Effect of anticancer drugs on invasive capacity of human small-cell lung cancer cells in vitro.

Morikawa, Tetsuyuki; Shibuya, Masabumi; Sakai, Shunta; Kudo, Shouji

doi:10.1272/jnms1923.62.320

Cited by 4 publications

(5 citation statements)

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“…The metastatic and invasive potential of many cancers also depends on the expression of MMPs and MMP-2 over expression and activity associated with the invasive potential of human tumours [21]. With the present study we demonstrated that basal MMP-2 activity only is detectable in culture media and cell lysates from PC E1Araf cell line, and that expression and activity of MMP-2 was decreased by cisPt in a dose-and timedependent manner (Fig 1), accordingly to data obtained in small-cell lung cancer cells [5] but not to those showed in parental normal PC Cl3 cells [9]. Thus, one could speculate that the MMP-2 is a general target of cisPt in thyroid cells; however, cisPt caused differential effects on MMP-2 in both normal and transformed thyroid cells, and these discrepancies may be accounted for in part by the presence of high basal level of activated ERK1/2.…”

Section: Discussionsupporting

confidence: 86%

“…The chemotherapeutic agent cisplatin (cis-diamminedichloroplatinum; cisPt), widely employed for treatment of human cancer, is a potent inducer of growth arrest and/or apoptosis in most cell types. Anti-invasive properties of cisPt associated with decrease in MMP-2 activity have been reported [3][4][5] with the underlying mechanisms still being poorly understood. Anyway, as regards to that several signalling transduction pathways that can be activated by cisPt treatment, such as mitogen activated protein kinase (MAPK) pathway components, have been correlated to MMPs activation and expression [6,7].…”

Section: Introductionmentioning

confidence: 99%

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Effects of cisplatin on matrix metalloproteinase-2 in transformed thyroid cells

Urso

Muscella

Calabriso

et al. 2010

Biochemical Pharmacology

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We investigated the effects of cisplatin (cisPt) on matrix metalloproteinase-2 (MMP-2) gelatinolitic activity in transformed PC E1Araf rat thyroid cells. Cells incubated with increasing cisPt concentrations showed dose-and time-dependent decrease of the MMP-2 protein and activity. CisPt provoked the translocation from the cytosol to the plasma membrane of atypical protein kinase C-zeta (PKC-δ) and the activation of PKB/AKT. The effect of cisPt on MMP-2 was dependent on PKC-δ activation since it was potentiated by a myristoylated PKC-δ pseudo substrate peptide or by PKC-δ down regulation by siRNA. Moreover, MMP-2 activity modulation by cisPt was also dependent on PKB/AKT activation since it was decreased by PKB/AKT down regulation by siRNA or by pharmacological inhibition of PI3K, thus indicating the importance of the balance of PKB/AKT and PKC-δ in regulating the cisPt effect on MMP-2 activity. The PC E1Araf cells displayed a migratory capacity that was blocked by MMP-2 down regulation using siRNA or pharmacological inhibition. The inhibition of cell migration was also obtained with cisPt; in cisPt-treated cells the administration of MMP-2 active protein was able to restore cell migration capacity. In conclusion, the decrease of MMP-2 secretion after cisPt was allowed by PKB/AKT and counteracted by PKC-δ; the cisPt-provoked inhibition of MMP-2 secretion ended in reduction of cell migration.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Effects of cisplatin on matrix metalloproteinase-2 in transformed thyroid cells

Urso

Muscella

Calabriso

et al. 2010

Biochemical Pharmacology

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“…Although an inhibitory action of cisplatin on MMP-2 has been described previously in small-cell lung cancer (Morikawa et al, 1995) and glioblastoma cells (Chintala et al, 1997), cisplatin did not exhibit a significant suppression of MMP-2 mRNA (Figure 2a) and MMP-2 protein levels (Figure 2b and c) in HeLa cells indicating a tumor-type specific modulation of this enzyme. Apart from MMP-2, cisplatin did also not influence MMP-9 and TIMP-2 expression (Figure 2c).…”

Section: Inhibition Of Cancer Cell Invasion By Cisplatin R Ramer Et Almentioning

confidence: 46%

“…In addition, a broad array of actions independent of DNA adduct production has been described, including activation of mitochondrial (Biroccio et al, 2004) and Fas-associated apoptotic pathways (Razzaque et al, 1999) as well as induction of mitogen-activated protein kinases (MAPKs) (Zhang et al, 2005;Villedieu et al, 2006). Moreover, anti-invasive properties of cisplatin have been reported (Morikawa et al, 1995;Mabuchi et al, 2004) with the underlying mechanisms still being poorly understood.…”

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confidence: 99%

Upregulation of tissue inhibitor of matrix metalloproteinases-1 confers the anti-invasive action of cisplatin on human cancer cells

2007

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Cancer cell invasion is one of the crucial events in local spreading, growth and metastasis of tumors. The present study investigates the mechanism underlying the antiinvasive action of the chemotherapeutic cisplatin. In human cervical carcinoma cells (HeLa), cisplatin caused a time-and concentration-dependent suppression of cell invasion through Matrigel. Inhibition of invasion was accompanied by upregulation of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1), whereas levels of matrix metalloproteinase-2 (MMP-2), MMP-9 and TIMP-2 remained unchanged. Cisplatin's effects on TIMP-1 expression and invasion were associated with phosphorylations of p38 and p42/44 mitogen-activated protein kinases and were abrogated by specific inhibitors of both pathways. The impact of TIMP-1 in the anti-invasive action of cisplatin was proven by transfecting cells with small interfering RNA targeting TIMP-1, which completely reversed suppression of invasion by cisplatin. A functional relevance of TIMP-1 upregulation was substantiated by findings showing a concentration-dependent inhibition of Matrigel invasion by recombinant TIMP-1. The essential role of TIMP-1 in the anti-invasive action of cisplatin was confirmed using another human cervical carcinoma cell line (C33A) and human lung carcinoma cells (A549). Altogether, our data demonstrate a hitherto unknown mechanism by which cisplatin exerts its antimetastatic properties on highly invasive cancer cells.

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“…Previous reports have shown a variable effect of cisplatin on MMPs in different human cancer cells, suggesting a tumor-type modulation of these enzymes. Although an inhibitory action of cisplatin on MMP2 activity has been described in lung cancer and glioblastoma cells [26], other studies have shown that cisplatin does not exhibit a significant suppression of MMP2 activity in human cervical and ovarian carcinoma cells [27,28]. To evaluate the effect of cisplatin on MMPs in vascular endothelial cells further studies were performed measuring MMP2 and MMP9 activity, the two most important MMPs expressed in endothelial cells, by zymographic analyses.…”

Section: Discussionmentioning

confidence: 99%

Cisplatin Reduces Endothelial Cell Migration Via Regulation of Type 2-Matrix Metalloproteinase Activity

Montiel¹,

Urso²,

Esther³

et al. 2009

Cell Physiol Biochem

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Aims: In this study we investigated the effect of cisplatin on endothelial cell migration, an essential process for vascular remodeling and regeneration in several physiological and pathological situations. Material and Methods: Human umbilical vein endothelial cells (HUVEC) were treated with cisplatin and endothelial cell migration analyzed by fluorescence and scratch-wound migration assay. MMP2 and MMP9 activity were determined by zymographic assay, and MAPK activation by Western blotting analysis. Results: We demonstrated that cisplatin provoked a time- and dose-dependent decrease of HUVEC migration; this effect was clearly independent from its well known cytotoxic activity. In addition, cisplatin markedly reduced MMP2 activity in both conditioned media and cell lysates, increased p38 MAPK and JNK phosphorylation, but did not affect ERK phosphorylation. Endothelial cell migration was attenuated by treatment of cells with GM6001, a non-specific inhibitor of MMPs, or by a selective anti-MMP2 antibody. However, treatment of cells with SB202190 or SP600125, inhibitors of p38 MAPK and JNK respectively, did not affect HUVEC migration. Conclusion: These results suggested that cisplatin induced a reduction of endothelial cell migration through an inhibition of MMP2 activity by downstream signal transduction pathways independent of JNK and p38 MAPK activation.

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Effect of anticancer drugs on invasive capacity of human small-cell lung cancer cells in vitro.

Cited by 4 publications

References 0 publications

Effects of cisplatin on matrix metalloproteinase-2 in transformed thyroid cells

Effects of cisplatin on matrix metalloproteinase-2 in transformed thyroid cells

Upregulation of tissue inhibitor of matrix metalloproteinases-1 confers the anti-invasive action of cisplatin on human cancer cells

Cisplatin Reduces Endothelial Cell Migration Via Regulation of Type 2-Matrix Metalloproteinase Activity

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