Effect of Interleukin-8 Gene Silencing With Liposome-Encapsulated Small Interfering RNA on Ovarian Cancer Cell Growth

Merritt, William M.; Lin, Yvonne G.; Spannuth, Whitney A.; Fletcher, Mavis S.; Kamat, Aparna A.; Han, Liz Y.; Landen, Charles N.; Jennings, Nicholas B.; Geest, Koen De; Langley, Robert R.; Villares, Gabriel J.; Sanguino, Ángela; Lutgendorf, Susan K.; López-Berestein, Gabriel; Bar‐Eli, Menashe; Sood, Anil K.

doi:10.1093/jnci/djn024

Cited by 226 publications

(173 citation statements)

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“…reduces microvessel density and significantly enhances the antiproliferative effect of docetaxel on HeyA8 and SKOV3ip1 ovarian tumour growth (Merritt et al, 2008). Dexamethasone has been shown to suppress proangiogenic gene transcription and secretion in a range of CRPC cells in vitro, whereas a subcutaneous administration of DEX inhibits tumour growth and angiogenesis in an in vivo DU145 xenograft model of CRPC (Yano et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the ability of DEX to suppress IL-8, CXCL1 and VEGF would appear to underpin an enhanced suppression of the tumour vasculature in the PC3 model of CRPC and potentiate the antiangiogenic effect of docetaxel. Consequently, using either DEX to inhibit IL-8 gene expression in CRPC cells or the IL-8 gene-silencing strategy in ovarian cancer cells (Merritt et al, 2008) indicates that IL-8 signalling does not modulate the mechanistic basis of taxane-induced cell death in tumour cells. Instead, these studies both suggest that suppressing the level of IL-8 signalling capacity within the microenvironment of the tumour clearly enhances the therapeutic benefit of taxanes, mediated through a pronounced suppression of angiogenesis within the tumour.…”

Section: Discussionmentioning

confidence: 99%

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Dexamethasone potentiates the antiangiogenic activity of docetaxel in castration-resistant prostate cancer

Wilson¹,

Scullin²,

Worthington³

et al. 2008

Br J Cancer

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We sought to characterise whether dexamethasone (DEX) may enhance tumour response to docetaxel in in vitro and in vivo models of metastatic prostate cancer (CaP). In vitro experiments conducted on PC3 and human bone marrow endothelial cells (hBMECs) determined that administration of DEX (10 nM) reduced constitutive nuclear factor-kB (NF-kB) activity, decreasing interleukin (IL)-8, CXCL1 and VEGF gene expression in PC3 cells. Dexamethasone also attenuated docetaxel-induced NF-kB and activator protein-1 transcription and reduced docetaxel-promoted expression/secretion of IL-8 and CXCL1 in PC3 and hBMECs. Although DEX failed to enhance docetaxel cytotoxicity on PC3 cells, DEX potentiated the antiangiogenic activity of docetaxel in vitro, further reducing vessel area and vessel length in developing endothelial tubes (Po0.05). Docetaxel had a potent antiangiogenic activity in the dorsal skin flap-implanted PC3 tumours in vivo. Small blood vessel formation was further suppressed in tumours co-treated with docetaxel and DEX, substantiated by an increased average vessel diameter and segment length and a decreased number of branch points in the residual tumour vasculature (Po0.001). Our data show that DEX potentiates the antiangiogenic activity of docetaxel, suggesting a putative mechanism for the palliative and survival benefits of these agents in metastatic CaP.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Dexamethasone potentiates the antiangiogenic activity of docetaxel in castration-resistant prostate cancer

Wilson¹,

Scullin²,

Worthington³

et al. 2008

Br J Cancer

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show abstract

“…Blockade of IL-8 activity with a monoclonal antibody has been shown to decrease tumor growth in two murine cancer models (22,23). Moreover, Merritt et al (24) used systemic sirNA delivery to silence IL-8 expression in an orthotopic murine model of ovarian carcinoma, leading to a statistically significant reduction in orthotopic tumor growth and spread, suggesting that IL-8 may be a potential therapeutic target in ovarian cancer. however, few studies have investigated the targeting of IL-8 as a therapeutic strategy in ovarian cancer.…”

Section: Discussionmentioning

confidence: 99%

Tetramethylpyrazine inhibits migration of SKOV3 human ovarian carcinoma cells and decreases the expression of interleukin-8 via the ERK1/2, p38 and AP-1 signaling pathways

Yang¹

2011

Oncol Rep

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Abstract. expression by melanoma cells may influence their metastatic capabilities. tetramethylpyrazine (tMp) from Ligusticum wallichil Franch. possesses anti-inflammatory and antitumor activities. It has recently been suggested that autocrine IL-8 may play a role in tumor cell survival, invasion and migration. the role of tMp in association with IL-8 in the tumor cell migratory process remains unclear. the purpose of the present study was to determine whether TMP influences the migratory ability of a human ovarian carcinoma cell line (sKOV3) via regulation of IL-8 expression in vitro. Cell counts showed that treatment of sKOV3 with tMp (25-100 µg/ml) for 24 h did not decrease cell numbers, while an effect of tMp on the down-regulation of the expression of IL-8 was observed. In addition, migration of sKOV3 cells was suppressed after treatment with tMp (25-100 µg/ml) for 24 h. therefore, expression of IL-8 by sKOV3 cells correlates with their metastatic potential. Western blot analysis revealed that erK1/2 and p38 phosphorylation was blocked by tMp. Furthermore, IL-8 mrNA expression was inhibited significantly after co-incubation with PD98059 (erK inhibitor) and sB203580 (p38 inhibitor), respectively. Notably, these changes were the results of activator protein-1 (Ap-1) activity suppression rather than that of NF-κB. Our data suggest that tMp may inhibit tumor cell invasion and migration, at least in part, through its down-regulation of IL-8 expression. Our results provide evidence that anti-inflammation plays an important role in integrative cancer therapies. IntroductionThe functional relationship between inflammation and cancer is widely accepted. Inflammation is a critical component of tumor progression, such as tumor cell metastasis (1). Metastasis, a complex and multiple process in which tumor cells spread from the primary site to distant organs, is one of the most common causes of morbidity and mortality in patients with ovarian carcinoma. the migratory capacity of cancer cells can be regulated by various factors including growth factors and cytokines (2), such as CXC-chemokine IL-8 (CXCL-8), a pro-inflammatory cytokine initially described as a neutrophil and monocyte chemoattactant, which modulates monocyte adhesion to endothelium and vascular smooth muscle cell migration (3-5). A direct correlation has also been demonstrated between overexpressed IL-8 and the increased metastasis of tumor cells (6-8). Evidence has confirmed that tumor cells are able to respond to the autocrine release of IL-8, which enables tumor cells to have an additional growth and progression advantage (9). De Larco et al (10) reported that the concentration gradient of IL-8 produced by tumor cells, which is higher at the primary tumor site than that at noncancerous sites, promotes distant metastasis of tumor cells. Moreover, IL-8 can recruit neutrophils to the primary tumor site through its chemoattractant capacity. In response to IL-8, the recruited neutrophils release proteases and heparanase which hydrolyze components of the ext...

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“…In mouse models of ovarian cancer, liposomes containing IL-8 siRNA reduced tumor weight compared with empty control liposomes. 7 Wicha agreed that augmenting chemotherapy with CXCR1 blockade could be especially useful. "Bulk tumor cells are known to secrete IL-8 when they're killed by chemotherapy," he noted.…”

Section: Combo Plattermentioning

confidence: 99%

“…[4][5][6][7] IL-8 has also been shown to stimulate self-renewal of breast cancer stem cells in vitro. 2 The UM-INSERM team now has taken the next step and studied the effects of small molecule and antibody antagonists of CXCR1.…”

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confidence: 99%

Targeting chemokines in breast cancer

Fulmer¹

2010

Science-Business eXchange

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American and French researchers have identified CXC chemokine receptor 1 as a new target for blocking the formation of breast cancer stem cells that drive tumor growth and metastasis. 1 The findings could represent a repurposing opportunity for Italian biotech Dompe Farmaceutici S.p.A., which is exploring new indications for its small molecule inhibitor of the receptor after the compound missed the primary endpoint in Phase II transplant dysfunction trials.The therapeutic rationale for targeting cancer stem cells is clear: deplete the subset of cancer cells with the ability to self-renew and generate the full range of cells that make up a bulk tumor 2 so the disease cannot progress or relapse. The challenge has been identifying druggable targets unique to cancer stem cells.Researchers at the University of Michigan and the Institut National de la Santé et de la Recherche Médicale (INSERM) have used gene expression profiling to identify a breast cancer stem cell signature. 3 In 2009, the team found that CXC chemokine receptor 1 (CXCR1) was among the genes almost exclusively expressed in the cancer stem cell population compared with its expression in bulk tumor cells.CXCR1 is a receptor for IL-8 (CXCL8), a proinflammatory chemokine that has been implicated in the metastasis and progression of multiple malignancies, including glioma and prostate, breast and ovarian cancers. 4-7 IL-8 has also been shown to stimulate self-renewal of breast cancer stem cells in vitro. 2 The UM-INSERM team now has taken the next step and studied the effects of small molecule and antibody antagonists of CXCR1.In a human breast cancer cell line, both the small molecule CXCR1 inhibitor reparixin and an anti-CXCR1 antibody reduced the number of breast cancer stem cells compared with no treatment.After four days, both molecules abolished the entire cancer cell population even though CXCR1-expressing stem cells comprised about 2% of the total. That result suggested that CXCR1 blockade directly decreased the survival of cancer stem cells and indirectly induced cell death in the bulk tumor population.Mechanistic studies showed that inhibiting CXCR1 induced the production of soluble Fas ligand (TNF superfamily, member 6; FASL) by cancer stem cells. The proapoptotic FASL then bound its receptor on bulk tumor cells, triggering apoptosis and cell death (see Figure 1, "Chemokine blockade in breast cancer").In mice with primary human breast cancer xenografts, reparixin alone or in combination with docetaxel reduced tumor growth compared with saline control. The combination had greater efficacy than either reparixin or docetaxel alone.Additional experiments showed that reparixin could reduce cancer metastasis. Three groups of mice were injected with breast cancer cell lines. The animals then received reparixin twice daily for 28 days. At the end of that period, two of the three groups showed significant reductions in metastasis compared with animals that received saline control (p<0.01).The team was led by Max Wicha, professor of oncology and intern...

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Effect of Interleukin-8 Gene Silencing With Liposome-Encapsulated Small Interfering RNA on Ovarian Cancer Cell Growth

Abstract: Increased IL-8 expression is associated with poor clinical outcome in human ovarian carcinoma, and IL-8 gene silencing decreases tumor growth through antiangiogenic mechanisms.

Cited by 226 publications

References 49 publications

Dexamethasone potentiates the antiangiogenic activity of docetaxel in castration-resistant prostate cancer

Dexamethasone potentiates the antiangiogenic activity of docetaxel in castration-resistant prostate cancer

Tetramethylpyrazine inhibits migration of SKOV3 human ovarian carcinoma cells and decreases the expression of interleukin-8 via the ERK1/2, p38 and AP-1 signaling pathways

Targeting chemokines in breast cancer

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