI-H1299细胞具有高亲和力结合并升高胞质Ca2+,但不抑制NCI-H1299细胞的增殖。此外,Hem-LA-BA1抑制125I-DTyr-Gln-Trp-Ala-Val-βAla-His-Phe-Nle-NH2(BA2)与转染了BB1R或BB2R以及BRS-3的Balb/3T3细胞的结合,IC50值分别为130、8和540 nM。这些结果表明,Hem-BB偶联物对含有BB2R的癌细胞具有细胞毒性。