A marine sponge alkaloid derivative 4-chloro fascaplysin inhibits tumor growth and VEGF mediated angiogenesis by disrupting PI3K/Akt/mTOR signaling cascade

Sharma, Shrestha; Guru, Santosh Kumar; Manda, Sudhakar; Kumar, Ashok; Mintoo, Mubashir J.; Prasad, Venna Deva; Sharma, Parduman R.; Mondhe, Dilip M.; Bharate, Sandip B.; Bhushan, Shashi

doi:10.1016/j.cbi.2017.07.017

Cited by 62 publications

(51 citation statements)

References 33 publications

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“…VEGF activates PI3K, which triggers the phosphorylation of AKT, leading to increased endothelial nitric oxide synthase activity. PI3K/AKT/mTOR is a pivotal signaling pathway responsible for cell proliferation, metabolism and motility (38,39). Previous studies have also confirmed its involvement in angiogenesis (40,41).…”

Section: Discussionmentioning

confidence: 92%

Synergistic anti-hepatoma effect of bufalin combined with sorafenib via mediating the tumor vascular microenvironment by targeting mTOR/VEGF signaling

2018

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Sorafenib inhibits tumor growth primarily by inhibiting vessel formation, however, its efficacy requires improvement, therefore, the development of strategies which augment its antiangiogenic effect are of primary concern. Bufalin inhibits tumor cell proliferation and metastasis, and induces apoptosis. In our previous study, it was demonstrated that the antiangiogenic effect of sorafenib was improved by bufalin in human umbilical vein endothelial cells (HUVECs). However, whether bufalin synergizes with sorafenib by affecting the tumor vascular microenvironment remains to be elucidated. In the present study, it was found that hepatocellular carcinoma (HCC) cell proliferation was inhibited by either bufalin or sorafenib following incubation for 24 h, and the inhibition was enhanced upon treatment with a combination of the two. Conditioned medium (CM), comprising supernatant from HCC cells was collected from each of the treatment groups. The migration and tubule formation were suppressed the most in the combination-CM treated HUVECs. The secretion of vascular endothelial growth factor (VEGF) was decreased in HCC cells treated with the combination-CM, as determined by an angiogenesis array, enzyme-linked immunosorbent assay (ELISA) and western blot analysis. The inhibition of tube formation in HUVECs treated with the combination-CM was reversed by incubation with VEGF. The in vivo experiments demonstrated that subcutaneous HCC cell tumors from mice treated with the combination treatment expressed the lowest levels of VEGF, as evidenced by immunohistochemistry and ELISA. Additionally, the level of phosphorylated mechanistic target of rapamycin (mTOR) was reduced in HUVECs pretreated with the phosphoinositide 3-kinase inhibitor PI103. Furthermore, the migration of HCC cells and HUVEC tube formation were attenuated by PI103 pretreatment. In conclusion, the results revealed a synergistic anti-hepatoma effect of bufalin combined with sorafenib via affecting the tumor vascular microenvironment by targeting mTOR/VEGF signaling.

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Section: Discussionmentioning

confidence: 92%

Synergistic anti-hepatoma effect of bufalin combined with sorafenib via mediating the tumor vascular microenvironment by targeting mTOR/VEGF signaling

2018

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“…Anticancer agents that target the PI3K/AKT/mTOR signaling pathway can induce apoptosis, autophagy and inhibit growth. For example, a marine sponge alkaloid derivative 4-chloro fascaplysin inhibits tumor growth by disrupting the PI3K/AKT/mTOR signaling cascade (41), and sinulariolide suppresses cell migration and invasion through the PI3K/AKT/mTOR signaling pathway in human bladder cancer cells (42).…”

Section: Discussionmentioning

confidence: 99%

Isoliquiritigenin inhibits proliferation and metastasis of MKN28 gastric cancer cells by suppressing the PI3K/AKT/mTOR signaling pathway

Zhang

Wang

Sun³

et al. 2018

Mol Med Report

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Isoliquiritigenin (ISL) is a ﬂavonoid extracted from licorice root, which is known to serve important antitumor roles in numerous types of cancers; however, its effect on gastric cancer remains to be elucidated. The present study aimed to explore the roles and underlying mechanisms of ISL in MKN28 gastric cancer cells. MKN28 cell proliferation was measured using the Cell Counting Kit‑8 (CCK8) assay. A Transwell assay was used to determine the effects of ISL on the migration and invasion of MKN28 cells. Apoptosis was assessed by flow cytometry, and the expression levels of apoptosis‑, autophagy‑ and signaling pathway‑related proteins were detected by western blot analysis. The results of the CCK8 assay demonstrated that ISL significantly inhibited the proliferation of MKN28 cells (P<0.05). Transwell assays demonstrated that the migration and invasion of MKN28 cells were significantly inhibited following treatment with ISL (P<0.05). Flow cytometric analysis indicated that ISL induced apoptosis of MKN28 cells. In addition, western blot analysis revealed that the ratio of microtubule‑associated proteins 1A/1B light chain 3B (LC3)II/LC3I was upregulated, as was Beclin 1 expression; however, p62 was downregulated following ISL pretreatment, thus suggesting that ISL triggered autophagy in MKN28 cells. In addition, the phosphorylation levels of protein kinase B (AKT) and mammalian target of rapamycin (mTOR) were significantly reduced following ISL treatment. These results indicated that ISL may influence apoptosis and autophagy in MKN28 cells by suppressing the phosphoinositide 3‑kinase/AKT/mTOR signaling pathway. In conclusion, the findings of the present study suggested that ISL may inhibit MKN28 cell proliferation, migration and invasion by inducing apoptosis and autophagy, implying potential as a therapeutic agent for gastric cancer.

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“…The PI3K/AKT pathway has close relationship with tumor progression and abnormity of this pathway can be frequently observed in a variety of tumors [22][23][24] . In both rabbit cornea model [25] and mouse ischemic retinal model [26] , PI3K/AKT pathway were confirmed to contain effective angiogenesis characteristics. Moreover, it was found the level of phosphorylation of AKT was significantly reduced while the total amount of AKT remains when the gastric cancer cells were transfected with small interfering RNA containing shA2 plasmid which further indicated that ANXA2 may play a role by influencing the phosphorylation of AKT [27] .…”

Section: Discussionmentioning

confidence: 90%

Annexin A2 Promotes Development of Retinal Neovascularization through PI3K/ AKT Pathway

Zhao

Zhao³

2020

Preprint

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Background RNV is a pathological characteristic of PDR and ANXA2 play an important role in the process of RNV while the mechanism remains unclear. We explore the role and molecular basis of ANXA2 in the formation of RNV and seek for new potential targets for the prevention and treatment of PDR. Methods Lentivirus containing plasmids which can interfere ANXA2 and overexpress ANXA2 were packaged and infected HRECs, dividing HRECs into 4 groups. Moreover, 1ul SC79 solution was added in shA2 group and 1ul LY294002 solution was added into lentiA2 group. Western Blot was used to detect expression of ANXA2 and changes in phosphorylation degree of major proteins in PI3K/AKT signaling pathway in each group of HRECs. HRECs of all groups were used to perform EDu cell proliferation assay, Transwell cell migration assay and Matrix tube formation assay. C57BL/6J mice were randomly divided into 3 groups. Mice of OIR group were injected intraperitoneally with 0.05ml PBS every day from 7th to 10th day while mice of LY294002 treatment group were injected with 0.05ml LY294002 solution and no treatment in the control group. Lectin GS-IB4 fluorescence staining was used to observe RNV in mice in all groups. The expression of ANXA2 in mouse retinas was detected by Westen-blot. Results The proliferation, immigration and angiogenesis ability of HRECs is lower in shA2 group than shNC and SC79 treatment group while higher in lentiA2 group than lenti-EGFP and LY294002 treatment group. ANXA2 expression is significantly higher in retina of mice in OIR group and LY294002 treatment group. RNV is significantly less severe in LY294002 treatment group than that in OIR group. Conclusions ANXA2 can promote development of RNV through PI3K/ AKT Pathway.

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A marine sponge alkaloid derivative 4-chloro fascaplysin inhibits tumor growth and VEGF mediated angiogenesis by disrupting PI3K/Akt/mTOR signaling cascade

Cited by 62 publications

References 33 publications

Synergistic anti-hepatoma effect of bufalin combined with sorafenib via mediating the tumor vascular microenvironment by targeting mTOR/VEGF signaling

Synergistic anti-hepatoma effect of bufalin combined with sorafenib via mediating the tumor vascular microenvironment by targeting mTOR/VEGF signaling

Isoliquiritigenin inhibits proliferation and metastasis of MKN28 gastric cancer cells by suppressing the PI3K/AKT/mTOR signaling pathway

Annexin A2 Promotes Development of Retinal Neovascularization through PI3K/ AKT Pathway

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