Bufalin Induces the Apoptosis of Acute Promyelocytic Leukemia Cells via the Downregulation of Survivin Expression

Zhu, Zhou; Li, Enze; Liu, Yangyang; Gao, Yu; Sun, Hongzhi; Wáng, Ying; Wang, Zhenghua; Liu, Xiaomei; Wang, Qingjun; Liu, Yunpeng

doi:10.1159/000339424

Cited by 28 publications

(27 citation statements)

References 20 publications

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“…Thus, targeting survivin with small-molecule inhibitors by their anti-sense approaches or natural IAP antagonist mimetics may be an attractive strategy of anti-leukemia treatment. Such agents can either directly induce apoptosis of tumor cells or sensitize them to other cytotoxic agents, hence overcoming drug resistance (31,32). Thereofore, the present study evaluated the effect of AA on survivin in HL-60 cells.…”

Section: Discussionmentioning

confidence: 99%

Apoptosis of HL-60 human leukemia cells induced by Asiatic acid through modulation of B-cell lymphoma 2 family proteins and the mitogen-activated protein kinase signaling pathway

Yan

et al. 2012

Molecular Medicine Reports

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Abstract. The toxicities of conventional chemotherapeutic agents to normal cells restrict their dosage and clinical efficacy in acute leukemia; therefore, it is important to develop novel chemotherapeutics, including natural products, which selectively target cancer-specific pathways. The present study aimed to explore the effect of the chemopreventive agent asiatic acid (AA) on the proliferation and apoptotic rate of the leukemia cell line HL-60 and investigated the mechanisms underlying its anti-tumor activity. The effect of AA on the proliferation of HL-60 cells was evaluated using the MTT assay. Annexin V-fluorescein isothiocyanate/propidium iodide double staining followed by flow cytometric analysis as well as Hoechst 33258 staining were used to analyze the apoptotic rate of the cells. Furthermore, changes of survivin, B-cell lymphoma 2 (Bcl-2), myeloid cell leukemia 1 (Mcl-1), extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 expressions were detected by western blot analysis. AA blocked the growth of HL-60 cells in a dose-and time-dependent manner. The IC 50 -value of AA on HL-60 cells was 46.67±5.08 µmol/l for 24 h. AA induced apoptosis in a dose-dependent manner, which was inhibited in the presence of Z-DEVD-FMK, a specific inhibitor of caspase. The anti-apoptotic proteins Bcl-2, Mcl-1 and survivin were downregulated by AA in a dose-dependent manner. Concurrently, AA inhibited ERK and p38 phosphorylation in a dose-dependent manner, while JNK phosphorylation was not affected. In conclusion, the present study indicated that the p38 and ERK pathways, as well as modulation of Bcl-2 family and survivin proteins were key regulators of apoptosis induced in HL-60 cells in response to AA.

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Section: Discussionmentioning

confidence: 99%

Apoptosis of HL-60 human leukemia cells induced by Asiatic acid through modulation of B-cell lymphoma 2 family proteins and the mitogen-activated protein kinase signaling pathway

Yan

et al. 2012

Molecular Medicine Reports

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“…Bufalin, one of the major components of the Chinese medicine Chan'Su, was shown to exhibit marked anti-tumor activity against leukemia and various types of solid tumor, including prostate cancer, lung cancer and hepatoma (12)(13)(14)(15)(16)(17)(18)(19). This anti-tumor activity is achieved by inhibition of proliferation and induction of apoptosis (18,19).…”

Section: Introductionmentioning

confidence: 99%

“…This anti-tumor activity is achieved by inhibition of proliferation and induction of apoptosis (18,19). Bufalin was shown to be potent against human OS tissues and cell lines via inducing apoptosis (20,21); however, the specific underlying mechanism has remained elusive.…”

Section: Introductionmentioning

confidence: 99%

Bufalin induces apoptosis in the U-2OS human osteosarcoma cell line via triggering the mitochondrial pathway

Chen¹,

Li²,

Li³

et al. 2015

Molecular Medicine Reports

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Abstract. Bufalin has been shown to induce apoptosis in osteosarcoma cells; however, the underlying mechanism has not been elucidated. The purpose of the present study was to investigate whether mitochondria-mediated signaling pathways trigger the process of apoptosis in the U-2OS osteosarcoma cell line. Bufalin inhibited the proliferation and induced apoptosis in U-2OS cells in a time-and dose-dependent manner. Bufalin-induced apoptosis was accompanied with a significant reduction of the mitochondrial membrane potential, release of mitochondrial cytochrome c into the cytosol, activation of caspase-3, caspase-9 and poly(adenosine diphosphate ribose) polymerase, as well as downregulation of B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein. Cyclosporin A, a specific inhibitor of the mitochondrial permeability transition pore, attenuated bufalin-induced apoptosis. In conclusion, the present study revealed that bufalin induced apoptosis in the U-2OS human osteosarcoma cell line via triggering of the mitochondrial pathway.

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“…Owing to the similarity in the chemical structure between bufalin and digoxin, bufalin is expected to have a digoxin-like function (5,6). Bufalin has been shown to induce apoptosis in leukemia and solid tumor cells (5)(6)(7)(8)(9)(10). In recent years, studies have revealed that bufalin could effectively inhibit the proliferation of tumor cells, and also assessed its possible molecular mechanism (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Bufalin induces apoptosis in human esophageal carcinoma ECA109 cells by inhibiting the activation of the mTOR/p70S6K pathway

Ding

Liu²,

Wang

et al. 2018

Oncol Lett

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Abstract. The present study examined whether bufalin could induce human esophageal carcinoma ECA109 cells apoptosis via inhibiting the activation of mechanistic target of rapamycin (mTOR)/p70 S6 kinase (p70S6K) pathway is discussed in this article. The present study used the esophageal squamous cell carcinoma ECA109 cell line to assess the apoptosis-inducing effects of bufalin via inhibition of the mTOR/p70S6K pathways. A plasmid containing the wild-type mTOR gene (wtmTOR) was transfected into ECA109 cells. The levels of p70S6K, phosphorylated (p)-p70S6K, cellular inhibitor of apoptosis-1 (cIAP-1) and Bcl-2-associated death promoter (BAD) in ECA109 cells were examined by western blot analysis, and apoptosis was detected by flow cytometry analysis and Giemsa staining. The results revealed that the expression of p-p70S6K was increased as the time progressed (at 0, 12 and 24 h), and then decreased at 30, 36, 42 and 48 h after transfection. The expression of cIAP-1 was significantly decreased as time progressed following the addition of bufalin, whereas that of BAD was increased. The levels of p-p70S6K and cIAP-1 were significantly higher in the wtmTOR-transfected group than in the control and empty vector-transfected groups, and then reduced following addition of bufalin; however, BAD expression was significantly lower in the wtmTOR-transfected group. The results of flow cytometry revealed the cell cycle of ECA109 was arrested at G 2 /M phase and the apoptotic rate was significantly lower in the wtmTOR-transfected group than in the control and empty vector-transfected groups, and then increased following addition of bufalin. In conclusion, the findings of the present study demonstrated that bufalin induced apoptosis in esophageal carcinoma cells via the inhibition of the mTOR/p70S6K pathway and indicated that treatment with bufalin could be combined with chemotherapy to overcome the resistance of esophageal carcinoma cells to chemotherapeutic-induced apoptosis. IntroductionEsophageal carcinoma, which including squamous cell carcinoma (SCC) and adenocarcinoma, is a common serious malignancy worldwide; it ranks eighth in incidence and fourth in mortality of all cancer types owing to its extremely aggressive nature and the poor survival rate of patients (1-3). The genesis of esophageal carcinoma is a gradual process that combining variety of carcinogenic factors and multiple stages, which includes various physical and chemical factors, the abnormal activation of signaling pathways, disequilibrium of apoptosis regulation and anti-apoptotic signaling. All of these changes result in the loss of normal regulatory mechanisms of cells, culminating in over-proliferation, which leads to the occurrence of cancer (4).Bufalin is a cardiotonic steroid and a component of the traditional Chinese medicine, Chansu, which is obtained from the skin and parotid venom gland of toads (5). Owing to the similarity in the chemical structure between bufalin and digoxin, bufalin is expected to have a digoxin-like function (5,6). Bufalin has be...

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Bufalin Induces the Apoptosis of Acute Promyelocytic Leukemia Cells via the Downregulation of Survivin Expression

Cited by 28 publications

References 20 publications

Apoptosis of HL-60 human leukemia cells induced by Asiatic acid through modulation of B-cell lymphoma 2 family proteins and the mitogen-activated protein kinase signaling pathway

Apoptosis of HL-60 human leukemia cells induced by Asiatic acid through modulation of B-cell lymphoma 2 family proteins and the mitogen-activated protein kinase signaling pathway

Bufalin induces apoptosis in the U-2OS human osteosarcoma cell line via triggering the mitochondrial pathway

Bufalin induces apoptosis in human esophageal carcinoma ECA109 cells by inhibiting the activation of the mTOR/p70S6K pathway

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