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DCLAK11, a multi-tyrosine kinase inhibitor, exhibits potent antitumor and antiangiogenic activity in vitro.

Guo XB, Chen XJ, Tong LJ, Peng X, Huang M, Liu HC, Liu H, Ding J - Acta Pharmacol. Sin. (2015)

Bottom Line: Furthermore, DCLAK11 effectively induced EGFR/HER2-driven cell apoptosis.Moreover, DCLAK11 exhibited anti-angiogenic activity, as shown by its inhibitory effect on the proliferation, migration and tube formation of human umbilical vascular endothelial cells and the microvessel outgrowth of rat aortic rings.DCLAK11 is a multi-targeted kinase inhibitor with remarkable potency against tyrosine kinases EGFR, HER2 and VEGFR2, which confirms its potent anti-cancer activity in EGFR- and HER2-addicted cancers and its anti-angiogenic activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Pharmacology, Xiangya Hospital and Institute of Clinical Pharmacology, Central South University, Changsha 410078, China.

ABSTRACT

Aim: To investigate the molecular targets of DCLAK11, a novel compound discovered from a series of substituted pyridin-3-amine derivatives, and to characterize its anti-tumor properties in vitro.

Methods: Kinase inhibition was measured by an ELISA assay. Cell viability was assessed with an SRB or a CCK8 assay. The alterations induced by kinase signaling proteins in cancer cells were detected by Western blot. Apoptosis was determined by an Annexin V-PI assay. The following assays were used to evaluate the impact on angiogenesis: wound-healing, Transwell, tube formation and microvessel outgrowth from rat aortic rings.

Results: DCLAK11 was a multi-targeted kinase inhibitor that primarily inhibited the EGFR, HER2, and VEGFR2 tyrosine kinases with IC50 value of 6.5, 18, and 31 nmol/L, respectively. DCLAK11 potently inhibited the proliferation of EGFR- and HER2-driven cancer cells: its IC50 value was 12 and 22 nmol/L, respectively, in HCC827 and HCC4006 cells with EGFR exon deletions, and 19 and 81 nmol/L, respectively, in NCI-N87 and BT474 cells with HER2 amplification. Consistently, DCLAK11 blocked the EGFR and HER2 signaling in cancer cells with either an EGFR or a HER2 aberration. Furthermore, DCLAK11 effectively induced EGFR/HER2-driven cell apoptosis. Moreover, DCLAK11 exhibited anti-angiogenic activity, as shown by its inhibitory effect on the proliferation, migration and tube formation of human umbilical vascular endothelial cells and the microvessel outgrowth of rat aortic rings.

Conclusions: DCLAK11 is a multi-targeted kinase inhibitor with remarkable potency against tyrosine kinases EGFR, HER2 and VEGFR2, which confirms its potent anti-cancer activity in EGFR- and HER2-addicted cancers and its anti-angiogenic activity.

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DCLAK11 inhibits HER2 signaling and induces apoptosis in cancer cells with HER2 amplification. (A, B) Concentration- and time-dependent inhibitive activity of DCLAK11 on HER2, AKT, and Erk1/2 phosphorylation in NCI-N87 (A) and BT474 (B) cells. Cells treated with increasing concentrations of DCLAK11 for 2 h or treated with indicated concentrations of DCLAK11 for increasing durations (0.25–6 h) were lysated and subjected to Western blot analysis.
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fig4: DCLAK11 inhibits HER2 signaling and induces apoptosis in cancer cells with HER2 amplification. (A, B) Concentration- and time-dependent inhibitive activity of DCLAK11 on HER2, AKT, and Erk1/2 phosphorylation in NCI-N87 (A) and BT474 (B) cells. Cells treated with increasing concentrations of DCLAK11 for 2 h or treated with indicated concentrations of DCLAK11 for increasing durations (0.25–6 h) were lysated and subjected to Western blot analysis.

Mentions: Similarly, we also examined the effect of DCLAK11 on HER2 signaling in NCI-N87 and BT474 cells (Figure 4A and 4B). After DCLAK11 treatment, the phosphorylation of HER2 and its key downstream signaling molecules Erk1/2 and AKT were significantly decreased in NCI-N87 (Figure 4A) and BT474 cells (Figure 4B) in a concentration- and time-dependent manner.


DCLAK11, a multi-tyrosine kinase inhibitor, exhibits potent antitumor and antiangiogenic activity in vitro.

Guo XB, Chen XJ, Tong LJ, Peng X, Huang M, Liu HC, Liu H, Ding J - Acta Pharmacol. Sin. (2015)

DCLAK11 inhibits HER2 signaling and induces apoptosis in cancer cells with HER2 amplification. (A, B) Concentration- and time-dependent inhibitive activity of DCLAK11 on HER2, AKT, and Erk1/2 phosphorylation in NCI-N87 (A) and BT474 (B) cells. Cells treated with increasing concentrations of DCLAK11 for 2 h or treated with indicated concentrations of DCLAK11 for increasing durations (0.25–6 h) were lysated and subjected to Western blot analysis.
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Related In: Results  -  Collection

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fig4: DCLAK11 inhibits HER2 signaling and induces apoptosis in cancer cells with HER2 amplification. (A, B) Concentration- and time-dependent inhibitive activity of DCLAK11 on HER2, AKT, and Erk1/2 phosphorylation in NCI-N87 (A) and BT474 (B) cells. Cells treated with increasing concentrations of DCLAK11 for 2 h or treated with indicated concentrations of DCLAK11 for increasing durations (0.25–6 h) were lysated and subjected to Western blot analysis.
Mentions: Similarly, we also examined the effect of DCLAK11 on HER2 signaling in NCI-N87 and BT474 cells (Figure 4A and 4B). After DCLAK11 treatment, the phosphorylation of HER2 and its key downstream signaling molecules Erk1/2 and AKT were significantly decreased in NCI-N87 (Figure 4A) and BT474 cells (Figure 4B) in a concentration- and time-dependent manner.

Bottom Line: Furthermore, DCLAK11 effectively induced EGFR/HER2-driven cell apoptosis.Moreover, DCLAK11 exhibited anti-angiogenic activity, as shown by its inhibitory effect on the proliferation, migration and tube formation of human umbilical vascular endothelial cells and the microvessel outgrowth of rat aortic rings.DCLAK11 is a multi-targeted kinase inhibitor with remarkable potency against tyrosine kinases EGFR, HER2 and VEGFR2, which confirms its potent anti-cancer activity in EGFR- and HER2-addicted cancers and its anti-angiogenic activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Pharmacology, Xiangya Hospital and Institute of Clinical Pharmacology, Central South University, Changsha 410078, China.

ABSTRACT

Aim: To investigate the molecular targets of DCLAK11, a novel compound discovered from a series of substituted pyridin-3-amine derivatives, and to characterize its anti-tumor properties in vitro.

Methods: Kinase inhibition was measured by an ELISA assay. Cell viability was assessed with an SRB or a CCK8 assay. The alterations induced by kinase signaling proteins in cancer cells were detected by Western blot. Apoptosis was determined by an Annexin V-PI assay. The following assays were used to evaluate the impact on angiogenesis: wound-healing, Transwell, tube formation and microvessel outgrowth from rat aortic rings.

Results: DCLAK11 was a multi-targeted kinase inhibitor that primarily inhibited the EGFR, HER2, and VEGFR2 tyrosine kinases with IC50 value of 6.5, 18, and 31 nmol/L, respectively. DCLAK11 potently inhibited the proliferation of EGFR- and HER2-driven cancer cells: its IC50 value was 12 and 22 nmol/L, respectively, in HCC827 and HCC4006 cells with EGFR exon deletions, and 19 and 81 nmol/L, respectively, in NCI-N87 and BT474 cells with HER2 amplification. Consistently, DCLAK11 blocked the EGFR and HER2 signaling in cancer cells with either an EGFR or a HER2 aberration. Furthermore, DCLAK11 effectively induced EGFR/HER2-driven cell apoptosis. Moreover, DCLAK11 exhibited anti-angiogenic activity, as shown by its inhibitory effect on the proliferation, migration and tube formation of human umbilical vascular endothelial cells and the microvessel outgrowth of rat aortic rings.

Conclusions: DCLAK11 is a multi-targeted kinase inhibitor with remarkable potency against tyrosine kinases EGFR, HER2 and VEGFR2, which confirms its potent anti-cancer activity in EGFR- and HER2-addicted cancers and its anti-angiogenic activity.

Show MeSH
Related in: MedlinePlus