Levamisole Inhibits Angiogenesis in vitro and Tumor Growth in vivo

Friis, T; Engel, Anne-Marie; Klein, Bjarke M.; Rygaard, Jørgen

doi:10.1007/s10456-005-3588-0

Cited by 19 publications

(16 citation statements)

References 28 publications

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“…However, 2-ME had previously shown low inhibition at 10 μM and moderate inhibition at 50 μM (Kang et al, 2006), whereas our assay showed low and moderate inhibition at 0.01–0.2 and 1 μM, respectively. Moreover, compared to the method by Friis et al (2003, 2005), which is a similar assay to ours, levamisole was reported to have mild inhibition at 500 μM (in our study 0.01–1 μM), moderate at 750–1000 μM (in our study 100–500 μM), and strong at 2000 μM (in our study 1000–2000 μM). The anti-VEGF was reported to have moderate to strong inhibition at 0.1–10 mg/ml in an in vitro model with different study setup (Sims et al, 2008) compared to our assay (inhibition at 0.5–50 μg/ml).…”

Section: Discussionsupporting

confidence: 88%

Intra-Laboratory Pre-Validation of a Human Cell Based in vitro Angiogenesis Assay for Testing Angiogenesis Modulators

Sarkanen¹,

Mannerström²,

Vuorenpää³

et al. 2011

Front. Pharmacol.

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The developed standardized human cell based in vitro angiogenesis assay was intra-laboratory pre-validated to verify that the method is reliable and relevant for routine testing of modulators of angiogenesis, e.g., pharmaceuticals and industrial chemicals. This assay is based on the earlier published method but it was improved and shown to be more sensitive and rapid than the previous assay. The performance of the assay was assessed by using six reference chemicals, which are widely used pharmaceuticals that inhibit angiogenesis: acetyl salicylic acid, erlotinib, 2-methoxyestradiol, levamisole, thalidomide, and anti-vascular endothelial growth factor. In the intra-laboratory pre-validation, the sensitivity of the assay (upper and lower limits of detection and linearity of response in tubule formation), batch to batch variation in tubule formation between different Master cell bank batches, and precision as well as the reliability of the assay (reproducibility and repeatability) were tested. The pre-set acceptance criteria for the intra-laboratory pre-validation study were met. The relevance of the assay in man was investigated by comparing the effects of reference chemicals and their concentrations to the published human data. The comparison showed a good concordance, which indicates that this human cell based angiogenesis model predicts well the effects in man and has the potential to be used to supplement and/or replace of animal tests.

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Section: Discussionsupporting

confidence: 88%

Intra-Laboratory Pre-Validation of a Human Cell Based in vitro Angiogenesis Assay for Testing Angiogenesis Modulators

Sarkanen¹,

Mannerström²,

Vuorenpää³

et al. 2011

Front. Pharmacol.

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“…Notably, this effect is identical to what is observed in the assay when VEGF is omitted from the growth medium [37], [38], which may indicate that N -methyllevamisole triflate ( 7a ) effectively interferes with VEGF signalling, albeit at relatively high concentrations. Though, based on this preliminary test, we cannot rule out possible interaction of these chemotypes with other phosphatases and/or kinases.…”

Section: Resultssupporting

confidence: 67%

“…Likewise the anthelminthic drug ( S )-levamisole hydrochloride (Ergamisol ® ; 1 ) [29], [30], which has also been used in the treatment of rheumatoid arthritis [31], [32], as well as an immunostimulant adjuvant in chemotherapy for several types of cancer [33]–[36], was recently shown to exhibit angiogenesis inhibitory activity in vitro and tumor growth inhibition in vivo [37], [38]. The in vitro antiangiogenic effect resembled that of Avastin in several respects, but especially with regard to inhibition of network formation and induction of non-differentiated clusters of cells [38].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Antiangiogenic Activity of N-Alkylated Levamisole Derivatives

et al. 2012

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Inhibition of angiogenesis is a promising addition to current cancer treatment strategies. Neutralization of vascular endothelial growth factor by monoclonal antibodies is clinically effective but may cause side effects due to thrombosis. Low molecular weight angiogenesis inhibitors are currently less effective than antibody treatment and are also associated with serious side effects. The discovery of new chemotypes with efficient antiangiogenic activity is therefore of pertinent interest. (S)-Levamisole hydrochloride, an anthelminthic drug approved for human use and with a known clinical profile, was recently shown to be an inhibitor of angiogenesis in vitro and exhibited tumor growth inhibition in mice. Here we describe the synthesis and in vitro evaluation of a series of N-alkylated analogues of levamisole with the aim of characterizing structure–activity relationships with regard to inhibition of angiogenesis. N-Methyllevamisole and p-bromolevamisole proved more effective than the parent compound, (S)-levamisole hydrochloride, with respect to inhibition of angiogenesis and induction of undifferentiated cluster morphology in human umbilical vein endothelial cells grown in co-culture with normal human dermal fibroblasts. Interestingly, the cluster morphology caused by N-methyllevamisole was different than the clusters observed for levamisole, and a third “cord-like” morphology resembling that of the known drug suramin was observed for an aniline-containing derivative. New chemotypes exhibiting antiangiogenic effects in vitro are thus described, and further investigation of their underlying mechanism of action is warranted.

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“…Previously, it has been shown that it affects cell proliferation in different cancers [15] and modulates the phosphorylation relevant for both cell cycle progression and apoptosis. Studies have also shown that it can be used for anti- helminthic infestations and various autoimmune diseases [16], [17]. Besides, it has been shown that levamisole has anticancer activity in combination with fluorouracil (5-FU) as adjuvant therapy for tumor-node-metastasis (TNM) stage III (Dukes' C) colon carcinoma [18].…”

Section: Introductionmentioning

confidence: 99%

Novel Levamisole Derivative Induces Extrinsic Pathway of Apoptosis in Cancer Cells and Inhibits Tumor Progression in Mice

et al. 2012

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BackgroundLevamisole, an imidazo(2,1-b)thiazole derivative, has been reported to be a potential antitumor agent. In the present study, we have investigated the mechanism of action of one of the recently identified analogues, 4a (2-benzyl-6-(4′-fluorophenyl)-5-thiocyanato-imidazo[2,1-b][1], [3], [4]thiadiazole).Materials and MethodsROS production and expression of various apoptotic proteins were measured following 4a treatment in leukemia cell lines. Tumor animal models were used to evaluate the effect of 4a in comparison with Levamisole on progression of breast adenocarcinoma and survival. Immunohistochemistry and western blotting studies were performed to understand the mechanism of 4a action both ex vivo and in vivo.ResultsWe have determined the IC50 value of 4a in many leukemic and breast cancer cell lines and found CEM cells most sensitive (IC50 5 µM). Results showed that 4a treatment leads to the accumulation of ROS. Western blot analysis showed upregulation of pro-apoptotic proteins t-BID and BAX, upon treatment with 4a. Besides, dose-dependent activation of p53 along with FAS, FAS-L, and cleavage of CASPASE-8 suggest that it induces death receptor mediated apoptotic pathway in CEM cells. More importantly, we observed a reduction in tumor growth and significant increase in survival upon oral administration of 4a (20 mg/kg, six doses) in mice. In comparison, 4a was found to be more potent than its parental analogue Levamisole based on both ex vivo and in vivo studies. Further, immunohistochemistry and western blotting studies indicate that 4a treatment led to abrogation of tumor cell proliferation and activation of apoptosis by the extrinsic pathway even in animal models.ConclusionThus, our results suggest that 4a could be used as a potent chemotherapeutic agent.

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Levamisole Inhibits Angiogenesis in vitro and Tumor Growth in vivo

Cited by 19 publications

References 28 publications

Intra-Laboratory Pre-Validation of a Human Cell Based in vitro Angiogenesis Assay for Testing Angiogenesis Modulators

Intra-Laboratory Pre-Validation of a Human Cell Based in vitro Angiogenesis Assay for Testing Angiogenesis Modulators

Synthesis and Antiangiogenic Activity of N-Alkylated Levamisole Derivatives

Novel Levamisole Derivative Induces Extrinsic Pathway of Apoptosis in Cancer Cells and Inhibits Tumor Progression in Mice

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