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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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Related in: MedlinePlus

Catechins induced mitochondrial trans-membrane potential collapse, cytochrome C loss and ROS production in NB4 cells. (A) The inhibitory effect of NB4-R1, NB4-R2 and NB4 cells in response to ATRA (1 μM), As2O3 (1 μM), EGCG (100 μM), ECG (100 μM), EGC (100 μM) and Catechins (100 μM) treatment for 24 and 48 h. (B) Growth inhibition of NB4 cells was significantly abrogated by pan-caspase inhibitor ZVAD-FMK (50 μM). **P < 0.01 comparing with the Catechins group. (C) The mitochrondrial trans-membrane potential was decreased in NB4-R1, NB4-R2 and NB4 cells treated with 100 μM and 200 μM Catechins for 24 h. The numbers below the scatter plots represented the percentage of Rh123 low cells. (D) The mitochondrial cytochrome c was accordingly decreased in NB4-R1, NB4-R2 and NB4 cells treated with 100 μM and 200 μM Catechins for 24 h. (E) ROS generation by Catechins in NB4-R1, NB4-R2 and NB4 cells. DCF-derived fluorescence in untreated and in those treated for 2 h with 200 μM Catechins was shown. *P < 0.05, **P < 0.01, ***P < 0.001 comparing with the untreated cells.
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Fig2: Catechins induced mitochondrial trans-membrane potential collapse, cytochrome C loss and ROS production in NB4 cells. (A) The inhibitory effect of NB4-R1, NB4-R2 and NB4 cells in response to ATRA (1 μM), As2O3 (1 μM), EGCG (100 μM), ECG (100 μM), EGC (100 μM) and Catechins (100 μM) treatment for 24 and 48 h. (B) Growth inhibition of NB4 cells was significantly abrogated by pan-caspase inhibitor ZVAD-FMK (50 μM). **P < 0.01 comparing with the Catechins group. (C) The mitochrondrial trans-membrane potential was decreased in NB4-R1, NB4-R2 and NB4 cells treated with 100 μM and 200 μM Catechins for 24 h. The numbers below the scatter plots represented the percentage of Rh123 low cells. (D) The mitochondrial cytochrome c was accordingly decreased in NB4-R1, NB4-R2 and NB4 cells treated with 100 μM and 200 μM Catechins for 24 h. (E) ROS generation by Catechins in NB4-R1, NB4-R2 and NB4 cells. DCF-derived fluorescence in untreated and in those treated for 2 h with 200 μM Catechins was shown. *P < 0.05, **P < 0.01, ***P < 0.001 comparing with the untreated cells.

Mentions: The anti-leukemia effect of APL cell lines treated by ATRA (1 μM), As2O3 (1 μM), EGCG (100 μM), ECG (100 μM), EGC (100 μM) and Catechins (100 μM) were further compared. As shown in Figure 2A, Catechins, more effiently than its main active components, exhibited a significant growth inhibitory effect as observed in the As2O3 group, indicating that Catechins was equally effective as As2O3.Figure 2


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)

Catechins induced mitochondrial trans-membrane potential collapse, cytochrome C loss and ROS production in NB4 cells. (A) The inhibitory effect of NB4-R1, NB4-R2 and NB4 cells in response to ATRA (1 μM), As2O3 (1 μM), EGCG (100 μM), ECG (100 μM), EGC (100 μM) and Catechins (100 μM) treatment for 24 and 48 h. (B) Growth inhibition of NB4 cells was significantly abrogated by pan-caspase inhibitor ZVAD-FMK (50 μM). **P < 0.01 comparing with the Catechins group. (C) The mitochrondrial trans-membrane potential was decreased in NB4-R1, NB4-R2 and NB4 cells treated with 100 μM and 200 μM Catechins for 24 h. The numbers below the scatter plots represented the percentage of Rh123 low cells. (D) The mitochondrial cytochrome c was accordingly decreased in NB4-R1, NB4-R2 and NB4 cells treated with 100 μM and 200 μM Catechins for 24 h. (E) ROS generation by Catechins in NB4-R1, NB4-R2 and NB4 cells. DCF-derived fluorescence in untreated and in those treated for 2 h with 200 μM Catechins was shown. *P < 0.05, **P < 0.01, ***P < 0.001 comparing with the untreated cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
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Fig2: Catechins induced mitochondrial trans-membrane potential collapse, cytochrome C loss and ROS production in NB4 cells. (A) The inhibitory effect of NB4-R1, NB4-R2 and NB4 cells in response to ATRA (1 μM), As2O3 (1 μM), EGCG (100 μM), ECG (100 μM), EGC (100 μM) and Catechins (100 μM) treatment for 24 and 48 h. (B) Growth inhibition of NB4 cells was significantly abrogated by pan-caspase inhibitor ZVAD-FMK (50 μM). **P < 0.01 comparing with the Catechins group. (C) The mitochrondrial trans-membrane potential was decreased in NB4-R1, NB4-R2 and NB4 cells treated with 100 μM and 200 μM Catechins for 24 h. The numbers below the scatter plots represented the percentage of Rh123 low cells. (D) The mitochondrial cytochrome c was accordingly decreased in NB4-R1, NB4-R2 and NB4 cells treated with 100 μM and 200 μM Catechins for 24 h. (E) ROS generation by Catechins in NB4-R1, NB4-R2 and NB4 cells. DCF-derived fluorescence in untreated and in those treated for 2 h with 200 μM Catechins was shown. *P < 0.05, **P < 0.01, ***P < 0.001 comparing with the untreated cells.
Mentions: The anti-leukemia effect of APL cell lines treated by ATRA (1 μM), As2O3 (1 μM), EGCG (100 μM), ECG (100 μM), EGC (100 μM) and Catechins (100 μM) were further compared. As shown in Figure 2A, Catechins, more effiently than its main active components, exhibited a significant growth inhibitory effect as observed in the As2O3 group, indicating that Catechins was equally effective as As2O3.Figure 2

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