Bufalin enhances radiosensitivity of glioblastoma by suppressing mitochondrial function and DNA damage repair

Zhang, Xin; Huang, Qibing; Wang, Xuehai; Xu, Yangyang; Xu, Ran; Han, Mingzhi; Huang, Bin; Chen, Anjing; Qiu, Chen; Sun, Tao; Wang, Feng; Li, Xingang; Wang, Jian; Zhao, Peng; Wang, Xinyu

doi:10.1016/j.biopha.2017.07.136

Cited by 26 publications

(33 citation statements)

References 30 publications

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“…Isolated bufalin had an antiangiogenic effect, potently inhibiting the proliferation and formation of vascular endothelial cells by inhibiting the G2/M phase of the cell cycle (Lee et al 1997). Bufalin was also observed to induce apoptosis (Watabe et al 1998;Han et al 2007), mitochondrial dysfunction and increase radiosensitivity in glioblastoma cells (Zhang et al 2017) and to reverse acquired resistance to antineoplastic agents (Sun et al 2017). Marinobufagin showed cytotoxic activity in tests with four tumor cell lines (HL-60, HCT-116, OVCAR-8 and SF-295), as well as toxicity, cytotoxicity and genotoxicity in the root meristem of Allium cepa, through changes in root growth, inhibition of mitotic index, and chromosomal aberrations (Machado et al 2018).…”

Section: Resultsmentioning

confidence: 99%

Evaluation of antimutagenic and cytotoxic activity of skin secretion extract of Rhinella marina and Rhaebo guttatus (Anura, Bufonidae)

et al. 2019

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The skin secretion from toads of the Bufonidae family has great potential in the search for new active compounds to be used as drug candidates in treating some diseases, among them cancer. In this context, this study aimed to evaluate the cytotoxic and antimutagenic activity of the parotoid gland secretion extracts of Rhinella marina and Rhaebo guttatus, as well as biochemically analyze transaminases and serum creatinine for liver and renal damage, respectively. Cytotoxicity was performed by the colorimetric method based on MTT (3- [4, 5-dimethyl-2-thiazolyl]-2, 5-diphenyl-2H-tetrazolium bromide) with different concentrations of the extracts in Walker or splenic tumor cell cultures from rats and mice. The micronucleus test was performed with male Swiss mice treated orally with the extracts for 15 days, and then intraperitoneally with N-ethyl-N-nitrosurea (50 mg kg-1). Micronucleated polychromatic erythrocytes (MNPCE) were evaluated in bone marrow. The extracts showed cytotoxic activity in the evaluated cells. There was a significant reduction in the frequency of MNPCE (R. marina = 56% and R. guttatus = 75%, p < 0.001), indicating antimutagenic potential of the extracts. The groups treated only with extract showed an increase in MNPCE frequency, evidencing mutagenic potential. Biochemical analyzes showed no significant difference between treatments. Thus, under our experimental conditions, the extracts of R. marina and R. guttatus skin secretions presented chemopreventive potential for cancer.

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Section: Resultsmentioning

confidence: 99%

Evaluation of antimutagenic and cytotoxic activity of skin secretion extract of Rhinella marina and Rhaebo guttatus (Anura, Bufonidae)

et al. 2019

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“…Bufalin-loaded calcium phosphate/DPPE-polyethylene glycol-epidermal growth factor nanospheres were reported to have antitumor effects in colon cancer via slow release from dialysis membranes ( 39 ). Bufalin inhibits cell proliferation and induces apoptosis via DNA damage, chromatin condensation and endoplasmic reticulum stress ( 37 , 40 - 42 ). However, there remains limited knowledge regarding the potential mechanisms of bufalin, and the substrates of bufalin remain unknown, which hinders our further understanding of the molecular mechanism underlying its antitumor effects, as well as its potential toxicity.…”

Section: Discussionmentioning

confidence: 99%

Bufalin exerts antitumor effects in neuroblastoma via the induction of reactive oxygen species‑mediated apoptosis by targeting the electron transport chain

et al. 2020

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The prognosis of high-risk neuroblastoma remains poor. Clinical first-line drugs for treating neuroblastoma have been developed over the previous half-century; however, progress in the identification of new drugs with high efficiency is required. Bufalin, one of the major components of extracts obtained from the venom of the Chinese toad Bufo gargarizans , which is used to treat heart failure in Asian Pacific countries, has been reported to be a potential drug against multiple types of tumor; however, the detailed mechanisms underlying its antitumor activities remain unclear, largely due to lack of knowledge regarding its targets. In the present study, bufalin was revealed to exhibit potent antitumor effects against neuroblastoma, both in vitro and in vivo , using cell proliferation, colony formation, Transwell migration and flow cytometry assays, as well as a nude mouse subcutaneous xenograft model. Moreover, a chemically modified bufalin probe was designed to identify the potential targets of bufalin in neuroblastoma via chemical proteomics. With this strategy, it was revealed that the electron transport chain (ETC) on the inner membrane of mitochondria may contain potential targets for bufalin, and that bufalin-induced mitochondrial-dependent apoptosis may be caused by disruption of the ETC. Collectively, the present study suggests that bufalin may a promising drug for chemotherapy against neuroblastoma, and provides a foundation for further studies into the antitumor mechanisms of bufalin.

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“…Certain agents utilized for cancer therapy, including traditional chemotherapeutic drugs and small-molecule compounds, increase H2A.X levels. The increase in H2A.X is associated with the susceptibility of cancer cells to treatment options (16)(17)(18). In the present study, 2,3-DCPE increased p-H2A.X levels in DLD-1 cells in a time-dependent manner, indicating its DNA-damaging effect.…”

Section: Discussionmentioning

confidence: 99%

Small molecule 2,3‑DCPE induces S phase arrest by activating the ATM/ATR‑Chk1‑Cdc25A signaling pathway in DLD‑1 colon cancer cells

et al. 2020

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In our previous study, it was reported that 2[[3-(2,3-dichlorophenoxy)propyl]amino]ethanol (2,3-DCPE) induces apoptosis and cell cycle arrest. The current study aimed to investigate the molecular mechanism involved in 2,3-DCPE-induced S phase arrest. The results demonstrated that 2,3-DCPE upregulated phosphorylated (p-)H2A histone family member X, a biomarker of DNA damage, in the DLD-1 colon cancer cell line. Western blotting revealed that 2,3-DCPE increased the checkpoint kinase (Chk)1 (Ser317 and Ser345) level and decreased the expression of M-phase inducer phosphatase 1 (Cdc25A) in a time-dependent manner. Subsequently, the results demonstrated that the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia and Rad3-related (ATR) inhibitors wortmannin and caffeine had no effect on the cell cycle; however, the inhibitors partially abrogated 2,3-DCPE-induced S phase arrest. Flow cytometry assays revealed that caffeine (2 mM) reduced the proportion of S phase cells from 83 to 39.6% and that wortmannin (500 nM) reduced the proportion of S phase cells from 83 to 48.2%. Furthermore, wortmannin and caffeine inhibited the 2,3-DCPE-mediated phosphorylation of Chk1 and the degradation of Cdc25A. However, these ATM/ATR inhibitors had limited effect on 2,3-DCPE-induced apoptosis. Taken together, the data of the current study indicated that 2,3-DCPE caused DNA damage in colon cancer cells and that 2,3-DCPE-induced S phase arrest was associated with the activation of the ATM/ATR-Chk1-Cdc25A pathway.

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Bufalin enhances radiosensitivity of glioblastoma by suppressing mitochondrial function and DNA damage repair

Cited by 26 publications

References 30 publications

Evaluation of antimutagenic and cytotoxic activity of skin secretion extract of Rhinella marina and Rhaebo guttatus (Anura, Bufonidae)

Evaluation of antimutagenic and cytotoxic activity of skin secretion extract of Rhinella marina and Rhaebo guttatus (Anura, Bufonidae)

Bufalin exerts antitumor effects in neuroblastoma via the induction of reactive oxygen species‑mediated apoptosis by targeting the electron transport chain

Small molecule 2,3‑DCPE induces S phase arrest by activating the ATM/ATR‑Chk1‑Cdc25A signaling pathway in DLD‑1 colon cancer cells

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