Anticancer Effect of COX-2 Inhibitor DuP-697 Alone and in Combination with Tyrosine Kinase Inhibitor (E7080) on Colon Cancer Cell Lines

Altun, Ahmet; Turgut, Nergiz Hacer; Kaya, Tijen

doi:10.7314/apjcp.2014.15.7.3113

Cited by 9 publications

(6 citation statements)

References 53 publications

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“…There is cross stimulation as PGE2 stimulates EGFR signaling while, EGRF transactivation stimulates COX2, in this way PGE2 expression (Ghosh et al, 2010). Recently we reported that DuP-697, a selective COX-2 inhibitor induces antiproliferative, antiangiogenic and apoptotic effects on HT29 CRC cells (Altun et al, 2014) and the combination of DuP-697 with E7080, a multi-targeted kinase inhibitor shows stronger effects. The combined use of two drugs produced synergistic effects.…”

Section: Discussionmentioning

confidence: 99%

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Effects of a Multikinase Inhibitor Motesanib (AMG 706) Alone and Combined with the Selective DuP-697 COX-2 Inhibitor on Colorectal Cancer Cells

Kaya¹,

Altun²,

Turgut³

et al. 2016

Asian Pacific Journal of Cancer Prevention

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In the present study, we investigated the effects of motesanib (AMG 706), a multikinase inhibitor alone and in combination with DuP-697, an irreversible selective inhibitor of COX-2, on cell proliferation, angiogenesis, and apoptosis induction in a human colorectal cancer cell line (HT29). Real time cell analysis (RTCA, Xcelligence system) was used to determine the effects on colorectal cancer cell proliferation. Apoptosis was assessed with annexin V staining and angiogenesis was determined with chorioallantoic membrane model. We found that motesanib alone exerted antiproliferative, antiangiogenic and apoptotic effects on HT29 colorectal cancer cells. Combination with DUP-697 increased the antiproliferative, antiangiogenic and apoptotic effects. Results of this study indicate that motesanib may be a good choice in treatment of colorectal tumors. In addition, the increased effects of combination of motesanib with DuP-697 raise the possibility of using lower doses of these drugs and therefore avoid/minimize the dose-dependent side effects generally observed.

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Section: Discussionmentioning

confidence: 99%

“…The partially effective cytotoxic dose of DuP-697 was chosen according to the results in our recently reported study (Altun et al, 2014). Combination of Motesanib+DuP caused complete cytotoxic effect on HT29 cells when compared to the motesanib 25 nM alone (p<0.05) ( Figure 2B).…”

Section: Monitoring Of Cytotoxicity In Real-time Using Xcelligence Symentioning

confidence: 94%

Effects of a Multikinase Inhibitor Motesanib (AMG 706) Alone and Combined with the Selective DuP-697 COX-2 Inhibitor on Colorectal Cancer Cells

Kaya¹,

Altun²,

Turgut³

et al. 2016

Asian Pacific Journal of Cancer Prevention

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“…It is important to emphasize that in vitro assays to determine IC 50 values depend to a significant degree on a number of factors, including cell viability, cell proliferation rates, cell confluency at the time of drug exposure and method used to determine cell viability (type of assay). This may explain why IC 50 values for certain tumor cell lines can differ [24], [25]. Nevertheless, with this panel of CRC cell lines we demonstrate a relatively low cytotoxic effect of E7080 on CRC cell viability in vitro.…”

Section: Discussionmentioning

confidence: 68%

E7080 (Lenvatinib), a Multi-Targeted Tyrosine Kinase Inhibitor, Demonstrates Antitumor Activities Against Colorectal Cancer Xenografts

et al. 2014

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Clinical prognosis of metastasized colorectal carcinoma (CRC) is still not at desired levels and novel drugs are needed. Here, we focused on the multi-tyrosine kinase inhibitor E7080 (Lenvatinib) and assessed its therapeutic efficacy against human CRC cell lines in vitro and human CRC xenografts in vivo. The effect of E7080 on cell viability was examined on 10 human CRC cell lines and human endothelial cells (HUVEC). The inhibitory effect of E7080 on VEGF-induced angiogenesis was studied in an ex vivo mouse aortic ring angiogenesis assay. In addition, the efficacy of E7080 against xenografts derived from CRC cell lines and CRC patient resection specimens with mutated KRAS was investigated in vivo. A relatively low cytotoxic effect of E7080 on CRC cell viability was observed in vitro. Endothelial cells (HUVEC) were more susceptible to the incubation with E7080. This is in line with the observation that E7080 demonstrated an anti-angiogenic effect in a three-dimensional ex vivo mouse aortic ring angiogenesis assay. E7080 effectively disrupted CRC cell-mediated VEGF-stimulated growth of HUVEC in vitro. Daily in vivo treatment with E7080 (5 mg/kg) significantly delayed the growth of KRAS mutated CRC xenografts with decreased density of tumor-associated vessel formations and without tumor regression. This observation is in line with results that E7080 did not significantly reduce the number of Ki67-positive cells in CRC xenografts. The results suggest antiangiogenic activity of E7080 at a dosage that was well tolerated by nude mice. E7080 may provide therapeutic benefits in the treatment of CRC with mutated KRAS.

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“…Drug repositioning in Europe and the United States is better established and this approach produced six drugs approved by the U.S. Food and Drug Administration (FDA) in 2009, compared to only one drug in 2001. New indications introduced by drug repositioning include thalidomide, a sedative hypnotic agent, for multiple myeloma and leprosy [ 2 – 4 ]; a COX-2 inhibitor for pancreatic cancer and colorectal cancer [ 13 , 14 ]; aspirin, an NSAID, for colorectal cancer [ 5 ]; and metformin, an antidiabetic drug, for endometrial cancer [ 6 ]. In this paper, we examine potential drug repositioning of PPAR ligands and ritonavir for ovarian cancer, metformin for endometrial cancer, and a COX-2 inhibitor for cervical cancer.…”

Section: Drug Repositioning As Drug Developmentmentioning

confidence: 99%

Drug Repositioning for Gynecologic Tumors: A New Therapeutic Strategy for Cancer

Banno

Iida

Yanokura

et al. 2015

The Scientific World Journal

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The goals of drug repositioning are to find a new pharmacological effect of a drug for which human safety and pharmacokinetics are established and to expand the therapeutic range of the drug to another disease. Such drug discovery can be performed at low cost and in the short term based on the results of previous clinical trials. New drugs for gynecologic tumors may be found by drug repositioning. For example, PPAR ligands may be effective against ovarian cancer, since PPAR activation eliminates COX-2 expression, arrests the cell cycle, and induces apoptosis. Metformin, an antidiabetic drug, is effective for endometrial cancer through inhibition of the PI3K-Akt-mTOR pathway by activating LKB1-AMPK and reduction of insulin and insulin-like growth factor-1 due to AMPK activation. COX-2 inhibitors for cervical cancer may also be examples of drug repositioning. PGE2 is induced in the arachidonate cascade by COX-2. PGE2 maintains high expression of COX-2 and induces angiogenic factors including VEGF and bFGF, causing carcinogenesis. COX-2 inhibitors suppress these actions and inhibit carcinogenesis. Combination therapy using drugs found by drug repositioning and current anticancer drugs may increase efficacy and reduce adverse drug reactions. Thus, drug repositioning may become a key approach for gynecologic cancer in drug discovery.

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Anticancer Effect of COX-2 Inhibitor DuP-697 Alone and in Combination with Tyrosine Kinase Inhibitor (E7080) on Colon Cancer Cell Lines

Cited by 9 publications

References 53 publications

Effects of a Multikinase Inhibitor Motesanib (AMG 706) Alone and Combined with the Selective DuP-697 COX-2 Inhibitor on Colorectal Cancer Cells

Effects of a Multikinase Inhibitor Motesanib (AMG 706) Alone and Combined with the Selective DuP-697 COX-2 Inhibitor on Colorectal Cancer Cells

E7080 (Lenvatinib), a Multi-Targeted Tyrosine Kinase Inhibitor, Demonstrates Antitumor Activities Against Colorectal Cancer Xenografts

Drug Repositioning for Gynecologic Tumors: A New Therapeutic Strategy for Cancer

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