Molecular mechanisms of bufadienolides and their novel strategies for cancer treatment

Deng, Lijuan; Li, Yong; Qi, Ming; Liu, Junshan; Wang, Sheng; Hu, Lijun; Lei, Yuhe; Jiang, Ren‐Wang; Chen, Weimin; Qi, Qi; Tian, Hai‐Yan; Wu, Han; Wu, Baojian; Chen, Jiaxu; Ye, Wen‐Cai; Zhang, Dongmei

doi:10.1016/j.ejphar.2020.173379

Cited by 31 publications

(23 citation statements)

References 152 publications

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“…Bufadienolide glycosides, orbicusides A-C, and tyledoside C, are cardiac glycosides that have been identified as the toxic principles of C. orbiculata (Steyn et al, 1999). Although cardiac glycosides are not associated with wound healing they have been shown to exert anti-inflammatory activity (Deng et al, 2020;Jansson et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the wound healing properties of South African medicinal plants using zebrafish and in vitro bioassays

Mhlongo

Cordero-Maldonado

Crawford

et al. 2022

Journal of Ethnopharmacology

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Section: Discussionmentioning

confidence: 99%

Evaluation of the wound healing properties of South African medicinal plants using zebrafish and in vitro bioassays

Mhlongo

Cordero-Maldonado

Crawford

et al. 2022

Journal of Ethnopharmacology

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“…However, due to limited supply of the natural raw drug material and difficulties in controlling drug composition and quality, it is impossible to develop cinobufacini as a therapeutic drug for cancer treatment. The bufadienolide glycosides cinobufagin and bufalin have been shown to be the major responsible pharmacological compounds in cinobufacini [ 29 , 30 , 35 , 42 ]. As pure compounds, cinobufagin and bufalin have both demonstrated potent anticancer activity, which establishes them as promising candidates for developing effective anticancer drugs [ 35 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

“…The bufadienolide glycosides cinobufagin and bufalin have been shown to be the major responsible pharmacological compounds in cinobufacini [ 29 , 30 , 35 , 42 ]. As pure compounds, cinobufagin and bufalin have both demonstrated potent anticancer activity, which establishes them as promising candidates for developing effective anticancer drugs [ 35 , 42 ]. However, they have also displayed other bioactivities including Na + /K + -ATPase inhibition [ 34 ], cardiotoxicity [ 43 ], generation of ROS [ 44 ], and inhibition of the PI3K/Akt/mTOR [ 45 , 46 ], MAPK [ 47 ], Notch [ 48 ], Wnt/β-catenin [ 49 ] and STAT3 [ 50 , 51 ] signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Cinobufagin-induced DNA damage response activates G2/M checkpoint and apoptosis to cause selective cytotoxicity in cancer cells

et al. 2021

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Background Processed extracts from toad skin and parotoid gland have long been used to treat various illnesses including cancer in many Asian countries. Recent studies have uncovered a family of bufadienolides as the responsible pharmacological compounds, and the two major molecules, cinobufagin and bufalin, have been shown to possess robust antitumor activity; however, the underlying mechanisms remain poorly understood. Methods Intracellular reactive oxygen species (ROS) were measured by DCFH-DA staining and flow cytometry, and DNA damage was analyzed by immunofluorescent staining and the alkaline comet assay. Cytotoxicity was measured by MTT as well as colony formation assays, and cell cycle and apoptosis were analyzed by flow cytometry. In addition, apoptosis was further characterized by TUNEL and mitochondrial membrane potential assays. Results Here we showed that sublethal doses of cinobufagin suppressed the viability of many cancer but not noncancerous cell lines. This tumor-selective cytotoxicity was preceded by a rapid, cancer-specific increase in cellular ROS and was significantly reduced by the ROS inhibitor N-acetyl cysteine (NAC), indicating oxidative stress as the primary source of cinobufagin-induced cancer cell toxicity. Sublethal cinobufagin-induced ROS overload resulted in oxidative DNA damage and intense replication stress in cancer cells, leading to strong DNA damage response (DDR) signaling. Subsequent phosphorylation of CDC25C and stabilization of p53 downstream of DDR resulted in activation of the G2/M checkpoint followed by induction of apoptosis. These data indicate that cinobufagin suppresses cancer cell viability via DDR-mediated G2 arrest and apoptosis. Conclusion As elevated oxidative pressure is shared by most cancer cells that renders them sensitive to further oxidative insult, these studies suggest that nontoxic doses of cinobufagin can be used to exploit a cancer vulnerability for induction of cancer-specific cytotoxicity.

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“…However, due to limited supply of the natural raw drug material and di culties in controlling drug composition and quality, it is impossible to develop cinobufacini as a therapeutic drug for cancer treatment. The bufadienolide glycosides cinobufagin and bufalin have been shown to be the major responsible pharmacological compounds in cinobufacini [29,30,35,42]. As pure compounds, cinobufagin and bufalin have both demonstrated potent anticancer activity, which establishes them as promising candidates for developing effective anticancer drugs [35,42].…”

Section: Discussionmentioning

confidence: 99%

“…The bufadienolide glycosides cinobufagin and bufalin have been shown to be the major responsible pharmacological compounds in cinobufacini [29,30,35,42]. As pure compounds, cinobufagin and bufalin have both demonstrated potent anticancer activity, which establishes them as promising candidates for developing effective anticancer drugs [35,42]. However, they have also displayed other bioactivities including Na + /K + -ATPase inhibition [34], cardiotoxicity [43], generation of ROS [44], and inhibition of the PI3K/Akt/mTOR [45,46], MAPK [47], Notch [48], Wnt/b-catenin [49] and STAT3 [50,51] signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Cinobufagin-Induced DNA Damage Response Activates G2/M Checkpoint and Apoptosis to Cause Selective Cytotoxicity in Cancer Cells

Niu

Wang

Zhang

et al. 2021

Preprint

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Background: Processed extracts from toad skin and parotoid gland have long been used to treat various illnesses including cancer in many Asian countries. Recent studies have uncovered a family of bufadienolides as the responsible pharmacological compounds, and the two major molecules, cinobufagin and bufalin, have been shown to possess robust antitumor activity; however, the underlying mechanisms remain poorly understood.Methods: Intracellular reactive oxygen species (ROS) were measured by DCFH-DA staining and flow cytometry, and DNA damage was analyzed by immunofluorescent staining and the alkaline comet assay. Cytotoxicity was measured by MTT as well as colony formation assays, and cell cycle and apoptosis were analyzed by flow cytometry. In addition, apoptosis was further characterized by TUNEL and mitochondrial membrane potential assays. Results: Here we showed that sublethal doses of cinobufagin suppressed the viability of many cancer but not noncancerous cell lines. This tumor-selective cytotoxicity was preceded by a rapid, cancer-specific increase in cellular ROS and was significantly reduced by the ROS inhibitor N-acetyl cysteine (NAC), indicating oxidative stress as the primary source of cinobufagin-induced cancer cell toxicity. Sublethal cinobufagin-induced ROS overload resulted in oxidative DNA damage and intense replication stress in cancer cells, leading to strong DNA damage response (DDR) signaling. Subsequent phosphorylation of CDC25C and stabilization of p53 downstream of DDR resulted in activation of the G2/M checkpoint followed by induction of apoptosis. These data indicate that cinobufagin suppresses cancer cell viability via DDR-mediated G2 arrest and apoptosis.Conclusion: As elevated oxidative pressure is shared by most cancer cells that renders them sensitive to further oxidative insult, these studies suggest that nontoxic doses of cinobufagin can be used to exploit a cancer vulnerability for induction of cancer-specific cytotoxicity.

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Molecular mechanisms of bufadienolides and their novel strategies for cancer treatment

Cited by 31 publications

References 152 publications

Evaluation of the wound healing properties of South African medicinal plants using zebrafish and in vitro bioassays

Evaluation of the wound healing properties of South African medicinal plants using zebrafish and in vitro bioassays

Cinobufagin-induced DNA damage response activates G2/M checkpoint and apoptosis to cause selective cytotoxicity in cancer cells

Cinobufagin-Induced DNA Damage Response Activates G2/M Checkpoint and Apoptosis to Cause Selective Cytotoxicity in Cancer Cells

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