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Catechins induced acute promyelocytic leukemia cell apoptosis and triggered PML-RARα oncoprotein degradation.

Zhang L, Chen QS, Xu PP, Qian Y, Wang AH, Xiao D, Zhao Y, Sheng Y, Wen XQ, Zhao WL - J Hematol Oncol (2014)

Bottom Line: It has recently been reported that the extracts of green tea polyphenol have cancer preventive effects.Catechins-mediated apoptotic effect was also observed in primary APL cells without affecting normal hematopoietic progenitor cells.Catechins might be a potential candidate for APL treatment by activating intrinsic apoptotic pathway and targeting PML-RARα oncoprotein.

View Article: PubMed Central - PubMed

ABSTRACT

Background: It has recently been reported that the extracts of green tea polyphenol have cancer preventive effects. In this study, we investigated the effect of the natural composition from green tea leaves Catechins on acute promyelocytic leukemia (APL).

Methods: In vitro, APL cell lines NB4, retinoic acid-resistant NB4-R1 and NB4-R2 were treated with different concentrations of Catechins. Cell viability and cell apoptosis were analyzed using MTT assay and flow cytometric assay, respectively. Expression of proteins related to apoptosis and PML-RARα oncoprotein were assessed by Western blot. In vivo anti-tumor activity of Catechins was examined in nude mice xenografted with NB4 cells and in situ cell apoptosis was detected by terminal deoxytransferase-catalyzed DNA nick-end labeling assay.

Results: Catechins at micromolar concentration levels significantly inhibited APL cell proliferation and induced cell apoptosis, in association with mitochondria damage, ROS production and caspase activation. The anti-apoptotic Bcl-2 family member Bcl-xL was down regulated, with pro-apoptotic member Bax remaining unchanged. Moreover, Catechins induced the degradation of PML-RARα oncoprotein. Catechins-mediated apoptotic effect was also observed in primary APL cells without affecting normal hematopoietic progenitor cells. In the murine xenograft model, Catechins remarkably inhibited tumor growth and induced in situ leukemic cell apoptosis.

Conclusions: Catechins might be a potential candidate for APL treatment by activating intrinsic apoptotic pathway and targeting PML-RARα oncoprotein.

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In vivo effect of Catechins on murine models of APL. (A) Catechins decreased the tumor volumes in a murine xenograft model. Nude mice were received 3 Gy radiation one day before subcutaneous injection with NB4 cells. The treatments began 10 days later including control diluent (n = 5) and Catechins (10 mM) (n = 5) daily for 21 days. The tumor volumes of control mice and Catechins-treated mice on Day 31 were measured. Catechins significantly reduced the xenograft tumor volumes (*P < 0.05). (B) Apoptotic cells detected by TdT-FragEL™ DNA Fragmentation Detection kit were calculated. A significantly increased number of apoptotic cells was observed in the Catechins group, comparing with the untreated group ***P<0.001.
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Fig5: In vivo effect of Catechins on murine models of APL. (A) Catechins decreased the tumor volumes in a murine xenograft model. Nude mice were received 3 Gy radiation one day before subcutaneous injection with NB4 cells. The treatments began 10 days later including control diluent (n = 5) and Catechins (10 mM) (n = 5) daily for 21 days. The tumor volumes of control mice and Catechins-treated mice on Day 31 were measured. Catechins significantly reduced the xenograft tumor volumes (*P < 0.05). (B) Apoptotic cells detected by TdT-FragEL™ DNA Fragmentation Detection kit were calculated. A significantly increased number of apoptotic cells was observed in the Catechins group, comparing with the untreated group ***P<0.001.

Mentions: We established the human APL model in nude mice using NB4 cells. NB4 cells (1 × 107) were inoculated subcutaneously into the nude mice (Day 0). The latency of tumor formation at the site of injection was approximately 6–8 days. The mice were then treated with Catechins (10 mM) as the only drinking from Day 10 and tumor volume was measured daily until Day 31. Compared with the untreated group, Catechins significantly reduced the tumor size (P < 0.01) (Figure 5A). During treatment, Catechins-treated mice appeared with better condition than those of the control group. Pathologic analysis at autopsy revealed no tumor infiltration in any of the organs (data not shown).Figure 5


Catechins induced acute promyelocytic leukemia cell apoptosis and triggered PML-RARα oncoprotein degradation.

Zhang L, Chen QS, Xu PP, Qian Y, Wang AH, Xiao D, Zhao Y, Sheng Y, Wen XQ, Zhao WL - J Hematol Oncol (2014)

In vivo effect of Catechins on murine models of APL. (A) Catechins decreased the tumor volumes in a murine xenograft model. Nude mice were received 3 Gy radiation one day before subcutaneous injection with NB4 cells. The treatments began 10 days later including control diluent (n = 5) and Catechins (10 mM) (n = 5) daily for 21 days. The tumor volumes of control mice and Catechins-treated mice on Day 31 were measured. Catechins significantly reduced the xenograft tumor volumes (*P < 0.05). (B) Apoptotic cells detected by TdT-FragEL™ DNA Fragmentation Detection kit were calculated. A significantly increased number of apoptotic cells was observed in the Catechins group, comparing with the untreated group ***P<0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4197244&req=5

Fig5: In vivo effect of Catechins on murine models of APL. (A) Catechins decreased the tumor volumes in a murine xenograft model. Nude mice were received 3 Gy radiation one day before subcutaneous injection with NB4 cells. The treatments began 10 days later including control diluent (n = 5) and Catechins (10 mM) (n = 5) daily for 21 days. The tumor volumes of control mice and Catechins-treated mice on Day 31 were measured. Catechins significantly reduced the xenograft tumor volumes (*P < 0.05). (B) Apoptotic cells detected by TdT-FragEL™ DNA Fragmentation Detection kit were calculated. A significantly increased number of apoptotic cells was observed in the Catechins group, comparing with the untreated group ***P<0.001.
Mentions: We established the human APL model in nude mice using NB4 cells. NB4 cells (1 × 107) were inoculated subcutaneously into the nude mice (Day 0). The latency of tumor formation at the site of injection was approximately 6–8 days. The mice were then treated with Catechins (10 mM) as the only drinking from Day 10 and tumor volume was measured daily until Day 31. Compared with the untreated group, Catechins significantly reduced the tumor size (P < 0.01) (Figure 5A). During treatment, Catechins-treated mice appeared with better condition than those of the control group. Pathologic analysis at autopsy revealed no tumor infiltration in any of the organs (data not shown).Figure 5

Bottom Line: It has recently been reported that the extracts of green tea polyphenol have cancer preventive effects.Catechins-mediated apoptotic effect was also observed in primary APL cells without affecting normal hematopoietic progenitor cells.Catechins might be a potential candidate for APL treatment by activating intrinsic apoptotic pathway and targeting PML-RARα oncoprotein.

View Article: PubMed Central - PubMed

ABSTRACT

Background: It has recently been reported that the extracts of green tea polyphenol have cancer preventive effects. In this study, we investigated the effect of the natural composition from green tea leaves Catechins on acute promyelocytic leukemia (APL).

Methods: In vitro, APL cell lines NB4, retinoic acid-resistant NB4-R1 and NB4-R2 were treated with different concentrations of Catechins. Cell viability and cell apoptosis were analyzed using MTT assay and flow cytometric assay, respectively. Expression of proteins related to apoptosis and PML-RARα oncoprotein were assessed by Western blot. In vivo anti-tumor activity of Catechins was examined in nude mice xenografted with NB4 cells and in situ cell apoptosis was detected by terminal deoxytransferase-catalyzed DNA nick-end labeling assay.

Results: Catechins at micromolar concentration levels significantly inhibited APL cell proliferation and induced cell apoptosis, in association with mitochondria damage, ROS production and caspase activation. The anti-apoptotic Bcl-2 family member Bcl-xL was down regulated, with pro-apoptotic member Bax remaining unchanged. Moreover, Catechins induced the degradation of PML-RARα oncoprotein. Catechins-mediated apoptotic effect was also observed in primary APL cells without affecting normal hematopoietic progenitor cells. In the murine xenograft model, Catechins remarkably inhibited tumor growth and induced in situ leukemic cell apoptosis.

Conclusions: Catechins might be a potential candidate for APL treatment by activating intrinsic apoptotic pathway and targeting PML-RARα oncoprotein.

Show MeSH
Related in: MedlinePlus