Ellagic Acid Inhibits VEGF/VEGFR2, PI3K/Akt and MAPK Signaling Cascades in the Hamster Cheek Pouch Carcinogenesis Model

Kowshik, Jaganathan; Giri, Hemant; Kishore, T. Kranthi Kiran; Kesavan, R.; Vankudavath, Raju Naik; Reddy, G. Bhanuprakash; Dixit, Madhulika; Nagini, Siddavaram

doi:10.2174/1871520614666140723114217

Cited by 63 publications

(40 citation statements)

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“…p38-phosphorylation. VEGF/VEGFR signaling pathway has been confirmed to play central roles in pathological angiogenesis, and binding of VEGFR2 with VEGF can activate numerous downstream signal pathways, including Akt and p38, which sequentially promote endothelial cell growth, migration and tube formation (32)(33)(34). Therefore, we further evaluated whether these signaling pathways are involved in the PC-3 CM AM -induced vasculogenesis of BM-EPCs.…”

Section: Pc-3 CM Am Induces Activation Of Vegfr2- Akt-andmentioning

confidence: 98%

Acidic extracellular pH promotes prostate cancer bone metastasis by enhancing PC-3 stem cell characteristics, cell invasiveness and VEGF-induced vasculogenesis of BM-EPCs

et al. 2016

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Bone metastasis is a main cause of cancer-related mortality in patients with advanced prostate cancer. Emerging evidence suggests that the acidic extracellular microenvironment plays significant roles in the growth and metastasis of tumors. However, the effects of acidity on bone metastasis of PCa remain undefined. In the present study, PC-3 cells were cultured in acidic medium (AM; pH 6.5) or neutral medium (NM; pH 7.4), aiming to investigate the effects and possible mechanisms of acidic extracellular microenvironment in bone metastasis of PCa. Our results showed that AM can promote spheroid and colony formations, cell viability and expression of stem cell characteristic-related markers in PC-3 cells. Moreover, AM stimulates MMP-9 secretion and promotes invasiveness of PC-3 cells, and these effects can be inhibited by blocking of MMP-9. Furthermore, AM stimulates VEGF secretion of PC-3 and AM conditioned medium (CMAM) promotes vasculogenesis of BM-EPCs by increasing cell viability, migration, tube formation, which involved activating the phosphorylation of VEGFR-2, Akt and P38, when pH of NM conditioned medium (CMNM) was modulated the same as AM conditioned medium (CMAM). Further studies have shown that CMNM induced vasculogenesis of BM-EPCs can be inhibited by the inhibition of VEGFR2 with DMH4. These findings suggest that acidic extracellular microenvironment may have the potential to modulate prostate cancer bone metastasis by enhancing PC-3 stem cell characteristics, cell invasiveness and VEGF-induced vasculogenesis of BM-EPCs. Improved anticancer strategies should be designed to selectively target acidic tumor microenvironment.

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Section: Pc-3 CM Am Induces Activation Of Vegfr2- Akt-andmentioning

confidence: 98%

Acidic extracellular pH promotes prostate cancer bone metastasis by enhancing PC-3 stem cell characteristics, cell invasiveness and VEGF-induced vasculogenesis of BM-EPCs

et al. 2016

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“…AKT and MAPK pathways, which play important roles in promoting cell growth and survival, are often abnormally activated in melanoma cells through N-RAS, BRAF and PTEN mutations (Jakob et al, 2012;Luo & Shen, 2017;Zebary et al, 2013). Moreover, other studies indicated that EA is related to the modulation of the AKT and MAPK signaling networks (Kowshik et al, 2014;Umesalma, Nagendraprabhu, & Sudhandiran, 2015). Also, EA increases p53 protein levels in some cancer cell lines (Li et al, 2005).…”

Section: Ellagic Acid Attenuates Akt and Mapk Signaling Pathways Anmentioning

confidence: 99%

Ellagic acid, extracted from Sanguisorba officinalis, induces G1 arrest by modulating PTEN activity in B16F10 melanoma cells

et al. 2019

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In Chinese medicine, herbal medicine is commonly used to treat individuals suffering from many types of diseases. We thus expected that some herbal medicines would contain promising compounds for cancer chemotherapy. Indeed, we found that Sanguisorba officinalis extracts strongly inhibit the growth of B16F10 melanoma cells, and we identified ellagic acid (EA) as the responsible ingredient. B16F10 cells treated with EA exhibited strong G1 arrest accompanied by accumulation of p53, followed by inactivation of AKT. Addition of a PTEN inhibitor, but not a p53 inhibitor, abrogated the EA‐induced AKT inactivation and G1 arrest. The PTEN inhibitor also diminished EA‐induced p53 accumulation. Furthermore, EA apparently increased the protein phosphatase activity of PTEN, as demonstrated by the reduced phosphorylation level of FAK, a protein substrate of PTEN. Furthermore, an in vitro PTEN phosphatase assay on PIP3 showed the direct modulation of PTEN activity by EA. These results suggest that EA functions as an allosteric modulator of PTEN, enhancing its protein phosphatase activity while inhibiting its lipid phosphatase activity. It is notable that a combination of EA and cisplatin, a widely used chemotherapy agent, dramatically enhanced cell death in B16F10 cells, suggesting a promising strategy in chemotherapy.

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“…In the resistant ovarian subcell line A2780CisR, pretreatment with EA for 48 hr could enhance the cytotoxicity of cisplatin resulting in the prevention of cisplatin resistance development . Furthermore, a hamster model with oral oncogenesis was developed to investigate the antiangiogenic effect of EA, which was mediated via the abrogation of hypoxia driven MAPK, VEGF/VEGFR2, and phosphoinositide‐3‐kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathways involving the suppression of HIF‐1α and HDAC6 response . Interestingly, EA was applied to combine with other natural products or anticancer drugs with the aim of potentiating their anticancer effects, including curcumin, quercetin, embelin, and 5‐fluorouracil (5‐FU) .…”

Section: Anticancer Activities and Potential Mechanismsmentioning

confidence: 99%

Recent Advances in Anticancer Activities and Drug Delivery Systems of Tannins

Cai

Zhang

Chen

et al. 2016

Medicinal Research Reviews

104

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Tannins, polyphenols in medicinal plants, have been divided into two groups of hydrolysable and condensed tannins, including gallotannins, ellagitannins, and (-)-epigallocatechin-3-gallate (EGCG). Potent anticancer activities have been observed in tannins (especially EGCG) with multiple mechanisms, such as apoptosis, cell cycle arrest, and inhibition of invasion and metastases. Furthermore, the combinational effects of tannins and anticancer drugs have been demonstrated in this review, including chemoprotective, chemosensitive, and antagonizing effects accompanying with anticancer effect. However, the applications of tannins have been hindered due to their poor liposolubility, low bioavailability, off-taste, and shorter half-life time in human body, such as EGCG, gallic acid, and ellagic acid. To tackle these obstacles, novel drug delivery systems have been employed to deliver tannins with the aim of improving their applications, such as gelatin nanoparticles, micelles, nanogold, liposomes, and so on. In this review, the chemical characteristics, anticancer properties, and drug delivery systems of tannins were discussed with an attempt to provide a systemic reference to promote the development of tannins as anticancer agents.

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Ellagic Acid Inhibits VEGF/VEGFR2, PI3K/Akt and MAPK Signaling Cascades in the Hamster Cheek Pouch Carcinogenesis Model

Abstract: Ellagic acid offers promise as a lead compound for anticancer therapeutics by virtue of its ability to inhibit key oncogenic signaling cascades and HDACs.

Cited by 63 publications

References 0 publications

Acidic extracellular pH promotes prostate cancer bone metastasis by enhancing PC-3 stem cell characteristics, cell invasiveness and VEGF-induced vasculogenesis of BM-EPCs

Acidic extracellular pH promotes prostate cancer bone metastasis by enhancing PC-3 stem cell characteristics, cell invasiveness and VEGF-induced vasculogenesis of BM-EPCs

Ellagic acid, extracted from Sanguisorba officinalis, induces G1 arrest by modulating PTEN activity in B16F10 melanoma cells

Recent Advances in Anticancer Activities and Drug Delivery Systems of Tannins

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