Anti-tumor Activity and Apoptosis-regulation Mechanisms of Bufalin in Various Cancers: New Hope for Cancer Patients

Yin, Peihao; Li, Xuan; Qiu, Yanyan; Cai, Jianfeng; Qin, Jianmin; Zhu, Huirong; Li, Qi

doi:10.7314/apjcp.2012.13.11.5339

Cited by 95 publications

(64 citation statements)

References 38 publications

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“…Our findings indicated that BF211 might influence multiple cellular functions, including transcription, translation and protein synthesis. Our results were consistent with previous reports demonstrating that bufalin influences transcription, translation and protein synthesis in cancer cells [7][8][9][10] . Interestingly, we found that BF211 disrupted proteasome function in the present study.…”

Section: Discussionsupporting

confidence: 83%

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Bufalin derivative BF211 inhibits proteasome activity in human lung cancer cells in vitro by inhibiting β1 subunit expression and disrupting proteasome assembly

et al. 2016

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Aim: Bufalin is one of the active components in the traditional Chinese medicine ChanSu that is used to treat arrhythmia, inflammation and cancer. BF211 is a bufalin derivative with stronger cytotoxic activity in cancer cells. The aim of this study was to identify the putative target proteins of BF211 and the signaling pathways in cancer cells. Methods: A549 human lung cancer cells were treated with BF211. A SILAC-based proteomic analysis was used to detect the protein expression profiles of BF211-treated A549 cells. Cellular proteasome activities were examined using fluorogenic peptide substrates, and the binding affinities of BF211 to recombinant proteasome subunit proteins were evaluated using the Biacore assay. The expression levels of proteasome subunits were determined using RT-PCR and Western blotting, and the levels of the integral 26S proteasome were evaluated using native PAGE analysis. Results: The proteomic analysis revealed that 1282 proteins were differentially expressed in BF211-treated A549 cells, and the putative target proteins of BF211 were associated with various cellular functions, including transcription, translation, mRNA splicing, ribosomal protein synthesis and proteasome function. In A549 cells, BF211 (5, 10, and 20 nmol/L) dose-dependently inhibited the enzymatic activities of proteasome. But BF211 displayed a moderate affinity in binding to proteasome β1 subunit and no binding affinity to the β2 and β5 subunits. Moreover, BF211 (0.1, 1, and 10 nmol/L) did not inhibit the proteasome activities in the cell lysates. BF211 (5, 10, and 20 nmol/L) significantly decreased the expression level of proteasome β1 subunit and the levels of integral 26S proteasome in A549 cells. Similarly, knockdown of the β1 subunit with siRNA in A549 cells significantly decreased integral 26S proteasome and proteasome activity. Conclusion: BF211 inhibits proteasome activity in A549 cells by decreasing β1 subunit expression and disrupting proteasome assembly.Keywords: bufalin; ChanSu; cardiac steroids; proteasome β1 subunit; proteasome assembly; A549 human lung cancer cells; In the present study, to identify the possible signaling network activated by BF211 in cancer cells, we conducted a SILAC-based proteomic analysis and compared the protein expression profiles of A549 human lung cancer cells treated with either BF211 or a solvent control. Our findings suggested that BF211 influences proteasome function, and we further evaluated the effects and potential mechanisms mediating this phenomenon.

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Section: Discussionsupporting

confidence: 83%

“…In a previous paper, we reported that BF211 exhibited stronger cytotoxic activity in cancer cells than bufalin [6] . Multiple papers have described the activities of BF and other bufadienolides in cancer cells [7][8][9][10][11][12] ; however, the effects…”

Section: Introductionmentioning

confidence: 99%

Bufalin derivative BF211 inhibits proteasome activity in human lung cancer cells in vitro by inhibiting β1 subunit expression and disrupting proteasome assembly

et al. 2016

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“…There are ~250 substances in the bufadienolide group, including B and CB (17). The bufadienolides have been previously investigated in several studies for their cytotoxic activity, as well as the underlying signaling pathway involved (3)(4)(5)(6). Bufadienolides act primarily through inhibiting the transport enzyme Na + /K + -adenosine triphosphatase (18), thus acting as their signal transducer.…”

Section: Discussionmentioning

confidence: 99%

“…In a previous study, we found that CB was able to significantly induce apoptotic cell death in the human lymphoma U937 cell line at concentrations >0.5 µM (2). In addition, B was demonstrated to significantly induce apoptotic cell death in various cancer cell types at concentrations >0.1 µM (3)(4)(5)(6). The preferential killing of tumor cells by bufadienolides has made them potential candidates for chemotherapeutic research in the last 50 years; however, owing to their structural resemblance to digitalis glycosides, they also act as potent cardiotonic steroids, which increase the contractile force of the heart muscle.…”

Section: Introductionmentioning

confidence: 99%

Hyperthermia and radiation reduce the toxic side-effects of bufadienolides for cancer therapy

et al. 2017

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Abstract. Bufadienolides are constituents of the traditional Chinese medicine Chan Su and are found in toad venom. Cardiovascular side-effects are one of the limiting factors towards developing bufadienolides as chemotherapeutic agents. Thus, in the present study, low doses of bufalin and cinobufotalin, prominent members of the bufadienolides, were investigated for their cytotoxic activity in combination with hyperthermia (HT) or radiation (Rad) therapy. In addition, the underlying mechanism involved was investigated. A DNA fragmentation assay, viability assay and microscopic observation were primarily used to assess the effect of low doses of the two drugs in human lymphoma U937 cells. Furthermore, the effects of these drugs on the mitochondrial membrane potential (MMP) and apoptotic-associated protein activation were investigated. HT/bufadienolide-and RT/bufadienolide-treated samples significantly increased the DNA fragmentation percentile and decreased the MMP, as well as increasing the apoptotic features observed microscopically within a relatively short time (6 h) after treatment. The two combinations affected the expression of important apoptotic markers, including caspase-3 and BH3 interacting domain death agonist. The findings of the current study confirm the additive effect of HT with this group of drugs, directing a novel therapeutic avenue for the clinical use of bufadienolides at lower doses with more restrained cardio toxic side-effects.

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“…Da-Wei Ding 1 , Yong-Hong Zhang 1 *, Xin-En Huang 2 ,Qing An 3 , Xun Zhang 4 (Yin et al, 2012), such as human gastric (Li et al, 2009), hepatocellular (Qi et al, 2011), endometrial and ovarian (Takai et al, 2008), leukemia (Chen et al, 2009) and other malignant cells (Xie et al, 2011). However, whether or not do bufalin inhibit the proliferation of human lung cancer cells and its molecular mechanisms are seldom reported.…”

Section: Bufalin Induces Mitochondrial Pathway-mediated Apoptosis In mentioning

confidence: 99%

Bufalin Induces Mitochondrial Pathway-Mediated Apoptosis in Lung Adenocarcinoma Cells

Ding

Zhang²,

Huang³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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Background: To evaluate the effects of bufalin in A549 human lung adenocarcinoma epithelial cells in vitro and assess the underlying mechanisms. Materials and Methods: Human A549 non-small cell lung cancer (NSCLC) cells were treated with various concentrations of bufalin. Cell proliferation was measured by CCK-8 assay, apoptotic cell percentage was calculated by flow cytometry and morphological change was observed by inverted phase contrast microscopy/transmission electron microscopy. In addition, the membrane potential of mitochondria was detected by JC-1 fluorescence microscopy assay, and the related protein expression of cytochrome C and caspase-3 was analyzed by Western blotting. Results: Bufalin could inhibit the proliferation of A549 cells via induction of apoptosis, with the evidence of characteristic morphological changes in the nucleus and mitochondria. Furthermore, bufalin decreased the mitochondrial membrane potential with up-regulation of cytochrome C in the cytosol, and activation of caspase-3. Conclusions: Bufalin inhibits the proliferation of A549 cells and triggers mitochondria-dependent apoptosis, pointing to therapeutic application for NSCLC.

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Anti-tumor Activity and Apoptosis-regulation Mechanisms of Bufalin in Various Cancers: New Hope for Cancer Patients

Cited by 95 publications

References 38 publications

Bufalin derivative BF211 inhibits proteasome activity in human lung cancer cells in vitro by inhibiting β1 subunit expression and disrupting proteasome assembly

Bufalin derivative BF211 inhibits proteasome activity in human lung cancer cells in vitro by inhibiting β1 subunit expression and disrupting proteasome assembly

Hyperthermia and radiation reduce the toxic side-effects of bufadienolides for cancer therapy

Bufalin Induces Mitochondrial Pathway-Mediated Apoptosis in Lung Adenocarcinoma Cells

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