Characterization of the cytotoxic activities of novel analogues of the antitumor agent, lavendamycin.
Lavendamycin is a bacterially derived quinolinedione that displays significant antimicrobial and antitumor activities. However, preclinical development of lavendamycin as an anticancer agent was halted due to the poor aqueous solubility and relatively nonspecific cytotoxic activity of this compound. In this report, we have examined the cytotoxic activities of a series of novel lavendamycin analogues. The cytotoxic activities of these compounds were evaluated in clonogenic survival assays with A549 lung carcinoma cells. Compounds bearing an amide or amine substituent at the R(3) position were the most potent inhibitors of colony formation. MB-97, the most active member of this subgroup, decreased clonogenic outgrowth by 70% at a concentration of 10 n. Treatment of A549 cells with MB-97 led to an increase in p53 protein expression and phosphorylation and a concomitant increase in the expression of the p53 target gene, p21. Exposure of p53-positive cells to MB-97 triggered cell cycle arrest in G(1) and G(2) phases but induced a selective G(2)-phase arrest in p53-negative cells. MB-97 treatment also induced a higher level of apoptosis in p53-null cells relative to their p53-positive counterparts. Finally, MB-97 showed significant cytotoxic activity in the National Cancer Institute's panel of 60 cancer cell lines and antitumor activity in vivo in hollow fiber tumorigenesis assays.
Fang
Yanan
Y
Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27710, USA.
Linardic
Corinne M
CM
Richardson
D Ashley
DA
Cai
Wen
W
Behforouz
Mohammad
M
Abraham
Robert T
RT
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D016195:G2 Phase; D006801:Humans; D015151:Immunoblotting; D008938:Mitosis; D008956:Models, Chemical; D010766:Phosphorylation; D016283:Proto-Oncogene Proteins p21(ras) / Q000096:biosynthesis; D013308:Streptonigrin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D013308:Streptonigrin; C034566:lavendamycin; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)