Antitumor and antiangiogenic activity of soy isoflavone genistein in mouse models of melanoma and breast cancer

Fariña, Hernán G.; Pomies, Monica; Alonso, Daniel F.; Gómez, Daniel E.

doi:10.3892/or.16.4.885

Cited by 93 publications

(88 citation statements)

References 29 publications

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“…However, matrix degradation by MMPs can alter the basic processes of cell proliferation and apoptosis. The chemopreventive effect of the flavonoids, flavonols (quercetin and kaempferol) and isofl avones (genistein, genistin and daidzein) has been observed through the suppression of cell proliferation [35] , inhibition of angiogenesis [36] , inhibition of invasion [37] and stimulation of apoptosis in breast carcinoma cells [38] . The inhibition of invasion of cancer cells is of great significance in cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of MMP-3 activity and invasion of the MDA-MB-231 human invasive breast carcinoma cell line by bioflavonoids

et al. 2009

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IntroductionMetastatic invasion is the primary cause of patient mortality during breast cancer progression. For a transformed cell to metastasize to a distant site in the body, it must first lose adhesion, penetrate and invade the surrounding extracellular matrix (ECM), enter the vascular system, and adhere to distant organs [1] . The inhibition of invasion of cancer cells has been an important strategy in cancer treatment [2] . A crucial step in the invasive processes is the proteolytic degradation of the ECM and basal membranes [3] . Several studies have shown that among the enzymes responsible for ECM degradation, the matrix metalloproteinases (MMPs) appear to play a critical role [4][5][6] . MMPs are zinc-dependent endopeptidases, which collectively can degrade all constituents of the ECM. Based on their structure and substrate specificity, they can be divided into subgroups of collagenases, stromelysins, gelatinases, membrane-type MMPs and other MMPs [7] .Breast cancer is the major cause of malignancy-related deaths of women worldwide. In Thailand, breast cancer is the second most common cancer among women and its incidence is increasing [8] . Cancer invasion and metastasis are leading causes of morbidity and mortality in patients with breast cancer. Several studies have demonstrated that upregulation of MMP-1, -2, -3, -7, -9, -13, and -14 is associated with breast cancer cell invasion [9][10][11] .MMP-3, also designated stromelysin 1, is a member of the matrixin family, which plays a pivotal role in the degradation and remodeling of the ECM. MMP-3 degrades several components of the ECM, such as fi bronectin, laminin, collagen type IV [12][13][14] and proteoglycans, and is thought to play an important role in rheumatoid arthritis, osteoarthritis [15,16] , tumor cell invasion and metastasis [17] . Aim: Stromelysin 1 (matrix metalloproteinase 3; MMP-3) is an enzyme known to be involved in tumor invasion and metastasis. In this study, fl avonoids from vegetables and fruits, such as quercetin, kaempferol, genistein, genistin, and daidzein, were tested for their ability to modulate the secretion and activity of MMP-3 in the MDA-MB-231 breast cancer cell line. In addition, we investigated the in vitro effects of fl avonoids on MDA-MB-231 cell invasion. Methods: The toxic concentration range of fl avonoids was evaluated using the MTT assay. The ability of MDA-MB-231 cells to invade was evaluated using a modifi ed Boyden chamber system. The activity of MMP-3 was determined by casein zymography. The secretion of MMP-3 was evaluated using Western blotting, casein zymography and confi rmed by ELISA. Results: Some putative fl avonoids, ie, quercetin and kaempferol (fl avonols), signifi cantly inhibited the in vitro invasion of MDA-MB-231 cells in a concentration-dependent manner, with IC 50 values of 27 and 30 μmol/L, respectively. Quercetin and kaempferol also reduced MMP-3 activity in a dose-dependent manner, with IC 50 values in the range of 30 μmol/L and 45 μmol/L, respectively. None of the fl avonoids had a signif...

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Section: Discussionmentioning

confidence: 99%

Inhibition of MMP-3 activity and invasion of the MDA-MB-231 human invasive breast carcinoma cell line by bioflavonoids

et al. 2009

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“…Several studies have shown that genistein can inhibit the growth of various hormone-responsive cancer cell lines, such as breast and prostate, both in vitro and in vivo (12)(13)(14)(15). The anticancer effects of genistein have been ascribed to several signaling pathways and mechanisms that lead to cell cycle arrest, apoptosis, invasion, metastasis, and angiogenesis, attributes that could potentially prevent tumor initiation and progression (9,13).…”

Section: Introductionmentioning

confidence: 99%

Genistein down-regulates androgen receptor by modulating HDAC6-Hsp90 chaperone function

Basak

Pookot

Noonan

et al. 2008

Molecular Cancer Therapeutics

117

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Androgen receptor (AR) is a ligand-activated transcription factor belonging to the steroid hormone receptor family and is very important for the development and progression of prostate cancer. The soy isoflavone genistein has been shown previously to down-regulate AR in androgendependent prostate cancer cell lines such as LNCaP. However, the mechanism(s) by which AR is downregulated by genistein is still not known fully. We show a new mechanism by which genistein inhibits AR protein levels. We show that genistein-treated LNCaP cells exhibit increased ubiquitination of AR, suggesting that AR protein is down-regulated via a proteasome-mediated pathway. AR is normally stabilized by the chaperone activity of the heat shock protein Hsp90. The increased ubiquitination of AR after genistein treatment is attributed to decreased Hsp90 chaperone activity as assessed by its increased functionally inactive acetylated form. Consistent with this result, we find that HDAC6, which is a Hsp90 deacetylase, is inhibited by the antiestrogenic activity of genistein. Hence, in this study, we elucidate a novel mechanism of AR down-regulation by genistein through inhibition of HDAC6-Hsp90 cochaperone function required to stabilize AR protein. Our results suggest that genistein could be used as a potential chemopreventive agent for prostate cancers along with known inhibitors of HDAC6 and

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“…With the challenge of finding new drugs which could inhibit VM, the soybeans isoflavone called genistein was proposed. This molecule was found to be able to inhibit VM formation of uveal melanoma through down-regulation of VE-cadherin in vitro [27,28]. In another study Itzhaki et al tested the ability of nicotinamide to inhibit VM activity in melanoma cells [29].…”

Section: Discussionmentioning

confidence: 99%

Mig-7 expression and vasculogenic mimicry in malignant ovarian tumors

Czekierdowski

Czekierdowska

Stachowicz³

et al. 2017

Ginekol Pol

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Objectives:To investigate the possible association of vasculogenic mimicry (VM), VE-cadherin and MIG-7 expression with clinicopathological features of women with malignant ovarian masses. Material and methods:VM was studied with the PAS reaction and VE-cadherin was assessed with immunohistochemistry in 108 women with malignant ovarian tumors. Additionally, quantitative expression of MIG-7 mRNA was performed in 52 ovarian cancers with qRT-PCR.Results: VM was found in 48/108 cases (44%), more often in higher FIGO stage tumors (83% cases; 40 vs. 8; p = 0.01). High expression of VE-cadherin was present in 37% of all ovarian masses. Ovarian tumors without VM more often expressed low levels of VE-cadherin than tumors where VM was found (37.6% vs.14.6%). No expression or very low expression of MIG-7 mRNA was found in all normal ovarian tissues and in 32 cancer samples. Median RQ of MIG-7 mRNA in tumor samples was higher than in normal ovarian tissue (RQ = 0.29 vs. RQ = 0.05, respectively; p < 0.005) and higher than in non-malignant ovarian masses (0.98 vs. 0.05 respectively; p = 0.03). Expression of MIG-7 mRNA was significantly correlated with VM (p = 0.039). In tumors with PAS-positive structures median RQ MIG-7 mRNA was higher than in tumors with PAS-negative findings (1.89 vs. 0.13 respectively). VE-cadherin expression was more frequently found in tumors where MIG-7 mRNA was present (p = 0.004). Conclusions:Vasculogenic mimicry exists in malignant ovarian tumors and advanced clinical stages of malignancy are accompanied by a high incidence of VM formation. MIG-7 mRNA and VE-cadherin expression may serve as additional molecular markers of VM in ovarian malignancies.

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Antitumor and antiangiogenic activity of soy isoflavone genistein in mouse models of melanoma and breast cancer

Cited by 93 publications

References 29 publications

Inhibition of MMP-3 activity and invasion of the MDA-MB-231 human invasive breast carcinoma cell line by bioflavonoids

Inhibition of MMP-3 activity and invasion of the MDA-MB-231 human invasive breast carcinoma cell line by bioflavonoids

Genistein down-regulates androgen receptor by modulating HDAC6-Hsp90 chaperone function

Mig-7 expression and vasculogenic mimicry in malignant ovarian tumors

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