Cinobufagin inhibits tumor growth by inducing intrinsic apoptosis through AKT signaling pathway in human nonsmall cell lung cancer cells

Zhang, Guangxin; Wang, Chao; Sun, Mei; Li, Jindong; Wang, Bin; Jin, Chengyan; Hua, Peiyan; Song, Ge; Zhang, Yifan; Nguyen, Lisa; Cui, Ranji; Liu, Runhua; Wang, Lizhong; Zhang, Xingyi

doi:10.18632/oncotarget.7898

Cited by 45 publications

(50 citation statements)

References 57 publications

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“…Numerous studies showed that apoptosis or a reciprocal action between apoptosis and autophagy is the major process to control cell fates [8,9,12,24,25]. Interestingly, the findings of this study showed that bufadienolides KB, KA, and BC do not induce cellular apoptosis but only induced cell autophagy.…”

Section: Discussionmentioning

confidence: 57%

“…Cinobufagin induced intrinsic apoptosis through AKT signaling pathway in human non-small cell lung cancer cells, including A549, H1299, H460, and SK-MES-1 [12]. In the clinical cases, 40% of patients suffer from a stage III or IV of non-small cell lung cancer, pancreatic cancer or hepatocellular carcinoma maintained a stable disease with the treatment of bufadienolidescontaining toad venom [13].…”

Section: Introductionmentioning

confidence: 99%

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Three Bufadienolides-Induced Human Lung Cancer CL1-5 Cell Death Mainly through Autophagy

Huang¹,

M²,

Chang³

et al. 2018

Preprint

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Lung cancer is almost the most common cause of cancer death in the world. Clinically, the conventional therapy to eradicate the cancer cells is chemotherapy but a better drug remains required. In this study, the effects of three bufadienolides, kalantuboside B, kalantuboside A and bryotoxin C, isolated from Kalanchoe tubiflora (Harvey) were evaluated and characterized in CL1-5 highly metastatic human lung cancer cells. Contrary to the apoptosis-promoting activity in other cancer cells, these three bufadienolides did not induce apoptosis in CL1-5 cancer cells. Instead, they activated an autophagy pathway, as indicated by the increase of autophagosomes formation. The induction of autophagy by these three bufadienolides was demonstrated to link to down-regulation of p-mTOR as well as up-regulation of LC3-II, ATG5, ATG7, Beclin-1. Moreover, among these three compounds, kalantuboside B in which a monosaccharide is attached at the bufadienolide aglycon, exhibited a better autophagy induction. Our findings revealed an alternative mechanism of drug action by bufadienolides in lung cancer cells and provided evidence for the possibility of treating highly metastatic human lung cancer through an autophagy pathway.

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Section: Discussionmentioning

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Three Bufadienolides-Induced Human Lung Cancer CL1-5 Cell Death Mainly through Autophagy

Huang¹,

M²,

Chang³

et al. 2018

Preprint

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“…Excessive generation of ROS leads to oxidative damage to the mitochondrial membrane and, ultimately, triggers a series of mitochondrial associated events, including apoptosis [19, 20]. In view of the cinobufagin results showing that ROS generation is induced in A549/H1299 and HepG2 cells [9, 21], the ROS levels of U2OS and 143B cells were also detected after cinobufagin treatment. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Cinobufagin (Fig. 1A) is a primary and active components of Chan-su [8, 9]. Cinobufagin is reported to have anti-tumor effects in various types of cancer, such as non-small cell lung cancer, colorectal cancer, hepatocellular carcinoma, breast cancer and prostate cancer [9-14].…”

Section: Introductionmentioning

confidence: 99%

“…Cinobufagin is reported to have anti-tumor effects in various types of cancer, such as non-small cell lung cancer, colorectal cancer, hepatocellular carcinoma, breast cancer and prostate cancer [9-14]. Zhang et al [9]. found that cinobufagin inhibits human non-small cell lung cancer cell growth via the induction of intrinsic apoptosis pathway, mediated through the inhibition of the AKT/mTOR signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

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Cinobufagin Induces Apoptosis in Osteosarcoma Cells Via the Mitochondria-Mediated Apoptotic Pathway

Dai

Zheng

Guo

et al. 2018

Cell Physiol Biochem

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Background/Aims: Osteosarcoma is a common primary malignant bone tumor that mainly occurs in childhood and adolescence. Despite developments in the diagnosis and treatment of osteosarcoma, the prognosis is still very poor. Cinobufagin is an active component in the anti-tumor Chinese medicine called “Chan Su”, and we previously revealed that cinobufagin induced apoptosis and reduced the viability of osteosarcoma cells; however, the underlying mechanism remains to be elucidated. Herein, the present study was undertaken to illuminate the molecular mechanism of cinobufagin-induced apoptosis of osteosarcoma cell. Methods: U2OS and 143B cells were treated with different concentrations of cinobufagin. Cell viability, colony formation ability and morphological changes were assessed by a CCK-8 assay, a clonogenic assay and light microscopy, respectively. Cell apoptosis was detected by Hoechst 33258 and Annexin V-FITC/PI staining. Reactive oxygen species (ROS) and mitochondrial membrane potential (ΔΨm) were determined by flow cytometry. Glutathione (GSH) levels were detected by a GSH and GSSG assay kit. The levels of apoptosis-related proteins were determined by western blotting, and 143B cells were introduced to establish a xenograft tumor model. The effect of cinobufagin on osteosarcoma was further investigated in vivo. Results: Our results showed that cinobufagin significantly reduced the viability of U2OS and 143B cells in vitro in a dose-and time-dependent manner. In addition, cinobufagin-induced apoptosis in U2OS and 143B cells was concentration-dependent. Moreover, we found that cinobufagin treatment increased the level of intracellular ROS, decreased ΔΨm, reduced GSH and inhibited GSH reductase (GR). The effects of cinobufagin on cell proliferation, apoptosis, ROS generation and ΔΨm loss were dramatically reversed when the cells were pretreated with the thiol-antioxidants NAC or GSH. Moreover, cinobufagin treatment increased the expression of the pro-apoptotic protein Bax and decreased the expression of the anti-apoptitic protein Bcl-2, thus altering the ratio of Bax to Bcl-2. Furthermore, Cinobufagin treatment caused cytochrome c release from the mitochondria to cytoplasm, thus increasing the protein levels of cleaved-caspase family members to induce apoptosis. Ac-DEVD-CHO or Z-LEHD-FMK significantly reduced cinobufagin-induced apoptosis. Finally, a subcutaneous xenograft animal study verified that cinobufagin also significantly suppressed osteosarcoma growth in vivo. Conclusions: Our present data demonstrated that cinobufagin triggered cell apoptosis in osteosarcoma cells via the intrinsic mitochondria-dependent apoptosis pathway by the accumulation of ROS and the loss of ΔΨm. In an in vivo subcutaneous xenograft model, cinobufagin exhibited excellent tumor inhibitory effects. These results suggest that cinobufagin might potentially be further developed as an anti-tumor candidate for treating osteosarcoma patients in the clinic.

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Toad venom: A comprehensive review of chemical constituents, anticancer activities, and mechanisms

Ren

et al. 2021

Archiv der Pharmazie

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Toad venom, a traditional natural medicine, has been used for hundreds of years in China for treating different diseases. Many studies have been performed to elucidate the cardiotonic and analgesic activities of toad venom. Until the last decade, an increasing number of studies have documented that toad venom is a source of lead compound(s) for the development of potential cancer treatment drugs. Research has shown that toad venom contains 96 types of bufadienolide monomers and 23 types of indole alkaloids, such as bufalin, cinobufagin, arenobufagin, and resibufogenin, which exhibit a wide range of anticancer activities in vitro and, in particular, in vivo for a range of cancers. The main antitumor mechanisms are likely to be apoptosis or/and autophagy induction, cell cycle arrest, cell metastasis suppression, reversal of drug resistance, or growth inhibition of cancer cells. This review summarizes the chemical constituents of toad venom, analyzing their anticancer activities and molecular mechanisms for cancer treatments. We also outline the importance of further studies regarding the material basis and anticancer mechanisms of toad venom.

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Cinobufagin inhibits tumor growth by inducing intrinsic apoptosis through AKT signaling pathway in human nonsmall cell lung cancer cells

Cited by 45 publications

References 57 publications

Three Bufadienolides-Induced Human Lung Cancer CL1-5 Cell Death Mainly through Autophagy

Three Bufadienolides-Induced Human Lung Cancer CL1-5 Cell Death Mainly through Autophagy

Cinobufagin Induces Apoptosis in Osteosarcoma Cells Via the Mitochondria-Mediated Apoptotic Pathway

Toad venom: A comprehensive review of chemical constituents, anticancer activities, and mechanisms

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