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.