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Small Molecule Inhibitors of Plasminogen Activator Inhibitor-1 Elicit Anti-Tumorigenic and Anti-Angiogenic Activity.

Placencio VR, Ichimura A, Miyata T, DeClerck YA - PLoS ONE (2015)

Bottom Line: In vivo, oral administration of TM5441 (20 mg/kg daily) to HT1080 and HCT116 xenotransplanted mice increased tumor cell apoptosis and had a significant disruptive effect on the tumor vasculature that was associated with a decrease in tumor growth and an increase in survival that, however, were not statistically significant.The effect on tumor vasculature in vivo was further examined in endothelial cells (EC) in vitro and this analysis indicated that both TM5275 and TM5441 inhibited EC branching in a 3D Matrigel assay at concentrations where they had little effect on EC apoptosis.These studies bring novel insight on the activity of PAI-1 inhibitors and provide important information for the future design of inhibitors targeting PAI-1 as therapeutic agents in cancer.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology, Oncology and Blood and Bone Marrow Transplantation, Department of Pediatrics, University of Southern California, Los Angeles, California, United States of America; The Saban Research Institute of Children's Hospital, Los Angeles, California, 90027, United States of America.

ABSTRACT
Numerous studies have shown a paradoxical positive correlation between elevated levels of plasminogen activator inhibitior-1 (PAI-1) in tumors and blood of cancer patients with poor clinical outcome, suggesting that PAI-1 could be a therapeutic target. Here we tested two orally bioavailable small molecule inhibitors of PAI-1 (TM5275 and TM5441) for their efficacy in pre-clinical models of cancer. We demonstrated that these inhibitors decreased cell viability in several human cancer cell lines with an IC50 in the 9.7 to 60.3 μM range and induced intrinsic apoptosis at concentrations of 50 μM. In vivo, oral administration of TM5441 (20 mg/kg daily) to HT1080 and HCT116 xenotransplanted mice increased tumor cell apoptosis and had a significant disruptive effect on the tumor vasculature that was associated with a decrease in tumor growth and an increase in survival that, however, were not statistically significant. Pharmacokinetics studies indicated an average peak plasma concentration of 11.4 μM one hour after oral administration and undetectable levels 23 hours after administration. The effect on tumor vasculature in vivo was further examined in endothelial cells (EC) in vitro and this analysis indicated that both TM5275 and TM5441 inhibited EC branching in a 3D Matrigel assay at concentrations where they had little effect on EC apoptosis. These studies bring novel insight on the activity of PAI-1 inhibitors and provide important information for the future design of inhibitors targeting PAI-1 as therapeutic agents in cancer.

No MeSH data available.


Related in: MedlinePlus

Decreased proliferation in cancer cells treated with TM5275 and TM5441.Representative fluorescence-activated cell sorting (FACS) plots are shown in the upper panels with BrdU positive cells (purple) shown within the upper gate. The mean percentage (± SD) of HT1080 and HCT116 BrdU positive cells after treatment with DMSO (white bar), TM5275 (black bar) or TM5441 (red bar) was graphed, n = 3. * indicates P values compared to DMSO controls < 0.05, ** indicates P < 0.01, and *** indicates P < 0.001.
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pone.0133786.g002: Decreased proliferation in cancer cells treated with TM5275 and TM5441.Representative fluorescence-activated cell sorting (FACS) plots are shown in the upper panels with BrdU positive cells (purple) shown within the upper gate. The mean percentage (± SD) of HT1080 and HCT116 BrdU positive cells after treatment with DMSO (white bar), TM5275 (black bar) or TM5441 (red bar) was graphed, n = 3. * indicates P values compared to DMSO controls < 0.05, ** indicates P < 0.01, and *** indicates P < 0.001.

Mentions: To examine the effect of TM inhibitors on cell proliferation, we used BrdU incorporation to test cell cycle activity. This analysis (Fig 2) revealed a significant decrease in the percentage of BrdU positive cells with both cell lines treated with TM5275 and TM5441 (from 48.5% and 48.7% in DMSO-treated cells to 38.1% and 42.5% in TM5275-treated HT1080 and HCT116 cells and 28.3% and 34.6% for TM5441-treated cells, respectively). These results indicated that TM5275 and TM5441 decreased tumor cell viability in part through diminished proliferation.


Small Molecule Inhibitors of Plasminogen Activator Inhibitor-1 Elicit Anti-Tumorigenic and Anti-Angiogenic Activity.

Placencio VR, Ichimura A, Miyata T, DeClerck YA - PLoS ONE (2015)

Decreased proliferation in cancer cells treated with TM5275 and TM5441.Representative fluorescence-activated cell sorting (FACS) plots are shown in the upper panels with BrdU positive cells (purple) shown within the upper gate. The mean percentage (± SD) of HT1080 and HCT116 BrdU positive cells after treatment with DMSO (white bar), TM5275 (black bar) or TM5441 (red bar) was graphed, n = 3. * indicates P values compared to DMSO controls < 0.05, ** indicates P < 0.01, and *** indicates P < 0.001.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4514594&req=5

pone.0133786.g002: Decreased proliferation in cancer cells treated with TM5275 and TM5441.Representative fluorescence-activated cell sorting (FACS) plots are shown in the upper panels with BrdU positive cells (purple) shown within the upper gate. The mean percentage (± SD) of HT1080 and HCT116 BrdU positive cells after treatment with DMSO (white bar), TM5275 (black bar) or TM5441 (red bar) was graphed, n = 3. * indicates P values compared to DMSO controls < 0.05, ** indicates P < 0.01, and *** indicates P < 0.001.
Mentions: To examine the effect of TM inhibitors on cell proliferation, we used BrdU incorporation to test cell cycle activity. This analysis (Fig 2) revealed a significant decrease in the percentage of BrdU positive cells with both cell lines treated with TM5275 and TM5441 (from 48.5% and 48.7% in DMSO-treated cells to 38.1% and 42.5% in TM5275-treated HT1080 and HCT116 cells and 28.3% and 34.6% for TM5441-treated cells, respectively). These results indicated that TM5275 and TM5441 decreased tumor cell viability in part through diminished proliferation.

Bottom Line: In vivo, oral administration of TM5441 (20 mg/kg daily) to HT1080 and HCT116 xenotransplanted mice increased tumor cell apoptosis and had a significant disruptive effect on the tumor vasculature that was associated with a decrease in tumor growth and an increase in survival that, however, were not statistically significant.The effect on tumor vasculature in vivo was further examined in endothelial cells (EC) in vitro and this analysis indicated that both TM5275 and TM5441 inhibited EC branching in a 3D Matrigel assay at concentrations where they had little effect on EC apoptosis.These studies bring novel insight on the activity of PAI-1 inhibitors and provide important information for the future design of inhibitors targeting PAI-1 as therapeutic agents in cancer.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology, Oncology and Blood and Bone Marrow Transplantation, Department of Pediatrics, University of Southern California, Los Angeles, California, United States of America; The Saban Research Institute of Children's Hospital, Los Angeles, California, 90027, United States of America.

ABSTRACT
Numerous studies have shown a paradoxical positive correlation between elevated levels of plasminogen activator inhibitior-1 (PAI-1) in tumors and blood of cancer patients with poor clinical outcome, suggesting that PAI-1 could be a therapeutic target. Here we tested two orally bioavailable small molecule inhibitors of PAI-1 (TM5275 and TM5441) for their efficacy in pre-clinical models of cancer. We demonstrated that these inhibitors decreased cell viability in several human cancer cell lines with an IC50 in the 9.7 to 60.3 μM range and induced intrinsic apoptosis at concentrations of 50 μM. In vivo, oral administration of TM5441 (20 mg/kg daily) to HT1080 and HCT116 xenotransplanted mice increased tumor cell apoptosis and had a significant disruptive effect on the tumor vasculature that was associated with a decrease in tumor growth and an increase in survival that, however, were not statistically significant. Pharmacokinetics studies indicated an average peak plasma concentration of 11.4 μM one hour after oral administration and undetectable levels 23 hours after administration. The effect on tumor vasculature in vivo was further examined in endothelial cells (EC) in vitro and this analysis indicated that both TM5275 and TM5441 inhibited EC branching in a 3D Matrigel assay at concentrations where they had little effect on EC apoptosis. These studies bring novel insight on the activity of PAI-1 inhibitors and provide important information for the future design of inhibitors targeting PAI-1 as therapeutic agents in cancer.

No MeSH data available.


Related in: MedlinePlus