Inhibition of MMP‐9 transcription and suppression of tumor metastasis by pyrrole‐imidazole polyamide

Wang, Xiaofei; Nagase, Hiroki; Watanabe, Tomohiro; Nobusue, Hiroyuki; Suzuki, Takahiro; Asami, Yukihiro; Shinojima, Yui; Kawashima, Hiroyuki; Takagi, Keiko; Mishra, Rajeev; Igarashi, Jun; Kimura, Makoto; Takayama, Tadatoshi; Fukuda, Noboru; Sugiyama, Hiroshi

doi:10.1111/j.1349-7006.2009.01435.x

Cited by 54 publications

(66 citation statements)

References 34 publications

(45 reference statements)

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“…Though MMP-9-AP-1 PIP is reported to have suppressive effect in the cell lines of breast cancer, colon cancer and cervical cancer (19), only MMP-9-NF-κB PIP showed suppression in the Caki-2 cell line. We presumed that mechanisms of the expression control vary among the cell types.…”

Section: Discussionmentioning

confidence: 99%

“…We reported previously the in vitro and in vivo effect of MMP-9-PIP on breast cancer and colon cancer cell line (19). In the mouse model, intravenous injection of MMP-9 PIP clearly inhibited colon cancer metastasis to the liver.…”

Section: Discussionmentioning

confidence: 99%

“…Since they can bind DNA with higher affinity and specificity than the usual DNA binding proteins, PIPs designed to recognize the binding Inhibition of MMP-9 using a pyrrole-imidazole polyamide reduces cell invasion in renal cell carcinoma (15)(16)(17)(18). Previously, we reported that PIP targeting for MMP-9 inhibit the migration and invasion of colon cancer cells in vitro and also inhibits their metastasis in vivo (19).…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of MMP-9 using a pyrrole-imidazole polyamide reduces cell invasion in renal cell carcinoma

Sato¹,

Nagase²,

Obinata³

et al. 2013

International Journal of Oncology

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Abstract.We investigated the clinical significance of the expression levels of matrix metalloproteinase 9 (MMP-9) in renal cell carcinoma (RCC). In addition, we validated the efficacy of pyrrole imidazole polyamide (PIP) targeting MMP-9 on inhibiting proliferation and invasion of RCC. We evaluated the expression levels of MMP-9 in 249 RCC specimens by immunostaining and analyzed the association between MMP-9 expression levels and cancer-specific survival. Furthermore, in a human RCC cell line, Caki-2, we tested the effect of a couple of PIPs targeting MMP-9 one recognizing an NF-κB binding site (MMP-9-NF-κB PIP) and another for the AP-1 binding site (MMP-9-AP-1 PIP) in the MMP-9 promoter. The expression levels of MMP-9, proliferative activity and invasive capability were tested by quantitative PCR, WST8 assay and Matrigel invasion assay, respectively. By immunostaining of the clinical specimens, strong MMP-9 staining was proven to be a significant predictor of poor prognosis for cancer-specific survival (P<0.01). In Caki-2 cells, MMP-9-NF-κB PIP significantly reduced the expression levels of MMP-9 mRNA and inhibited cell invasion, but did not affect the cell proliferation activity. On the other hand, no effect was found in MMP-9-AP-1 PIP on MMP-9 mRNA expression, cell proliferation and invasion. We confirmed the inhibitory effects of MMP-9-NF-κB PIP on the expression of MMP-9 and subsequent invasion of Caki-2 cells. Since it was clearly shown that high MMP-9 expression levels were associated with poor prognosis of RCC, MMP-9 is a potential candidate target for RCC treatment. Transcription therapy using a minor groove binder, such as NF-κB PIP, may be a potential therapeutic agent for RCC, although further investigation is required.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibition of MMP-9 using a pyrrole-imidazole polyamide reduces cell invasion in renal cell carcinoma

Sato¹,

Nagase²,

Obinata³

et al. 2013

International Journal of Oncology

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“…Hairpin pyrrole (Py)-imidazole (Im) (PI) polyamides can be designed to bind with high affinity to the minor groove of specific DNA sequences 8 : Py moieties preferentially bind T, A and C bases, but not G, whereas Im is a G-reader. These agents have shown efficacy in preclinical animal models of human diseases, including cancer, with minimal toxicity [9][10][11] . For example, PI polyamide conjugates with 1,2,9,9a-tetrahydrocyclopropa [1,2-c]benz [1,2-e]indol-4-one (CBI), which is converted to its cyclopropyl form via cyclization of a precursor containing a chloromethyl group to alkylate target DNA at the minor groove of N3 of adenine under neutral pH conditions, is a synthetic analogue of the alkylating moiety of duocarmycin A and can improve the limitations of targeting a coding sequence [12][13][14] .…”

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confidence: 99%

Inhibition of KRAS codon 12 mutants using a novel DNA-alkylating pyrrole–imidazole polyamide conjugate

et al. 2015

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Despite extensive efforts to target mutated RAS proteins, anticancer agents capable of selectively killing tumour cells harbouring KRAS mutations have remained unavailable. Here we demonstrate the direct targeting of KRAS mutant DNA using a synthetic alkylating agent (pyrrole-imidazole polyamide indole-seco-CBI conjugate; KR12) that selectively recognizes oncogenic codon 12 KRAS mutations. KR12 alkylates adenine N3 at the target sequence, causing strand cleavage and growth suppression in human colon cancer cells with G12D or G12V mutations, thus inducing senescence and apoptosis. In xenograft models, KR12 infusions induce significant tumour growth suppression, with low host toxicity in KRAS-mutated but not wild-type tumours. This newly developed approach may be applicable to the targeting of other mutant driver oncogenes in human tumours.

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“…We demonstrated significant improvement of colon tumor metastasis to liver by targeting to the human MMP9 AP1 binding site. 18) In the present study we designed and synthesized a PI polyamide to bind to an eight-base pair sequence partially overlapping the functional nuclear factor-kappa B (NF-κB) site (HN.49) and examined the ability of HN.49 polyamide compound to block MMP9 expression and exhibit biologically relevant effects in human SaOS-2 osteosarcomas cell line.…”

mentioning

confidence: 99%

Inhibition of Human Osteosarcoma Cell Migration and Invasion by a Gene Silencer, Pyrrole–Imidazole Polyamide, Targeted at the Human MMP9 NF-κB Binding Site

Kojima

Wang

Fujiwara

et al. 2014

Biological & Pharmaceutical Bulletin

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Osteosarcoma is one of the most prevalent bone tumors, occurring mostly in adolescence. However, no noticeable progress has been achieved in developing new therapeutic agents for this disease. Matrix metalloproteinase 9 (MMP9), a type IV collagenase, is a known anticancer target and is overexpressed in osteosarcomas. MMPs can degrade components of the extracellular matrix and are known to be involved in tumor invasion and metastasis. In the present study, we designed and synthesized a pyrrole-imidazole polyamide (HN.49), a gene-silencing agent that specifically targets the nuclear factor-kappa B (NF-κB) binding site of the human MMP9 promoter. We then examined the effect of HN.49 on the enzyme activity of MMP9 and the migration activity of osteosarcoma cells in vitro. Key words pyrrole-imidazole polyamide; matrix metalloproteinase 9; osteosarcoma Osteosarcoma is one of the most common primary malignant tumors of bone and occurs mainly in adolescents and young adults.1,2) There have been significant advances in its treatment in the recent years with a limb-salvage surgery and various chemotherapies. The elapse-free survival rates have been improved from less than 20% to 60%. However, these chemotherapies are not fully effective, and as a result, approximately 20% of all osteosarcoma patients still die owing to tumor metastasis.3) Therefore, the research should focus on developing new therapies for osteosarcoma.Matrix metalloproteinase 9 (MMP9), 92-kDa type IV collagenase (gelatinase B, MMP9), contains fibronectin-like domains for collagen-binding and is capable of degrading types I, IV, V, VII and XI collagens and laminin. 4,5) There is increasing evidence that MMP9 expression is elevated in malignant cancers compared with benign or non-invasive tumors and that for the role of MMP9 in tumor invasion in vitro and in vivo.6,7) Metastatic lesions of osteosarcoma in children have been shown to be strongly positive for MMP9 in immunohistochemical analysis.8) Hence, a compound that pre-transcriptionally deregulates MMP9 expression needs to be evaluated as a potentially useful MMP9 silencer for cancer therapy. Studies of the DNA minor groove binder of naturally occurring antitumor/antiviral antibiotics, including duocarmycin A and distamycin A, indicated the development of designable DNA recognition molecules in a sequence-dependent manner, including pyrrole-imidazole polyamide (PI polyamide).9-13) Since PI polyamides are low molecular organic compounds resistant to nucleolytic enzymes, PI polyamide could be transported across cell membrane and subsequently into cell nuclei without any delivery system and may not be influenced by any catabolic enzymes or metabolic enzymes, such as nucleases and p450 enzymes, even in animals. [14][15][16][17] Hence, PI polyamides show great promise as new medicines that might inhibit transcriptional control of target gene. Indeed, we have developed PI polyamides as gene silencers, including the design and synthesis of PI polyamides that target MMP9 effectively. We demonstrated significan...

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Inhibition of MMP‐9 transcription and suppression of tumor metastasis by pyrrole‐imidazole polyamide

Cited by 54 publications

References 34 publications

Inhibition of MMP-9 using a pyrrole-imidazole polyamide reduces cell invasion in renal cell carcinoma

Inhibition of MMP-9 using a pyrrole-imidazole polyamide reduces cell invasion in renal cell carcinoma

Inhibition of KRAS codon 12 mutants using a novel DNA-alkylating pyrrole–imidazole polyamide conjugate

Inhibition of Human Osteosarcoma Cell Migration and Invasion by a Gene Silencer, Pyrrole–Imidazole Polyamide, Targeted at the Human MMP9 NF-κB Binding Site

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