Cinobufagin suppresses colorectal cancer angiogenesis by disrupting the endothelial mammalian target of rapamycin/hypoxia‐inducible factor 1α axis

Abstract

Inducing angiogenesis is a hallmark of cancers that sustains tumor growth and metastasis. Neovascularization is a surprisingly early event during the multistage progression of cancer. Cinobufagin, an important bufadienolide originating from Chan Su, has been clinically used to treat cancer in China since the Tang dynasty. Here, we show that cinobufagin suppresses colorectal cancer ( CRC ) growth in vivo by downregulating angiogenesis. The hierarchized neovasculature is significantly decreased and the vascular network formation is disrupted in HUVEC by cinobufagin in a dose‐dependent way. Endothelial apoptosis is observed by inducing reactive oxygen species ( ROS ) accumulation and mitochondrial dysfunction which can be neutralized by N‐acetyl‐ l ‐cysteine ( NAC ). Expression of hypoxia‐inducible factor 1α ( HIF ‐1α) is reduced and phosphorylation of mTOR at Ser2481 and Akt at Ser473 is downregulated in HUVEC . Endothelial apoptosis is triggered by cinobufagin by stimulation of Bax and cascade activation of caspase 9 and caspase 3. Increased endothelial apoptosis rate and alterations in the HIF ‐1α/ mTOR pathway are recapitulated in tumor‐bearing mice in vivo. Further, the anti‐angiogenesis function of cinobufagin is consolidated based on its pro‐apoptotic effects on an EOMA ‐derived hemangioendothelioma model. In conclusion, cinobufagin suppresses tumor neovascularization by disrupting the endothelial mTOR / HIF ‐1α pathway to trigger ROS ‐mediated vascular endothelial cell apoptosis. Cinobufagin is a promising natural anti‐angiogenetic drug that has clinical translation potential and practical application value.

Cinobufagin Suppresses Melanoma Cell Growth by Inhibiting LEF1

“…Cinobufagin was found to induce apoptosis in osteosarcoma cancer cells by suppressing cancer-promoting signaling pathways such as STAT3, Notch and NF-kB, and activating mitochondria-mediated apoptosis pathways [41][42][43][44]. The anti-angiogenic effect of cinobufagin by suppressing the mammalian target of rapamycin (mTOR) and hypoxia-inducible factor-1α (HIF1α) signaling pathways has also been observed in colorectal cancer [45].…”

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“…In addition, an increase in the pro-apoptotic factor Bax and the epithelial marker E-cadherin, while a decline in the anti-apoptotic factor Bcl-2 and mesenchymal markers N-cadherin and Vimentin suggested that sh-KDM3A promoted apoptosis while suppressing EMT in CC cells in a cellular perspective. In addition, angiogenesis, a hallmark of cancers that is crucial for tumor growth and metastasis, 26 was found to be suppressed as well upon KDM3A downregulation.…”

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“…[ 102 ] In addition, cinobufagin could suppress tumor neovascularization by disrupting the endothelial mammalian target of rapamycin/hypoxia‐inducible factor‐1α (mTOR/HIF‐1α) pathway to trigger ROS‐mediated vascular endothelial cell apoptosis. [ 103 ]…”