A novel semi-synthetic andrographolide analogue A5 inhibits tumor angiogenesis via blocking the VEGFR2-p38/ERK1/2 signal pathway

Gong, Chenyuan; Xu, Chong; Ji, Lili; Wang, Zhengtao

doi:10.5582/bst.2013.v7.5.230

Cited by 13 publications

(15 citation statements)

References 35 publications

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“…For the regulation of angiogenesis, VEGF is a key regulator of vascular permeability and promotes EC proliferation and migration 7,47,48. A number of Chinese herbal components have demonstrated anti-angiogenesis effects on targeting the VEGF-induced angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Morusin shows potent antitumor activity for human hepatocellular carcinoma in vitro and in vivo through apoptosis induction and angiogenesis inhibition

Gao¹,

Wang²,

Sun³

et al. 2017

DDDT

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Hepatocellular carcinoma (HCC) is one of the most aggressive cancers with high mortality worldwide. Research and development of novel agents for HCC therapy is in demand, urgently. Morusin has been reported to exhibit potential cytotoxic activity in several cancer cell lines. However, whether it has potential antiangiogenic activity especially in HCC remains unclear. In the current study, we found that morusin exerted growth inhibition effects on human HCC cells (HepG2 and Hep3B) in vitro and human HCC cell (HepG2) xenografts in vivo. Moreover, apoptosis induction was observed in a dose-dependent manner after morusin treatment along with an increase in the expression of active caspase-3 and the Bax/Bcl-2 expression ratio. More importantly, morusin inhibited proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs) in vitro and downregulated angiogenic proteins in HCC cells and HUVECs. In vivo, tumor angiogenesis was also attenuated after morusin treatment. In addition, morusin suppressed constitutive as well as IL-6-induced STAT3 phosphorylation in HCC cells and corresponding tumor tissues. Overall, morusin has a potential anticancer effect on human HCC cells in vitro and in vivo by inducing apoptosis and inhibiting anti-angiogenesis. The corresponding mechanism might be associated with the attenuation of the IL-6/STAT3 signaling pathway. Morusin might serve as a promising novel anticancer agent in HCC therapy, and requires further study.

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Section: Discussionmentioning

confidence: 99%

Morusin shows potent antitumor activity for human hepatocellular carcinoma in vitro and in vivo through apoptosis induction and angiogenesis inhibition

Gao¹,

Wang²,

Sun³

et al. 2017

DDDT

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“…The results showed that morusin clearly and significantly increased the activity levels of SOD, GSH-PX and T-AOC, in comparison with those of the control group (P<0.01), in a dose-dependent manner, and thus increased the antioxidant abilities of the A549 cells. (30,31). The RT-PCR results revealed that the expression of VEGF was reduced by 18, 38 and 56% following treatment of A549 cells with 1, 10 and 30 µg/ml morusin, respectively (Fig.…”

Section: Effects Of Morusin On the Apoptosis And ∆ψ Of A549mentioning

confidence: 88%

Morusin suppresses A549 cell migration and induces cell apoptosis by downregulating the expression of COX‑2 and VEGF genes

Yin

Wang

et al. 2018

Oncol Rep

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The present study aimed to examine the inhibitory effects of morusin on the human lung cancer cell line A549. Various doses of morusin were applied to A549 cells and the effects were assessed by wound‑healing and MTT assays, flow cytometry analysis of apoptosis, a mitochondrial membrane potential assay and RT‑PCR. The results indicated that the concentrations of 10 and 30 µg/ml morusin significantly inhibited A549 cells and signs of apoptosis were observed. In addition, the wound‑healing assay results revealed that morusin inhibited cell migration. Flow cytometry analysis demonstrated that the rates of apoptosis were 16.46, 55.80 and 70.80% following treatment with 1, 10 and 30 µg/ml of morusin, respectively, and that the mitochondrial membrane potentials also decreased with the increase of morusin. Furthermore, morusin increased the antioxidant activities of the A549 cells. RT‑PCR analysis revealed that the expression levels of COX‑2 and VEGF were downregulated following morusin treatment. In conclusion, morusin significantly inhibited the proliferation of the lung cancer cell line A549, and may have affected the invasion and migration of the cells by downregulating the expression of tumor angiogenesis‑related genes.

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“…significantly lowered the tumor size and reduced the invasive and metastatic abilities of H22, though it showed less cytotoxic to various human cancer cell lines (Wu et al, 2013). Gong et al reported that a semi-synthetic analogue A5 (19-N-hexylamino-8-methylandrograpanin) of AD decreased tumor weight and size of hepatoma in a subcutaneous mouse xenograft model through intraperitoneal injection (Gong et al, 2013). As we have known that AD exerts hepatoprotective effect through its anti-inflammatory and antioxidant activities.…”

Section: Discussionmentioning

confidence: 99%

“…VEGF/VEGFR2 signaling is considered as an important therapeutic target for the treatment of pathogenic angiogenesis because it is a predominant mediator of vasculogenesis and angiogenesis by induction of multiple signaling cascades (Olsson et al, 2006;Meissner et al, 2009). It has been reported that AD decreases VEGFD expression in hepatoma cancer cells (Ji et al, 2015) and both AD and its derivative A5 have been revealed to inhibit tumor angiogenesis via blocking VEGF-induced activation of VEGFR2 and its downstream MAPKs signaling pathways (Gong et al, 2013;Shen et al, 2014). Here, we found that ADN-9 was more powerful than AD in down-regulating VEGF expression and blocking VEGF-induced activation of VEGFR2, resulting in enhanced inactivation of multiple intracellular signaling cascades in HUVECs.…”

Section: Discussionmentioning

confidence: 99%

In vivo inhibitory activity of andrographolide derivative ADN-9 against liver cancer and its mechanisms involved in inhibition of tumor angiogenesis

Yang

Zhao

Wang³

et al. 2017

Toxicology and Applied Pharmacology

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It is well known that liver cancer is a highly aggressive malignancy with poor prognosis. Andrographolide (AD), a major bioactive component of Andrographis paniculata (Burm. F.), is a potential anti-cancer pharmacophore and the synthesis of AD derivatives with better cytotoxicity to cancer cells has attracted considerable attentions. In the present study, we evaluated the in vivo inhibitory effects of ADN-9, a 15-benzylidene substituted derivative of AD, on the growth and metastasis of murine hepatoma H22 using an orthotopic xenograft model and a subcutaneous xenograft model, and we further studied the anti-angiogenic action and the related mechanisms of ADN-9 in vivo and in vitro. Importantly, ADN-9 remarkably suppressed the growth and metastasis of both orthotopic and subcutaneous xenograft tumors, and the serum AFP level in orthotopic hepatoma-bearing mice treated with 100mg/kg ADN-9 (ig.) was decreased to the normal level. We also found that ADN-9 showed stronger abilities than AD in shrinking tumors, suppressing the invasion and metastasis of H22 cells, decreasing the MVD and promoting tumor cell apoptosis in subcutaneous xenograft of mice. Additionally, ADN-9 exhibited stronger inhibitory activity than AD against the migration and VEGF-induced capillary-like tube formation in HUVECs, which was further proved to be associated with attenuating VEGF/VEGFR2/AKT signaling pathway. The present research provides the first evidence that a 15-substituted AD derivative is more promising than the parent compound in therapeutic treatment of liver cancer.

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A novel semi-synthetic andrographolide analogue A5 inhibits tumor angiogenesis via blocking the VEGFR2-p38/ERK1/2 signal pathway

Cited by 13 publications

References 35 publications

Morusin shows potent antitumor activity for human hepatocellular carcinoma in vitro and in vivo through apoptosis induction and angiogenesis inhibition

Morusin shows potent antitumor activity for human hepatocellular carcinoma in vitro and in vivo through apoptosis induction and angiogenesis inhibition

Morusin suppresses A549 cell migration and induces cell apoptosis by downregulating the expression of COX‑2 and VEGF genes

In vivo inhibitory activity of andrographolide derivative ADN-9 against liver cancer and its mechanisms involved in inhibition of tumor angiogenesis

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