Novel Mode of Action of Tylophorine Analogs as Antitumor Compounds
Wenli Gao1, Wing Lam1, Sanbao Zhong2, Conrad Kaczmarek2, David C. Baker2 and Yung-Chi Cheng1
1 Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, and
2 Department of Chemistry, The University of Tennessee, Knoxville, Tennessee
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 (GI50 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 ÁM DCB-3503 did not cause DNA breaks or apoptosis in HepG2 cells.
Tylophorine analogs induced albumin expression and decreased -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-B 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.
Cancer Research 64, 678-688, January 15, 2004
Asclepias asthmatica; Cynanchum indicum; Tylophora asthmatica; Tylophora indica
A plant genus of the family ASCLEPIADACEAE. Members contain phenanthro-indolizidine alkaloids.
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