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Identification of 5-Iodotubercidin as a genotoxic drug with anti-cancer potential.

Zhang X, Jia D, Liu H, Zhu N, Zhang W, Feng J, Yin J, Hao B, Cui D, Deng Y, Xie D, He L, Li B - PLoS ONE (2013)

Bottom Line: We found that 5-Iodotubercidin could cause DNA damage, verified by induction of DNA breaks and nuclear foci positive for γH2AX and TopBP1, activation of Atm and Chk2, and S15 phosphorylation and up-regulation of p53.Moreover, 5-Iodotubercidin showed anti-tumor activity as it could reduce the tumor size in carcinoma xenograft mouse models in p53-dependent and -independent manners.These findings reveal 5-Iodotubercidin as a novel genotoxic drug that has chemotherapeutic potential.

View Article: PubMed Central - PubMed

Affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.

ABSTRACT
Tumor suppressor p53, which is activated by various stress and oncogene activation, is a target for anti-cancer drug development. In this study, by screening panels of protein kinase inhibitors and protein phosphatase inhibitors, we identified 5-Iodotubercidin as a strong p53 activator. 5-Iodotubercidin is purine derivative and is used as an inhibitor for various kinases including adenosine kinase. We found that 5-Iodotubercidin could cause DNA damage, verified by induction of DNA breaks and nuclear foci positive for γH2AX and TopBP1, activation of Atm and Chk2, and S15 phosphorylation and up-regulation of p53. As such, 5-Iodotubercidin induces G2 cell cycle arrest in a p53-dependent manner. Itu also induces cell death in p53-dependent and -independent manners. DNA breaks were likely generated by incorporation of 5-Iodotubercidin metabolite into DNA. Moreover, 5-Iodotubercidin showed anti-tumor activity as it could reduce the tumor size in carcinoma xenograft mouse models in p53-dependent and -independent manners. These findings reveal 5-Iodotubercidin as a novel genotoxic drug that has chemotherapeutic potential.

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Itu showed anti-tumor activity.A. High dose of Itu resulted in tumor shrinkage in nude mice. p53+/+ and p53−/− HCT116 was injected into nude mice. Two weeks later, Itu was ip injected every day and the tumor size was measured. (n = 5) The tumor volumes at various days were normalized to that of day 1, which was set at 100%. *, p<0.05 when comparing Itu treatment with solvent injection. B. Low dose of Itu resulted in tumor shrinkage in nude mice. p53+/+ and p53−/− HCT116 was injected into nude mice. Two weeks later, Itu was ip injected every day and the tumor size was measured. (n = 5) The tumor volumes at various days were normalized to that of day 1, which was set at 100%. *, p<0.05 when comparing Itu treatment with solvent injection.
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pone-0062527-g007: Itu showed anti-tumor activity.A. High dose of Itu resulted in tumor shrinkage in nude mice. p53+/+ and p53−/− HCT116 was injected into nude mice. Two weeks later, Itu was ip injected every day and the tumor size was measured. (n = 5) The tumor volumes at various days were normalized to that of day 1, which was set at 100%. *, p<0.05 when comparing Itu treatment with solvent injection. B. Low dose of Itu resulted in tumor shrinkage in nude mice. p53+/+ and p53−/− HCT116 was injected into nude mice. Two weeks later, Itu was ip injected every day and the tumor size was measured. (n = 5) The tumor volumes at various days were normalized to that of day 1, which was set at 100%. *, p<0.05 when comparing Itu treatment with solvent injection.

Mentions: The above experiments show that Itu is a genotoxic drug that can inhibit cell proliferation and induce cell death in p53-dependent and independent manners. As such, Itu is likely to have anti-tumor activity. To test this possibility, we used HCT116-initiated colon carcinoma xenograft in nude mice. We found that Itu at 2.5 mg/kg induced rapid tumor regression (Fig. 7A), while the control group still showed marked tumor growth. At this dose, Itu treatment also led to a decrease in the body weights of the mice (down by 6% at the end of treatment), suggesting that Itu has an adverse side effect in vivo. Surprisingly, at this dose of Itu, p53 seems not to play an important role, as p53−/− HCT116-initiated tumor was repressed as well by Itu (Fig. 7A). We then lowered the dose of Itu to 0.625 mg/kg and repeated the experiments. Itu stilled showed an inhibitory effect on tumor growth, yet p53−/− tumors showed resistance to Itu treatment (Fig. 7B). At this dose, the body weights of these mice were not significantly affected. Thus, at low doses, Itu inhibits tumor growth via p53; however, at higher doses, p53-independent pathways might play an important role.


Identification of 5-Iodotubercidin as a genotoxic drug with anti-cancer potential.

Zhang X, Jia D, Liu H, Zhu N, Zhang W, Feng J, Yin J, Hao B, Cui D, Deng Y, Xie D, He L, Li B - PLoS ONE (2013)

Itu showed anti-tumor activity.A. High dose of Itu resulted in tumor shrinkage in nude mice. p53+/+ and p53−/− HCT116 was injected into nude mice. Two weeks later, Itu was ip injected every day and the tumor size was measured. (n = 5) The tumor volumes at various days were normalized to that of day 1, which was set at 100%. *, p<0.05 when comparing Itu treatment with solvent injection. B. Low dose of Itu resulted in tumor shrinkage in nude mice. p53+/+ and p53−/− HCT116 was injected into nude mice. Two weeks later, Itu was ip injected every day and the tumor size was measured. (n = 5) The tumor volumes at various days were normalized to that of day 1, which was set at 100%. *, p<0.05 when comparing Itu treatment with solvent injection.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3646850&req=5

pone-0062527-g007: Itu showed anti-tumor activity.A. High dose of Itu resulted in tumor shrinkage in nude mice. p53+/+ and p53−/− HCT116 was injected into nude mice. Two weeks later, Itu was ip injected every day and the tumor size was measured. (n = 5) The tumor volumes at various days were normalized to that of day 1, which was set at 100%. *, p<0.05 when comparing Itu treatment with solvent injection. B. Low dose of Itu resulted in tumor shrinkage in nude mice. p53+/+ and p53−/− HCT116 was injected into nude mice. Two weeks later, Itu was ip injected every day and the tumor size was measured. (n = 5) The tumor volumes at various days were normalized to that of day 1, which was set at 100%. *, p<0.05 when comparing Itu treatment with solvent injection.
Mentions: The above experiments show that Itu is a genotoxic drug that can inhibit cell proliferation and induce cell death in p53-dependent and independent manners. As such, Itu is likely to have anti-tumor activity. To test this possibility, we used HCT116-initiated colon carcinoma xenograft in nude mice. We found that Itu at 2.5 mg/kg induced rapid tumor regression (Fig. 7A), while the control group still showed marked tumor growth. At this dose, Itu treatment also led to a decrease in the body weights of the mice (down by 6% at the end of treatment), suggesting that Itu has an adverse side effect in vivo. Surprisingly, at this dose of Itu, p53 seems not to play an important role, as p53−/− HCT116-initiated tumor was repressed as well by Itu (Fig. 7A). We then lowered the dose of Itu to 0.625 mg/kg and repeated the experiments. Itu stilled showed an inhibitory effect on tumor growth, yet p53−/− tumors showed resistance to Itu treatment (Fig. 7B). At this dose, the body weights of these mice were not significantly affected. Thus, at low doses, Itu inhibits tumor growth via p53; however, at higher doses, p53-independent pathways might play an important role.

Bottom Line: We found that 5-Iodotubercidin could cause DNA damage, verified by induction of DNA breaks and nuclear foci positive for γH2AX and TopBP1, activation of Atm and Chk2, and S15 phosphorylation and up-regulation of p53.Moreover, 5-Iodotubercidin showed anti-tumor activity as it could reduce the tumor size in carcinoma xenograft mouse models in p53-dependent and -independent manners.These findings reveal 5-Iodotubercidin as a novel genotoxic drug that has chemotherapeutic potential.

View Article: PubMed Central - PubMed

Affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.

ABSTRACT
Tumor suppressor p53, which is activated by various stress and oncogene activation, is a target for anti-cancer drug development. In this study, by screening panels of protein kinase inhibitors and protein phosphatase inhibitors, we identified 5-Iodotubercidin as a strong p53 activator. 5-Iodotubercidin is purine derivative and is used as an inhibitor for various kinases including adenosine kinase. We found that 5-Iodotubercidin could cause DNA damage, verified by induction of DNA breaks and nuclear foci positive for γH2AX and TopBP1, activation of Atm and Chk2, and S15 phosphorylation and up-regulation of p53. As such, 5-Iodotubercidin induces G2 cell cycle arrest in a p53-dependent manner. Itu also induces cell death in p53-dependent and -independent manners. DNA breaks were likely generated by incorporation of 5-Iodotubercidin metabolite into DNA. Moreover, 5-Iodotubercidin showed anti-tumor activity as it could reduce the tumor size in carcinoma xenograft mouse models in p53-dependent and -independent manners. These findings reveal 5-Iodotubercidin as a novel genotoxic drug that has chemotherapeutic potential.

Show MeSH
Related in: MedlinePlus