TIMP-2 mediates the anti-invasive effects of the nitric oxide-releasing prodrug JS-K in breast cancer cells

Simeone, Ann-Marie; McMurtry, Vanity; Nieves-Alicea, René; Saavedra, Joseph E.; Keefer, Larry K.; Johnson, Marcella M.; Tari, Ana M.

doi:10.1186/bcr2095

Cited by 54 publications

(35 citation statements)

References 35 publications

(43 reference statements)

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“…TIMP-1 and TIMP-2 were known to have a particularly high affinity for MMP-9 and MMP-2, respectively (43). Many studies have found that TIMP-2 overexpression decreased invasion of endothelial and tumor cells both in vitro and in vivo (44,45). This study showed Angelica sinensis obviously increased TIMP-2 expression but decreased TIMP-1 expression, which can inhibit the enzyme activity of MMP-2 and MMP-9.…”

Section: Discussionmentioning

confidence: 73%

Angelica sinensis suppresses human lung adenocarcinoma A549 cell metastasis by regulating MMPs/TIMPs and TGF-β1

Gao

Zhang²,

Zhou³

et al. 2011

Oncol Rep

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Abstract. In this study we investigated the potential effects of Angelica sinensis on the growth and metastasis in human lung adenocarcinoma A549 cells. In vitro the Cck-8 assays showed that Angelica sinensis had weak antiproliferative effect on A549 cells only at high concentration. The cell adhesion assay showed that Angelica sinensis decreased the adhesive ability of A549 cells in a dose-and time-dependent manner. Transwell invasion and migration assay showed that Angelica sinensis reduced the invasive and migratory abilities of A549 cells in a dose-dependent manner. In vivo the animal experiments showed that Angelica sinensis suppressed lung metastasis of nude mice at high concentration. Then, we attempted to clarify the mechanisms of anti-metastatic activities of Angelica sinensis. The results showed Angelica sinensis inhibited the enzymatic activity of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), it involved the down-regulation of the expressions of MMP-2 and MMP-9 at both the protein and mRNA levels, which may be associated with Angelica sinensis suppressing the expression of TGF-β1. It also involved the increase of the tissue inhibitors of metalloproteinases TIMP-2, but TIMP-1 decreased upon incubation of A549 cells with Angelica sinensis. The results suggest that Angelica sinensis might exert anti-growth and anti-metastasis activity against lung cancer cells through the decrease of MMP-2, MMP-9, TGF-β1 and TIMP-1 and increase of TIMP-2. IntroductionNon-small cell lung carcinoma (NSCLC) is currently one of the leading causes of death in China, its high mortality is attributed to early metastasis. About 70-90% patients with lung cancer need radiation therapy, and therefore, radiation lung injury is the most common complication (1). It limits the increasing of radiation dose and influences the life quality of patients or even threatens their life. Many traditional Chinese medicines have great efficacy in radiation lung injury. The root of Angelica sinensis, also known as 'Danggui' was a popular herbal medicine and widely used for many diseases in China. It has been used for more than 10 years in our hospital to treat lung fibrosis and shows good curative effect in radiation pulmonary fibrosis (2-4).Angelica sinensis belongs to 'activating blood and dissolving stasis' kind of traditional Chinese medicine, and some researchers think this kind of medicine can promote tumor metastasis. Li et al first reported Salvia miltiorrhiza Bunge and Radix Paeoniae Rubra such as 'activating blood and dissolving stasis' traditional Chinese medicine can promote tumor metastasis, we pay high attention to it (5). Han et al found the metastasis rate of nasopharyngeal carcinoma increased to 2.67 times compare with the control after using 'activating blood and dissolving stasis' kind of traditional Chinese medicine (6). But also, there is research with the opposite conclusion (7). Therefore, the use of Angelica sinensis needs to be clarified to confirm whether it promotes or inhibits metastasis of l...

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Section: Discussionmentioning

confidence: 73%

Angelica sinensis suppresses human lung adenocarcinoma A549 cell metastasis by regulating MMPs/TIMPs and TGF-β1

Gao

Zhang²,

Zhou³

et al. 2011

Oncol Rep

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“…On the other side, NO-releasing agents have been shown to suppress the metastatic tumor cell behavior in various in vitro and in vivo tumor models by decreasing angiogenesis and, therefore, tumor cell invasion. [9][10][11][12][13] The anti-invasiveness and anti-metastatic properties of NO have been attributed either to inhibition of angiogenic factors such as β-FGF and TGFβ1, [9][10][11] or induction of TIMP-2 production and inhibition of p38. 13 Alternatively, NO has been proposed to interfere with the storeoperated calcium mobilization through regulation of the NO/ cGMP-mediated mechanism, 10 or it can prevent the excessive formation of oxygen radicals and peroxynitrate (ONOO -), which cause cell damage and facilitate tumor metastasis.…”

Section: Resultsmentioning

confidence: 99%

“…These findings are in agreement with other studies showing the inhibitory effects of NO-releasing agents in metastatic tumor cell behavior both in vitro and in vivo. [9][10][11][12][13] The challenge regarding NO donors as therapeutic agents is to deliver NO in a sustained and controlled manner. NO donors that spontaneously generate large amounts of NO, independent of iNOS induction, are activated at physiological pH.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of nitric oxide-mediated inhibition of EMT in cancer

Baritaki¹,

Huerta-Yépez²,

Sahakyan³

et al. 2010

Cell Cycle

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“…JS-K increased the percentages of acridine orange-stained cells in all breast cancer cell lines tested (Table I). On the other hand, JS-43-126, the non-NOreleasing control (22), did not increase the percentages of acridine orange-stained cells (Table I). Furthermore, JS-K hardly affected the formation of acidic vesicular organelles in HMECs or MCF-10A cells; at 5-μM concentration, JS-K increased the percentages of acridine orange-stained HMECs and MCF-10A cells only by 1.3% and 2.2%, respectively ( Fig.…”

Section: Js-k Induces Programmed Cell Death In Breast Cancer Cellsmentioning

confidence: 98%

“…The presumed metabolites of JS-K, such as DNP-SG, DNP, JS-9-29, and piperazine, and the non-NO-releasing control JS-43-126 (22) did not have any effect on the viability of MDA-MB-453 cells (Fig. 2 bottom panel) and MDA-MB-231 cells (not shown).…”

Section: Js-k Is More Cytotoxic To Breast Cancer Cells Than To Normalmentioning

confidence: 99%

JS-K, a nitric oxide-releasing prodrug, induces breast cancer cell death while sparing normal mammary epithelial cells

McMurtry

Saavedra²,

Nieves-Alicea³

et al. 2011

Int J Oncol

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Abstract. Targeted therapy with reduced side effects is a major goal in cancer research. We investigated the effects of JS-K, a nitric oxide (NO) prodrug designed to release high levels of NO when suitably activated, on human breast cancer cell lines, on non-transformed human MCF-10A mammary cells, and on normal human mammary epithelial cells (HMECs). Cell viability assay, flow cytometry, electron microscopy, and Western blot analysis were used to study the effects of JS-K on breast cancer and on mammary epithelial cells. After a 3-day incubation, the IC 50 s of JS-K against the breast cancer cells ranged from 0.8 to 3 μM. However, JS-K decreased the viability of the MCF-10A cells by only 20% at 10-μM concentration, and HMECs were unaffected by 10 μM JS-K. Flow cytometry indicated that JS-K increased the percentages of breast cancer cells under-going apoptosis. Interestingly, flow cytometry indicated that JS-K increased acidic vesicle organelle formation in breast cancer cells, suggesting that JS-K induced autophagy in breast cancer cells. Electron microscopy confirmed that JS-K-treated breast cancer cells underwent autophagic cell death. Western blot analysis showed that JS-K induced the expression of microtubule light chain 3-II, another autophagy marker, in breast cancer cells. However, JS-K did not induce apoptosis or autophagy in normal human mammary epithelial cells. These data indicate that JS-K selectively induces programmed cell death in breast cancer cells while sparing normal mammary epithelial cells under the same conditions. The selective antitumor activity of JS-K warrants its further investigation in breast tumors.

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TIMP-2 mediates the anti-invasive effects of the nitric oxide-releasing prodrug JS-K in breast cancer cells

Cited by 54 publications

References 35 publications

Angelica sinensis suppresses human lung adenocarcinoma A549 cell metastasis by regulating MMPs/TIMPs and TGF-β1

Angelica sinensis suppresses human lung adenocarcinoma A549 cell metastasis by regulating MMPs/TIMPs and TGF-β1

Mechanisms of nitric oxide-mediated inhibition of EMT in cancer

JS-K, a nitric oxide-releasing prodrug, induces breast cancer cell death while sparing normal mammary epithelial cells

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