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Tetrandrine induces autophagy and differentiation by activating ROS and Notch1 signaling in leukemia cells.

Liu T, Men Q, Wu G, Yu C, Huang Z, Liu X, Li W - Oncotarget (2015)

Bottom Line: Tetrandrine is a traditional Chinese medicinal herb extract with antitumor effects.The in vivo results indicated that low concentrations of tetrandrine inhibited leukemia cells proliferation and induced autophagy and then facilitated their differentiation, by activating ROS and Notch1 signaling.We suggest that tetrandrine is a potential agent for the treatment of APL by inducing differentiation of leukemia cells.

View Article: PubMed Central - PubMed

Affiliation: College of Life Sciences, Wuhan University, Wuhan, P. R. China.

ABSTRACT
All-trans retinoic acid (ATRA) is a differentiating agent for the treatment of acute promyelocytic leukemia (APL). However, the therapeutic efficacy of ATRA has limitations. Tetrandrine is a traditional Chinese medicinal herb extract with antitumor effects. In this study, we investigated the effects of tetrandrine on human PML-RARα-positive acute promyelocytic leukemia cells. Tetrandrine inhibited tumors in vivo. It induced autophagy and differentiation by triggering ROS generation and activating Notch1 signaling. Tetrandrine induced autophagy and differentiation in M5 type patient primary leukemia cells. The in vivo results indicated that low concentrations of tetrandrine inhibited leukemia cells proliferation and induced autophagy and then facilitated their differentiation, by activating ROS and Notch1 signaling. We suggest that tetrandrine is a potential agent for the treatment of APL by inducing differentiation of leukemia cells.

No MeSH data available.


Related in: MedlinePlus

Tetrandrine induces NB4 cell autophagy and differentiation and represses tumor growth in vivoNB4 cells were inoculated into mice to establish a tumor model, as indicated in the Materials and Methods. Mice bearing tumors were randomly placed into three groups (8 mice /group) and were treated daily with vehicle or tetrandrine (25 mg/kg or 50 mg/kg) for 20 days. Animal weight and tumor volume was measured daily. (A) Mean tumor volumes after treatment. Values represent the means ± SD.*p<0.05. (B) Tumor weight after 20 days of treatment are presented in a scatter plot; the bars represent the ±SD. *p<0.05. (C) The mean values of the mouse body weights. (D) Western blot analysis of tissue lysates isolated from 25 (Tet 25 mg/kg) or 50 mg/kg (Tet 50 mg/kg) tetrandrine-treated or vehicle-treated NB4 cell xenografts. 4 mice in each group have been defined as “1#” to “4#”, respectively. (E) Notch1 (both full length and NICD proteins) levels and CD14 were evaluated by immunohistochemistry in tumor tissues derived from the 50 mg/kg tetrandrine-treated and the control mouse models. Magnification: × 400. (F) MDA level of tumor tissue proteins exacted from NB4 tumor xenografts. *p<0.05.
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Figure 1: Tetrandrine induces NB4 cell autophagy and differentiation and represses tumor growth in vivoNB4 cells were inoculated into mice to establish a tumor model, as indicated in the Materials and Methods. Mice bearing tumors were randomly placed into three groups (8 mice /group) and were treated daily with vehicle or tetrandrine (25 mg/kg or 50 mg/kg) for 20 days. Animal weight and tumor volume was measured daily. (A) Mean tumor volumes after treatment. Values represent the means ± SD.*p<0.05. (B) Tumor weight after 20 days of treatment are presented in a scatter plot; the bars represent the ±SD. *p<0.05. (C) The mean values of the mouse body weights. (D) Western blot analysis of tissue lysates isolated from 25 (Tet 25 mg/kg) or 50 mg/kg (Tet 50 mg/kg) tetrandrine-treated or vehicle-treated NB4 cell xenografts. 4 mice in each group have been defined as “1#” to “4#”, respectively. (E) Notch1 (both full length and NICD proteins) levels and CD14 were evaluated by immunohistochemistry in tumor tissues derived from the 50 mg/kg tetrandrine-treated and the control mouse models. Magnification: × 400. (F) MDA level of tumor tissue proteins exacted from NB4 tumor xenografts. *p<0.05.

Mentions: To evaluate the anti-tumor effects of tetrandrine in vivo, we established NB4 subcutaneous tumor xenograft models with athymic nude mice. Nude mice bearing NB4 tumors (approximate volume 50 mm3) were randomly divided into three groups (8 mice/group) and were intragastrically treated with vehicle or tetrandrine (25 mg/kg or 50 mg/kg) once daily for 20 days. Mouse body weight and tumor size were measured daily. As shown as Fig. 1A, tetrandrine inhibited tumor growth. Consistent with the tumor volume results, tetrandrine treatment also led to a slowed the increase in tumor weight (Fig. 1B). Notably, we found no additional weight loss or other signs of toxicity, even in mice treated with 50 mg/kg tetrandrine for 3 weeks (Fig. 1C). Additionally, Western blot analysis of tumor tissue samples found that tetrandrine increased LC3-II protein levels and activated the Notch1 signaling pathway (Fig. 1D). Moreover, tetrandrine also upregulated CD14 expression on the NB4 cell surface in vivo (Fig. 1E). Additionally, the level of the lipid peroxidation product MDA, used as a presumptive measure of ROS, was increased in tumor tissues upon tetrandrine treatment (Fig. 1F). These observations suggest that tetrandrine exhibited good anti-tumor activity in vivo, and the potential mechanism was associated with the induction of tumor cell autophagy and differentiation by triggering ROS generation and activation of Notch1 signaling.


Tetrandrine induces autophagy and differentiation by activating ROS and Notch1 signaling in leukemia cells.

Liu T, Men Q, Wu G, Yu C, Huang Z, Liu X, Li W - Oncotarget (2015)

Tetrandrine induces NB4 cell autophagy and differentiation and represses tumor growth in vivoNB4 cells were inoculated into mice to establish a tumor model, as indicated in the Materials and Methods. Mice bearing tumors were randomly placed into three groups (8 mice /group) and were treated daily with vehicle or tetrandrine (25 mg/kg or 50 mg/kg) for 20 days. Animal weight and tumor volume was measured daily. (A) Mean tumor volumes after treatment. Values represent the means ± SD.*p<0.05. (B) Tumor weight after 20 days of treatment are presented in a scatter plot; the bars represent the ±SD. *p<0.05. (C) The mean values of the mouse body weights. (D) Western blot analysis of tissue lysates isolated from 25 (Tet 25 mg/kg) or 50 mg/kg (Tet 50 mg/kg) tetrandrine-treated or vehicle-treated NB4 cell xenografts. 4 mice in each group have been defined as “1#” to “4#”, respectively. (E) Notch1 (both full length and NICD proteins) levels and CD14 were evaluated by immunohistochemistry in tumor tissues derived from the 50 mg/kg tetrandrine-treated and the control mouse models. Magnification: × 400. (F) MDA level of tumor tissue proteins exacted from NB4 tumor xenografts. *p<0.05.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4480730&req=5

Figure 1: Tetrandrine induces NB4 cell autophagy and differentiation and represses tumor growth in vivoNB4 cells were inoculated into mice to establish a tumor model, as indicated in the Materials and Methods. Mice bearing tumors were randomly placed into three groups (8 mice /group) and were treated daily with vehicle or tetrandrine (25 mg/kg or 50 mg/kg) for 20 days. Animal weight and tumor volume was measured daily. (A) Mean tumor volumes after treatment. Values represent the means ± SD.*p<0.05. (B) Tumor weight after 20 days of treatment are presented in a scatter plot; the bars represent the ±SD. *p<0.05. (C) The mean values of the mouse body weights. (D) Western blot analysis of tissue lysates isolated from 25 (Tet 25 mg/kg) or 50 mg/kg (Tet 50 mg/kg) tetrandrine-treated or vehicle-treated NB4 cell xenografts. 4 mice in each group have been defined as “1#” to “4#”, respectively. (E) Notch1 (both full length and NICD proteins) levels and CD14 were evaluated by immunohistochemistry in tumor tissues derived from the 50 mg/kg tetrandrine-treated and the control mouse models. Magnification: × 400. (F) MDA level of tumor tissue proteins exacted from NB4 tumor xenografts. *p<0.05.
Mentions: To evaluate the anti-tumor effects of tetrandrine in vivo, we established NB4 subcutaneous tumor xenograft models with athymic nude mice. Nude mice bearing NB4 tumors (approximate volume 50 mm3) were randomly divided into three groups (8 mice/group) and were intragastrically treated with vehicle or tetrandrine (25 mg/kg or 50 mg/kg) once daily for 20 days. Mouse body weight and tumor size were measured daily. As shown as Fig. 1A, tetrandrine inhibited tumor growth. Consistent with the tumor volume results, tetrandrine treatment also led to a slowed the increase in tumor weight (Fig. 1B). Notably, we found no additional weight loss or other signs of toxicity, even in mice treated with 50 mg/kg tetrandrine for 3 weeks (Fig. 1C). Additionally, Western blot analysis of tumor tissue samples found that tetrandrine increased LC3-II protein levels and activated the Notch1 signaling pathway (Fig. 1D). Moreover, tetrandrine also upregulated CD14 expression on the NB4 cell surface in vivo (Fig. 1E). Additionally, the level of the lipid peroxidation product MDA, used as a presumptive measure of ROS, was increased in tumor tissues upon tetrandrine treatment (Fig. 1F). These observations suggest that tetrandrine exhibited good anti-tumor activity in vivo, and the potential mechanism was associated with the induction of tumor cell autophagy and differentiation by triggering ROS generation and activation of Notch1 signaling.

Bottom Line: Tetrandrine is a traditional Chinese medicinal herb extract with antitumor effects.The in vivo results indicated that low concentrations of tetrandrine inhibited leukemia cells proliferation and induced autophagy and then facilitated their differentiation, by activating ROS and Notch1 signaling.We suggest that tetrandrine is a potential agent for the treatment of APL by inducing differentiation of leukemia cells.

View Article: PubMed Central - PubMed

Affiliation: College of Life Sciences, Wuhan University, Wuhan, P. R. China.

ABSTRACT
All-trans retinoic acid (ATRA) is a differentiating agent for the treatment of acute promyelocytic leukemia (APL). However, the therapeutic efficacy of ATRA has limitations. Tetrandrine is a traditional Chinese medicinal herb extract with antitumor effects. In this study, we investigated the effects of tetrandrine on human PML-RARα-positive acute promyelocytic leukemia cells. Tetrandrine inhibited tumors in vivo. It induced autophagy and differentiation by triggering ROS generation and activating Notch1 signaling. Tetrandrine induced autophagy and differentiation in M5 type patient primary leukemia cells. The in vivo results indicated that low concentrations of tetrandrine inhibited leukemia cells proliferation and induced autophagy and then facilitated their differentiation, by activating ROS and Notch1 signaling. We suggest that tetrandrine is a potential agent for the treatment of APL by inducing differentiation of leukemia cells.

No MeSH data available.


Related in: MedlinePlus