Synergistic Interaction between Cisplatin and Gemcitabine in Ovarian and Colon Cancer Cell Lines

Bergman, Andries M.; Haperen, V. W. T. Ruiz Van; Veerman, G.; Kuiper, Catharina M.; Peters, Godefridus J.

doi:10.1007/978-1-4615-2584-4_32

Cited by 127 publications

(155 citation statements)

References 9 publications

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“…Moreover, the administered fluvastatin dose in our in vivo experiment was based on the study by Ferrara et al (2003), who showed, for the same total dose given in 14 days, serum concentrations of fluvastatin in mice higher than 1.2 mg ml À1 , representing drug levels of B2 times the mean drug concentration in human plasma after a 40 mg oral dose and confirming the potential translation to the clinic of our data. The chemotherapeutic activity of gemcitabine is well known (Bergman et al, 1996), and has been confirmed by MIA PaCa2 cells used in this study, whereas the antiproliferative activity of fluvastatin has been previously described only in breast cancer cells . Treatment with fluvastatin is associated with tumour cell rounding, followed by cell detachment and apoptosis.…”

Section: Discussionsupporting

confidence: 71%

Fluvastatin synergistically enhances the antiproliferative effect of gemcitabine in human pancreatic cancer MIAPaCa-2 cells

et al. 2005

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The new combination between the nucleoside analogue gemcitabine and the cholesterol-lowering drug fluvastatin was investigated in vitro and in vivo on the human pancreatic tumour cell line MIAPaCa-2. The present study demonstrates that fluvastatin inhibits proliferation, induces apoptosis in pancreatic cancer cells harbouring a p21ras mutation at codon 12 and synergistically potentiates the cytotoxic effect of gemcitabine. The pharmacologic activities of fluvastatin are prevented by administration of mevalonic acid, suggesting that the shown inhibition of geranyl-geranylation and farnesylation of cellular proteins, including p21rhoA and p21ras, plays a major role in its anticancer effect. Fluvastatin treatment also indirectly inhibits the phosphorylation of p42ERK2/mitogen-activated protein kinase, the cellular effector of ras and other signal transduction peptides. Moreover, fluvastatin administration significantly increases the expression of the deoxycytidine kinase, the enzyme required for the activation of gemcitabine, and simultaneously reduces the 5 0 -nucleotidase, responsible for deactivation of gemcitabine, suggesting a possible additional role of these enzymes in the enhanced cytotoxic activity of gemcitabine. Finally, a significant in vivo antitumour effect on MIAPaCa-2 xenografts was observed with the simultaneous combination of fluvastatin and gemcitabine, resulting in an almost complete suppression and a marked delay in relapse of tumour growth. In conclusion, the combination of fluvastatin and gemcitabine is an effective cytotoxic, proapoptotic treatment in vitro and in vivo against MIAPaCa-2 cells by a mechanism of action mediated, at least in part, by the inhibition of p21ras and rhoA prenylation. The obtained experimental findings might constitute the basis for a novel translational research in humans.

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Section: Discussionsupporting

confidence: 71%

Fluvastatin synergistically enhances the antiproliferative effect of gemcitabine in human pancreatic cancer MIAPaCa-2 cells

et al. 2005

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“…Growth inhibitory assays were carried out as described previously (38,39). Cells in logarithmic growth were transferred to 96-well plates (100 μL medium per well) at a density of 2,500 cells per well for HeLa, HT29, H460, A431, and DU145; 3,000 cells per well for SW480; 3,500 cells per well for MCF-7, BE2-C, and SJ-G2; and 2,000 cells per well for A2780.…”

Section: Mtt Assaymentioning

confidence: 99%

The Dynamin Inhibitors MiTMAB and OcTMAB Induce Cytokinesis Failure and Inhibit Cell Proliferation in Human Cancer Cells

Joshi

Perera²,

Gilbert³

et al. 2010

Molecular Cancer Therapeutics

100

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The endocytic protein dynamin II (dynII) participates in cell cycle progression and has roles in centrosome cohesion and cytokinesis. We have described a series of small-molecule inhibitors of dynamin [myristyl trimethyl ammonium bromides (MiTMAB)] that competitively interfere with the ability of dynamin to bind phospholipids and prevent receptor-mediated endocytosis. We now report that dynII functions specifically during the abscission phase of cytokinesis and that MiTMABs exclusively block this step in the cell cycle. Cells treated with MiTMABs (MiTMAB and octadecyltrimethyl ammonium bromide) and dyn-depleted cells remain connected via an intracellular bridge for a prolonged period with an intact midbody ring before membrane regression and binucleate formation. MiTMABs are the first compounds reported to exclusively block cytokinesis without affecting progression through any other stage of the cell cycle. Thus, MiTMABs represent a new class of antimitotic compounds. We show that MiTMABs are potent inhibitors of cancer cell growth and have minimal effect on nontumorigenic fibroblast cells. Thus, MiTMABs have toxicity and antiproliferative properties that preferentially target cancer cells. This suggests that dynII may be a novel target for pharmacologic intervention for the treatment of cancer.

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“…The measurements were limited to Pt-DNA adduct formation. Total uptake of OHP in cells was not measured, as it was considered unlikely that a nucleoside analogue would affect uptake of a platinum compound into a cell, because transport mechanisms for platinum analogs are not affected by nucleoside analogs, but Pt-DNA adduct formation and repair are (Bergman et al, 1996;Van Moorsel et al, 1999;Yang et al, 2000). With OHP alone adduct formation ranged from 1.8 to 2.6 pmol mg À1 DNA ( Figure 5).…”

Section: Formation Of Pt-dna Adductsmentioning

confidence: 99%

Mechanism of trifluorothymidine potentiation of oxaliplatin-induced cytotoxicity to colorectal cancer cells

et al. 2007

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Oxaliplatin (OHP) is an anticancer agent that acts by formation of Platinum-DNA (Pt-DNA) adducts resulting in DNA-strand breaks and is used for the treatment of colorectal cancer. The pyrimidine analog trifluorothymidine (TFT) forms together with a thymidine phosphorylase inhibitor (TPI) the anticancer drug formulation TAS-102, in which TPI enhances the bioavailability of TFT in vivo. In this in vitro study the combined cytotoxic effects of OHP with TFT were investigated in human colorectal cancer cells as a model for TAS-102 combinations. In a panel of five colon cancer cell lines (WiDr, H630, Colo320, SNU-C4 and SW1116) we evaluated the OHP-TFT drug combinations using the multiple drug -effect analysis with CalcuSyn software, in which the combination index (CI) indicates synergism (CIo0.9), additivity (CI ¼ 0.9 -1.1) or antagonism (CI41.1). Drug target analysis was used for WiDr, H630 and SW1116 to investigate whether there was an increase in Pt-DNA adduct formation, DNA damage induction, cell cycle delay and apoptosis. Trifluorothymidine combined with OHP resulted in synergism for all cell lines (all CIo0.9). This was irrespective of schedule in which either one of the drugs was kept at a constant concentration (using variable drug ratio) or when the two drugs were added in a 1 : 1 IC 50 -based molar ratio. Synergism could be increased for WiDr using sequential drug treatment schedules. Trifluorothymidine increased Pt-DNA adduct formation significantly in H630 and SW1116 (14.4 and 99.1%, respectively; Po0.05). Platinum-DNA adducts were retained best in SW1116 in the presence of TFT. More DNA-strand breaks were induced in SW1116 and the combination increased DNA damage induction (420%) compared with OHP alone. Exposure to the drugs induced a clear cell-cycle S-phase arrest, but was dose schedule and cell line dependent. Trifluorothymidine (TFT) and OHP both induced apoptosis, which increased significantly for WiDr and SW1116 after TFT -OHP exposure (18.8 and 20.6% respectively; Po0.05). The basal protein levels of ERCC1 DNA repair enzyme were not related to the DNA damage that was induced in the cell lines. In conclusion, the combination of TFT with the DNA synthesis inhibitor OHP induces synergism in colorectal cancer cells, but is dependent on the dose and treatment schedule used.

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Synergistic Interaction between Cisplatin and Gemcitabine in Ovarian and Colon Cancer Cell Lines

Cited by 127 publications

References 9 publications

Fluvastatin synergistically enhances the antiproliferative effect of gemcitabine in human pancreatic cancer MIAPaCa-2 cells

Fluvastatin synergistically enhances the antiproliferative effect of gemcitabine in human pancreatic cancer MIAPaCa-2 cells

The Dynamin Inhibitors MiTMAB and OcTMAB Induce Cytokinesis Failure and Inhibit Cell Proliferation in Human Cancer Cells

Mechanism of trifluorothymidine potentiation of oxaliplatin-induced cytotoxicity to colorectal cancer cells

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