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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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Related in: MedlinePlus

Itu induced cell death in p53-dependent and independent manners.A. HCT116 cells (p53+/+ and p53−/−) were treated with various concentrations of Itu for 48 hours and the number of cells were measured by Wst-1 assay. *p<0.05 when p53−/− cells were compared to p53+/+ cells. B. Atm+/+ and Atm−/− MEFs were treated with various concentrations of Itu for 48 hours and the number of cells were measured by Wst-1 assay. *p<0.05 when Atm−/− cells were compared to Atm+/+ cells. C. Wild type and p53−/− HCT116 cells were treated with Itu for 24 hours and the number of cells was measured by Wst-1 assay. Itu did not induce cell death when cells were cultured in 0.1% serum or confluent in wild type HCT116 cells. *p<0.05 when compared to untreated cells.
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pone-0062527-g006: Itu induced cell death in p53-dependent and independent manners.A. HCT116 cells (p53+/+ and p53−/−) were treated with various concentrations of Itu for 48 hours and the number of cells were measured by Wst-1 assay. *p<0.05 when p53−/− cells were compared to p53+/+ cells. B. Atm+/+ and Atm−/− MEFs were treated with various concentrations of Itu for 48 hours and the number of cells were measured by Wst-1 assay. *p<0.05 when Atm−/− cells were compared to Atm+/+ cells. C. Wild type and p53−/− HCT116 cells were treated with Itu for 24 hours and the number of cells was measured by Wst-1 assay. Itu did not induce cell death when cells were cultured in 0.1% serum or confluent in wild type HCT116 cells. *p<0.05 when compared to untreated cells.

Mentions: p53 has a strong proapoptotic role and it has been well established that DNA damage induces cell death mainly through the Atm-p53 pathway. We then tested the cytotoxicity of Itu in HCT116 and the involvement of Itu-induced p53 up-regulation. Itu treatment led to cell death in p53+/+ HCT116 cells (EC50 = 1.88 µM), yet p53−/− HCT116 cells showed resistance to Itu-induced cell death (EC50 = 7.8 µM) (Fig. 6A), suggesting an important role for p53 in mediating Itu-induced cell death. Moreover, Atm deficiency, which is known to diminish p53 induction, also inhibited Itu-induced cell death in MEFs (Fig. 6B) [36], consistent with the well-accepted role for Atm in promoting cell death under genotoxic stress. The less-than complete rescue of cell death by p53 deficiency suggest that Itu might possess cytotoxicity that is independent of p53, for example, by inhibiting pro-survival signaling such as Erk2.


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 induced cell death in p53-dependent and independent manners.A. HCT116 cells (p53+/+ and p53−/−) were treated with various concentrations of Itu for 48 hours and the number of cells were measured by Wst-1 assay. *p<0.05 when p53−/− cells were compared to p53+/+ cells. B. Atm+/+ and Atm−/− MEFs were treated with various concentrations of Itu for 48 hours and the number of cells were measured by Wst-1 assay. *p<0.05 when Atm−/− cells were compared to Atm+/+ cells. C. Wild type and p53−/− HCT116 cells were treated with Itu for 24 hours and the number of cells was measured by Wst-1 assay. Itu did not induce cell death when cells were cultured in 0.1% serum or confluent in wild type HCT116 cells. *p<0.05 when compared to untreated cells.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3646850&req=5

pone-0062527-g006: Itu induced cell death in p53-dependent and independent manners.A. HCT116 cells (p53+/+ and p53−/−) were treated with various concentrations of Itu for 48 hours and the number of cells were measured by Wst-1 assay. *p<0.05 when p53−/− cells were compared to p53+/+ cells. B. Atm+/+ and Atm−/− MEFs were treated with various concentrations of Itu for 48 hours and the number of cells were measured by Wst-1 assay. *p<0.05 when Atm−/− cells were compared to Atm+/+ cells. C. Wild type and p53−/− HCT116 cells were treated with Itu for 24 hours and the number of cells was measured by Wst-1 assay. Itu did not induce cell death when cells were cultured in 0.1% serum or confluent in wild type HCT116 cells. *p<0.05 when compared to untreated cells.
Mentions: p53 has a strong proapoptotic role and it has been well established that DNA damage induces cell death mainly through the Atm-p53 pathway. We then tested the cytotoxicity of Itu in HCT116 and the involvement of Itu-induced p53 up-regulation. Itu treatment led to cell death in p53+/+ HCT116 cells (EC50 = 1.88 µM), yet p53−/− HCT116 cells showed resistance to Itu-induced cell death (EC50 = 7.8 µM) (Fig. 6A), suggesting an important role for p53 in mediating Itu-induced cell death. Moreover, Atm deficiency, which is known to diminish p53 induction, also inhibited Itu-induced cell death in MEFs (Fig. 6B) [36], consistent with the well-accepted role for Atm in promoting cell death under genotoxic stress. The less-than complete rescue of cell death by p53 deficiency suggest that Itu might possess cytotoxicity that is independent of p53, for example, by inhibiting pro-survival signaling such as Erk2.

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