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Oridonin induces apoptosis and senescence in colorectal cancer cells by increasing histone hyperacetylation and regulation of p16, p21, p27 and c-myc.

Gao FH, Hu XH, Li W, Liu H, Zhang YJ, Guo ZY, Xu MH, Wang ST, Jiang B, Liu F, Zhao YZ, Fang Y, Chen FY, Wu YL - BMC Cancer (2010)

Bottom Line: Senescent cells were determined by senescence-associated β-galactosidase activity analysis.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: NO 3 People's Hospital affiliated to Shanghai Jiao-Tong University School of Medicine, Shanghai 201900, PR China.

ABSTRACT

Background: Oridonin, a tetracycline diterpenoid compound, has the potential antitumor activities. Here, we evaluate the antitumor activity and action mechanisms of oridonin in colorectal cancer.

Methods: Effects 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.

Results: Oridonin 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.

Conclusion: Oridonin 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.

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Oridonin inhibits cell proliferation of colorectal cancer cells. (A) Chemical structure of oridonin. (B), (C) and (D) HCT116, HT29 and SW1116 cells were treated with 0, 6.25, 12.5, 25, 50 100 μM oridonin for 1, 2 and 3 days. Effects of oridonin on cell proliferation were determined by using a CCK-8 Kit. Error bars represent SD of experiments.
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Figure 1: Oridonin inhibits cell proliferation of colorectal cancer cells. (A) Chemical structure of oridonin. (B), (C) and (D) HCT116, HT29 and SW1116 cells were treated with 0, 6.25, 12.5, 25, 50 100 μM oridonin for 1, 2 and 3 days. Effects of oridonin on cell proliferation were determined by using a CCK-8 Kit. Error bars represent SD of experiments.

Mentions: To investigate the possible effect of oridonin on the proliferation of colorectal cancer cells, three colorectal cancer cell lines HCT116, HT29, SW1116 were used. As shown in Figure 1, oridonin could inhibit proliferation of the three colorectal cancer cells in a time- and dose-dependent manner. These tumor cells showed different sensitivity to the oridonin treatment. It seemed that HT29 cells are more sensitive to oridonin treatment than HCT116 and SW1116 cells. The growth of HT29 cells was greatly inhibited by oridonin at 6.25 μM for 24 hours, which become more obvious on day 3. However, 12.5 μM oridonin was needed to obtain 50% inhibition in HCT1116 and SW1116 cells on day 3. At 25 μM, growth of all three colorectal cancer cell lines was completely inhibited.


Oridonin induces apoptosis and senescence in colorectal cancer cells by increasing histone hyperacetylation and regulation of p16, p21, p27 and c-myc.

Gao FH, Hu XH, Li W, Liu H, Zhang YJ, Guo ZY, Xu MH, Wang ST, Jiang B, Liu F, Zhao YZ, Fang Y, Chen FY, Wu YL - BMC Cancer (2010)

Oridonin inhibits cell proliferation of colorectal cancer cells. (A) Chemical structure of oridonin. (B), (C) and (D) HCT116, HT29 and SW1116 cells were treated with 0, 6.25, 12.5, 25, 50 100 μM oridonin for 1, 2 and 3 days. Effects of oridonin on cell proliferation were determined by using a CCK-8 Kit. Error bars represent SD of experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2992521&req=5

Figure 1: Oridonin inhibits cell proliferation of colorectal cancer cells. (A) Chemical structure of oridonin. (B), (C) and (D) HCT116, HT29 and SW1116 cells were treated with 0, 6.25, 12.5, 25, 50 100 μM oridonin for 1, 2 and 3 days. Effects of oridonin on cell proliferation were determined by using a CCK-8 Kit. Error bars represent SD of experiments.
Mentions: To investigate the possible effect of oridonin on the proliferation of colorectal cancer cells, three colorectal cancer cell lines HCT116, HT29, SW1116 were used. As shown in Figure 1, oridonin could inhibit proliferation of the three colorectal cancer cells in a time- and dose-dependent manner. These tumor cells showed different sensitivity to the oridonin treatment. It seemed that HT29 cells are more sensitive to oridonin treatment than HCT116 and SW1116 cells. The growth of HT29 cells was greatly inhibited by oridonin at 6.25 μM for 24 hours, which become more obvious on day 3. However, 12.5 μM oridonin was needed to obtain 50% inhibition in HCT1116 and SW1116 cells on day 3. At 25 μM, growth of all three colorectal cancer cell lines was completely inhibited.

Bottom Line: Senescent cells were determined by senescence-associated β-galactosidase activity analysis.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: NO 3 People's Hospital affiliated to Shanghai Jiao-Tong University School of Medicine, Shanghai 201900, PR China.

ABSTRACT

Background: Oridonin, a tetracycline diterpenoid compound, has the potential antitumor activities. Here, we evaluate the antitumor activity and action mechanisms of oridonin in colorectal cancer.

Methods: Effects 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.

Results: Oridonin 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.

Conclusion: Oridonin 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.

Show MeSH
Related in: MedlinePlus