Abstract
BackgroundOridonin, a tetracycline diterpenoid compound, has the potential antitumor activities. Here, we evaluate the antitumor activity and action mechanisms of oridonin in colorectal cancer.MethodsEffects of oridonin on cell proliferation were determined by using a CCK-8 Kit. Cell cycle distribution was determined by flow cytometry. Apoptosis was examined by analyzing subdiploid population and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. Senescent cells were determined by senescence-associated β-galactosidase activity analysis. Semi-quantitative RT-PCR was used to examine the changes of mRNA of p16, p21, p27 and c-myc. The concomitant changes of protein expression were analyzed with Western blot. Expression of AcH3 and AcH4 were examined by immunofluorescence staining and Western blots. Effects of oridonin on colony formation of SW1116 were examined by Soft Agar assay. The in vivo efficacy of oridonin was detected using a xenograft colorectal cancer model in nude mice.ResultsOridonin induced potent growth inhibition, cell cycle arrest, apoptosis, senescence and colony-forming inhibition in three colorectal cancer cell lines in a dose-dependent manner in vitro. Daily i.p. injection of oridonin (6.25, 12.5 or 25 mg/kg) for 28 days significantly inhibited the growth of SW1116 s.c. xenografts in BABL/C nude mice. With western blot and reverse transcription-PCR, we further showed that the antitumor activities of oridonin correlated with induction of histone (H3 and H4) hyperacetylation, activation of p21, p27 and p16, and suppression of c-myc expression.ConclusionOridonin possesses potent in vitro and in vivo anti-colorectal cancer activities that correlated with induction of histone hyperacetylation and regulation of pathways critical for maintaining growth inhibition and cell cycle arrest. Therefore, oridonin may represent a novel therapeutic option in colorectal cancer treatment.
Highlights
Oridonin, a tetracycline diterpenoid compound, has the potential antitumor activities
We found that oridonin could induce potent growth inhibition, cell cycle arrest, apoptosis and senescence of colorectal cancer cells in vitro and in vivo
Oridonin suppresses colorectal cell proliferation To investigate the possible effect of oridonin on the proliferation of colorectal cancer cells, three colorectal cancer cell lines HCT116, HT29, SW1116 were used
Summary
A tetracycline diterpenoid compound, has the potential antitumor activities. We evaluate the antitumor activity and action mechanisms of oridonin in colorectal cancer. The terpenoids constitute the largest family of natural products; over 22,000 individual compounds of this class have been described, and the number of defined structures has doubled every decade since the 1970s [6]. Terpenoids represent a chemical defense against environmental stress and provide a repair mechanism for wounds and injuries. Effective ingredients in several plant-derived medicinal extracts are terpenoid compounds of monoterpenoid, sesquiterpenoid, diterpenoid, triterpenoid and carotenoid groups. Plant-derived terpenoids provide a challenging field to identify new potent natural anticancer compound for the therapy of colorectal cancer
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