A Novel Bufalin Derivative Exhibited Stronger Apoptosis-Inducing Effect than Bufalin in A549 Lung Cancer Cells and Lower Acute Toxicity in Mice

Liu, Miao; Ling, Feng; Sun, Peng; Liu, Wang; Wu, Wanying; Jiang, Baohong; Yang, Min; Hu, Lihong; Guo, De‐An; Li, Xuan

doi:10.1371/journal.pone.0159789

Cited by 22 publications

(26 citation statements)

References 34 publications

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“…Recent experimental studies have indicated that Chan Su and its active compound bufalin have significant antitumor activity in various cancers. For example, bufalin can inhibit cancer cell proliferation [ 5 , 6 ], induce cancer cell apoptosis and autophagy [ 7 , 8 ], inhibit cancer metastasis and invasion [ 9 , 10 ], and reverse multidrug resistance [ 11 ]. Studies had found that bufalin inhibits GC proliferation, induces apoptosis, and reverses cisplatin resistance [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Bufalin inhibits gastric cancer invasion and metastasis by down-regulating Wnt/ASCL2 expression

et al. 2018

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Achaete-scute-like 2 (ASCL2) is a transcription factor containing a basic helix-loop-helix (bHLH) domain and is a downstream target of Wnt signaling in intestinal stem cells. Bufalin is the primary active ingredient in Chan Su, a traditional Chinese medicine obtained from the skin and parotid venom glands of toads. The purpose of this study was to research the anti-invasion and anti-metastasis activity of bufalin in gastric cancer and to identify the potential mechanism. Bufalin inhibited gastric cancer cell invasion and metastasis, suppressed cancer cell colony formation, and inhibited the growth of subcutaneous xenografted tumors in nude mice. Furthermore, bufalin inhibited ASCL2 expression and down-regulated the expression of invasion-related genes such as MMP2, MMP9, and vimentin, thereby suppressing epithelial-mesenchymal transition (EMT) in gastric cancer. A Wnt signaling inhibitor (XAV939) down-regulated invasion and the expression of ASCL2, β-catenin, and vimentin but up-regulated E-cadherin expression. In nude mice, bufalin inhibited the tumorigenic behavior of gastric cancer cells, induced cancer cell apoptosis, and regulated invasion-related gene expression. Together, our results suggest that bufalin arrests invasion and metastasis and that its mechanism of action may involve down-regulating Wnt/ASCL2 expression.

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Section: Introductionmentioning

confidence: 99%

Bufalin inhibits gastric cancer invasion and metastasis by down-regulating Wnt/ASCL2 expression

et al. 2018

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“…However, the concentration inducing cardiotoxicity was estimated as 1 mM which was significantly higher than those exerting anti-tumor effect presented in this manuscript, suggesting clinical usage of bufalin might spare cardiotoxicity. Indeed, there have been several reports showing in vivo findings ( 31 , 32 ). Given the low working concentration of bufalin, as low as nano-molar levels, the achievement of an effective concentration of bufalin should be possible.…”

Section: Discussionmentioning

confidence: 99%

Bufalin induces DNA damage response under hypoxic condition in myeloma cells

et al. 2018

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Hypoxia serves a crucial role in the development of drug resistance in various cancer cells. Therefore, many attempts targeting hypoxia are underway to overcome the drug resistance mediated by hypoxia. This strategy is useful for multiple myeloma (MM) cells, as MM cells reside within the bone marrow, where oxygen concentrations are relatively low. A natural compound library was screened to identify compounds exerting cytotoxicity in MM cells under hypoxic conditions. Bufalin exhibited marked cytotoxicity to MM cells under normoxic and hypoxic conditions. No significant toxicity was observed in lymphocytes obtained from healthy donors. Under normoxic conditions, bufalin induced a DNA double strand break (DSB) response, ROS induction and apoptosis within 24 with a rapid response compared with melphalan. Interestingly, the bufalin-induced DSB response was not impaired by low oxygen concentrations while the DSB response by melphalan was reduced. Furthermore, treatment with bufalin abolished HIF-1α expression under hypoxia, suggesting that bufalin exerts cytotoxicity under hypoxia by regulating HIF-1α. These results indicate that bufalin induces apoptosis in MM cells through DSB under hypoxic conditions by inhibiting HIF-1α, suggesting that bufalin could be useful for eradication of drug-resistant MM cells in the hypoxic microenvironment.

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“…Apart from its function as an ion pump, NKA is also a multifunctional protein in signal transduction, cell junctions, adhesion and motility ( 33 , 34 ). NKA contains four isoforms of the α-subunit (α1, α2, α3 and α4) and three of the β-subunit (β1, β2 and β3) in vertebrates, and the α-subunit of NKA is the active subunit participated in the binding of cardiac steroids and NKA ( 16 , 35 ). Generally, the α1 subunit is widely expressed in various cell types, and the α2 subunit is mostly expressed in the heart muscle, skeletal muscle and brain.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, Bufalin has significant antitumour activity in a wide spectrum of tumour models, such as the inhibition of cell proliferation and angiogenesis, induction of cell differentiation and apoptosis, disruption of the cell cycle, reversal of multidrug resistance and modulation of the immune response ( 13 , 14 ). Numerous studies have indicated that NKA is a main target of Bufalin, and an aberrantly expressed NKA subunit is tightly associated with cell apoptosis and proliferation in several cancers ( 15 , 16 ). However, the effect of Bufalin on cell proliferation and apoptosis of bladder cancer cells has not been thoroughly clarified, and the underlying mediating mechanisms such as antitumour effects remain to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Bufalin induced apoptosis of bladder carcinoma cells through the inactivation of Na+K+‑ATPase

Huang

Zhang

2018

Oncol Lett

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Bufalin has been demonstrated to possess a wide range of pharmacological effects. Among these is its antitumour effect, which has been confirmed in multiple organs or tissues and provoked many concerns. However, its cytostatic effect and underlying mechanism in bladder cancer has not thoroughly been elucidated. This study aimed to investigate the hypothesis that Bufalin induces cell apoptosis and inhibits cell growth in bladder cancer through the inactivation of Na+/K+-ATPase (NKA). In the current study, it was demonstrated that Bufalin remarkably inhibited cell viability and induced cell apoptosis in bladder cancer cell line T24. Subsequently, we found that the expression of NKA was significantly supressed in Bufalin-treated cells and the NKA-α3 isoform was most sensitive to Bufalin among all α subunits of NKA. By transfection with NKA-α3 overexpressing plasmids, the expression of the NKA-α3 subunit was upregulated and NKA-α3 overexpression was found to markedly attenuated Bufalin-induced cell apoptosis in T24 cells, suggesting NKA-α3 played a critical role in Bufalin-induced cell apoptosis. Taken together, the present study confirmed that Bufalin promotes tumour apoptosis and inhibits tumour growth in bladder cancer in vitro, and this antitumour effect may be ascribed to the inactivation of NKA.

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A Novel Bufalin Derivative Exhibited Stronger Apoptosis-Inducing Effect than Bufalin in A549 Lung Cancer Cells and Lower Acute Toxicity in Mice

Cited by 22 publications

References 34 publications

Bufalin inhibits gastric cancer invasion and metastasis by down-regulating Wnt/ASCL2 expression

Bufalin inhibits gastric cancer invasion and metastasis by down-regulating Wnt/ASCL2 expression

Bufalin induces DNA damage response under hypoxic condition in myeloma cells

Bufalin induced apoptosis of bladder carcinoma cells through the inactivation of Na+K+‑ATPase

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