Abstract
BackgroundDCB-3503, a tylophorine analog, inhibits the growth of PANC-1 (human pancreatic ductal cancer cell line) and HepG2 (human hepatocellular cancer cell line) tumor xenografts in nude mice. The inhibition of growth leads to cancer cell differentiation instead of cell death. However, the mechanisms of action of tylophorine analogs is unknown.Methodology/Principal FindingsIn this study, we show that DCB-3503 suppresses the expression of pro-oncogenic or pro-survival proteins with short half-lives, including cyclin D1, survivin, β-catenin, p53, and p21, without decreasing their mRNA levels. Proteasome inhibitor reversed the inhibitory effect of DCB-3503 on expression of these proteins. DCB-3503 inhibited the incorporation of radiolabeled amino acid and thymidine, and to a much lesser degree of uridine, in a panel of cell lines. The mechanism of inhibition of protein synthesis is different from that of cycloheximide (CHX) as assayed in cell culture and HeLa in vitro translation system. Furthermore, in contrast to rapamycin, DCB-3503 does not affect protein synthesis through the mTOR pathway. DCB-3503 treatment shifts the sedimentation profiles of ribosomes and mRNAs towards the polysomal fractions while diminishing monosome abundance, indicative of the inhibition of the elongation step of protein synthesis. Preferential down regulation of several studied proteins under these conditions is likely due to the relative short half-lives of these proteins.Conclusion/SignificanceThe inhibitory effect of DCB-3503 on translation is apparently distinct from any of the current anticancer compounds targeting protein synthesis. Translation inhibitors with novel mechanism could complement current chemotherapeutic agents for the treatment of human cancers and suppress the occurrence of drug resistance.
Highlights
Tylophorine analogs are phenanthroindolizidine alkaloids, their pharmacological actions were first described in 1935 [1]
This study demonstrates that cyclin D1 protein could be downregulated as early as 15 minutes after DCB-3503 treatment (Fig. 1)
Availability of cyclin D1 mRNA remain unchanged under similar condition (Fig. 2A and B)
Summary
Tylophorine analogs are phenanthroindolizidine alkaloids, their pharmacological actions were first described in 1935 [1]. Evaluation of (+)-(S)tylophorine [DCB-3500 (NSC-717335)] and its analog DCB3503 (NSC-716802) (Fig. 1A) in the antitumor screen at the National Cancer Institute (NCI) showed a fairly consistent and potent growth inhibitory activity (GI50 ,1028 M) in all 60 cancer cell lines, with notable selectivity toward several cell lines, such as melanoma and lung tumor cell lines [5]. DCB-3503 has suppressive activity against HepG2 and PANC-1 tumor xenografts in nude mice [5,6]. It could decrease clonogenic activity of HepG2 and PANC-1 cells [5,6,7]. DCB-3503, a tylophorine analog, inhibits the growth of PANC-1 (human pancreatic ductal cancer cell line) and HepG2 (human hepatocellular cancer cell line) tumor xenografts in nude mice.
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