Novel mode of action of tylophorine analogs as antitumor compounds.
Tylophorine and its analogs are phenanthroindolizidine alkaloids, several of which have been isolated from the Tylophora genus of plants. Evaluation of (+)-S-tylophorine [DCB-3500 (NSC-717335)] and its analog DCB-3503 (NSC-716802) in the National Cancer Institute tumor screen showed a fairly uniform and potent inhibition of cell growth in all 60 cell lines (GI(50) approximately 10(-8) M). To further evaluate the antitumor potential of these compounds, we synthesized four tylophorine analogs, designated DCB-3500, DCB-3501, DCB-3502, and DCB-3503. All four tylophorine analogs exerted potent growth-inhibitory effects against HepG2, a human hepatocellular carcinoma cell line, and KB, a human nasopharyngeal carcinoma cell line. HepG2 cells were more sensitive than KB in terms of loss of clonogenicity. KB variants, which are resistant to etoposide, hydroxyurea, or camptothecin, have similar sensitivities to the tylophorine analogs, as do the parental KB cells. Treatment of nude mice bearing HepG2 tumor xenografts by i.p. injections of DCB-3503 at 6 mg/kg every 8 h on days 0 and 3 resulted in significant tumor growth suppression (P < 0.0001). Unlike conventional antitumor drugs, 3 micro M DCB-3503 did not cause DNA breaks or apoptosis in HepG2 cells. Tylophorine analogs induced albumin expression and decreased alpha-fetoprotein expression in HepG2 cells, which suggests that tylophorine analogs could induce HepG2 differentiation. Tylophorine analogs had an inhibitory effect on cyclic AMP response elements, activator protein-1 sites, or nuclear factor-kappaB binding site-mediated transcriptions. In summary, these tylophorine analogs are a unique class of antitumor compounds that have a mode of action different from known antitumor drugs.
Gao
Wenli
W
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA.
Lam
Wing
W
Zhong
Sanbao
S
Kaczmarek
Conrad
C
Baker
David C
DC
Cheng
Yung-Chi
YC
D000470:Alkaloids; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D017930:Genes, Reporter; D006801:Humans; D007212:Indolizines / Q000633:toxicity*; D007624:KB Cells; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D010616:Phenanthrenes; D013329:Structure-Activity Relationship; D014162:Transfection; D014410:Tumor Stem Cell Assay
D000470:Alkaloids; D000970:Antineoplastic Agents; D007212:Indolizines; D010616:Phenanthrenes; C004218:tylophorine