Cytostatic mechanism and antitumor potential of novel 1H-cyclopenta[b]benzofuran lignans isolated from Aglaia elliptica.
A total of five 1H-cyclopenta[b]benzofuran lignans (1-5) isolated from the stems of Aglaia elliptica B1. (Meliaceae) inhibited the growth of human cancer cells in culture. Of particular note, the IC50 values observed with 1 (methyl rocaglate), 2 (4'-demethoxy-3',4'-methylenedioxy-methyl rocaglate) and 5 (1-O-formyl-4'-demethoxy-3',4'-methylenedioxy-methyl rocaglate) were in the 1-30 ng/ml range. Prompted by the high potency of these responses, additional studies were performed with 2, a structurally representative isolate that was available in sufficient quantity as a result of the isolation process. Utilizing cultured Lu1 (human lung carcinoma) cells as a model, compound 2 induced accumulation in the G1/G0 phase of the cell cycle after 24 or 32 h of incubation; normal cell-cycle dynamics were observed at subsequent time periods. Cell proliferation was inhibited in a dose-dependent manner, but during the course of wash-out experiments, colony formation was not reduced. In addition, as judged by [3H]leucine incorporation, the test compound strongly inhibited protein biosynthesis (IC50 = 25 ng/ml). In analogous studies, nucleic acid biosynthesis was not reduced, even when cells were treated with concentrations as high as 1 microg/ml. These data suggest inhibition of protein synthesis is a key mode of action, and the compound functions by a cytostatic mechanism. Utilizing a human breast cancer cell line (BC1) sensitive to compound 2 in culture (IC50 = 0.9 ng/ml), an initial assessment of antitumor potential was performed. In accord with the in vitro results, the growth of BC1 in athymic mice was delayed by treatment with compound 2 (10 mg/kg body weight, three times per week, i.p.). Body weight was unaffected and no signs of overt toxicity were observed. However, growth paralleled that of the control group at later time points. Thus, novel 1H-cyclopenta[b]benzofuran lignans are potent cytostatic inhibitors of protein biosynthesis and are capable of delaying tumor growth in an in vivo model. Their full clinical or basic utility requires further investigation.
Lee
S K
SK
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 60612, USA.
Cui
B
B
Mehta
R R
RR
Kinghorn
A D
AD
Pezzuto
J M
JM
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology*; D001572:Benzofurans / Q000302:isolation & purification / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D010946:Plants, Medicinal / Q000737:chemistry*; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D014407:Tumor Cells, Cultured
C116198:4-demethoxy-3',4'-methylenedioxy-methyl rocaglate; D000972:Antineoplastic Agents, Phytogenic; D001572:Benzofurans; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm