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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 blocks EGFR phosphorylation and downstream signaling in HCC827 (A) and HCC4006 (B) cells with concentration-dependent and time-dependent manner. Cells were cultured in the presence of different concentrations of DCLAK11 for 2 h or treated with indicated concentrations of DCLAK11 for increasing durations (0.25–6 h), then whole-cell lysates were assayed by Western blots.
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fig2: DCLAK11 blocks EGFR phosphorylation and downstream signaling in HCC827 (A) and HCC4006 (B) cells with concentration-dependent and time-dependent manner. Cells were cultured in the presence of different concentrations of DCLAK11 for 2 h or treated with indicated concentrations of DCLAK11 for increasing durations (0.25–6 h), then whole-cell lysates were assayed by Western blots.

Mentions: We next examined the effect of DCLAK11 on EGFR signaling in HCC827 and HCC4006 cells. As shown in Figure 2A and 2B, EGFR phosphorylation was largely inhibited by DCLAK11 in both HCC827 (Figure 2A) and in HCC4006 (Figure 2B) cells in a time- and concentration-dependent manner. AKT and Erk1/2 are two major signaling molecules that function downstream of activated EGFR to drive diverse cellular events33. In addition to EGFR inhibition, we also observed the effective inhibition of both AKT and Erk1/2 phosphorylation, which suggests the complete blockage of the EGFR signaling by DCLAK11.


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 blocks EGFR phosphorylation and downstream signaling in HCC827 (A) and HCC4006 (B) cells with concentration-dependent and time-dependent manner. Cells were cultured in the presence of different concentrations of DCLAK11 for 2 h or treated with indicated concentrations of DCLAK11 for increasing durations (0.25–6 h), then whole-cell lysates were assayed by Western blots.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4814203&req=5

fig2: DCLAK11 blocks EGFR phosphorylation and downstream signaling in HCC827 (A) and HCC4006 (B) cells with concentration-dependent and time-dependent manner. Cells were cultured in the presence of different concentrations of DCLAK11 for 2 h or treated with indicated concentrations of DCLAK11 for increasing durations (0.25–6 h), then whole-cell lysates were assayed by Western blots.
Mentions: We next examined the effect of DCLAK11 on EGFR signaling in HCC827 and HCC4006 cells. As shown in Figure 2A and 2B, EGFR phosphorylation was largely inhibited by DCLAK11 in both HCC827 (Figure 2A) and in HCC4006 (Figure 2B) cells in a time- and concentration-dependent manner. AKT and Erk1/2 are two major signaling molecules that function downstream of activated EGFR to drive diverse cellular events33. In addition to EGFR inhibition, we also observed the effective inhibition of both AKT and Erk1/2 phosphorylation, which suggests the complete blockage of the EGFR signaling by DCLAK11.

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