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Irreversible dual inhibitory mode: the novel Btk inhibitor PLS-123 demonstrates promising anti-tumor activity in human B-cell lymphoma.

Ding N, Li X, Shi Y, Ping L, Wu L, Fu K, Feng L, Zheng X, Song Y, Pan Z, Zhu J - Oncotarget (2015)

Bottom Line: Here we present a novel covalent irreversible Btk inhibitor PLS-123 with more potent anti-proliferative activity compared with ibrutinib in multiple cellular and in vivo models through effective apoptosis induction and dual-action inhibitory mode of Btk activation.The phosphorylation of BCR downstream activating AKT/mTOR and MAPK signal pathways was also more significantly reduced after treatment with PLS-123 than ibrutinib.Gene expression profile analysis further suggested that the different selectivity profile of PLS-123 led to significant downregulation of oncogenic gene PTPN11 expression, which might also offer new opportunities beyond what ibrutinib has achieved.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital and Institute, Beijing, China.

ABSTRACT
The B-cell receptor (BCR) signaling pathway has gained significant attention as a therapeutic target in B-cell malignancies. Recently, several drugs that target the BCR signaling pathway, especially the Btk inhibitor ibrutinib, have demonstrated notable therapeutic effects in relapsed/refractory patients, which indicates that pharmacological inhibition of BCR pathway holds promise in B-cell lymphoma treatment. Here we present a novel covalent irreversible Btk inhibitor PLS-123 with more potent anti-proliferative activity compared with ibrutinib in multiple cellular and in vivo models through effective apoptosis induction and dual-action inhibitory mode of Btk activation. The phosphorylation of BCR downstream activating AKT/mTOR and MAPK signal pathways was also more significantly reduced after treatment with PLS-123 than ibrutinib. Gene expression profile analysis further suggested that the different selectivity profile of PLS-123 led to significant downregulation of oncogenic gene PTPN11 expression, which might also offer new opportunities beyond what ibrutinib has achieved. In addition, PLS-123 dose-dependently attenuated BCR- and chemokine-mediated lymphoma cell adhesion and migration. Taken together, Btk inhibitor PLS-123 suggested a new direction to pharmacologically modulate Btk function and develop novel therapeutic drug for B-cell lymphoma treatment.

No MeSH data available.


Related in: MedlinePlus

PLS-123 overcomes BCR- and chemokine-mediated lymphoma cell adhesion and migrationA.Namalwa cells pretreated with increasing concentrations of ibrutinib, PLS-123 (0.2, 0.5, 1, 2 and 5 μM) or vehicle were stimulated with anti-IgM or CXCL12 for 30 mins, and then tumor cells were subjected to adhesion assays on plates precoated with fibronectin or VCAM-1. B. Namalwa cells were treated with increasing concentration of ibrutinib, PLS-123 (0.2, 0.5, 1, 2 and 5 μM) or vehicle and subjected to a chemotaxis migration assay in transwell plates with filters coated with VCAM-1, and CXCL12 was added into the lower chamber as a chemoattractant. C. Namalwa cells were pretreated with 1 μM ibrutinib, 1 μM PLS-123 or vehicle for 1 hour and then stimulated or not with CXCL12 for 10 minutes. Whole cell extracts were probed by indicated antibodies for Western blot analysis. *Significantly decreased compared with ibrutinib treatment (p < 0.05). The results are representative of at least three similar experiments.
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Figure 5: PLS-123 overcomes BCR- and chemokine-mediated lymphoma cell adhesion and migrationA.Namalwa cells pretreated with increasing concentrations of ibrutinib, PLS-123 (0.2, 0.5, 1, 2 and 5 μM) or vehicle were stimulated with anti-IgM or CXCL12 for 30 mins, and then tumor cells were subjected to adhesion assays on plates precoated with fibronectin or VCAM-1. B. Namalwa cells were treated with increasing concentration of ibrutinib, PLS-123 (0.2, 0.5, 1, 2 and 5 μM) or vehicle and subjected to a chemotaxis migration assay in transwell plates with filters coated with VCAM-1, and CXCL12 was added into the lower chamber as a chemoattractant. C. Namalwa cells were pretreated with 1 μM ibrutinib, 1 μM PLS-123 or vehicle for 1 hour and then stimulated or not with CXCL12 for 10 minutes. Whole cell extracts were probed by indicated antibodies for Western blot analysis. *Significantly decreased compared with ibrutinib treatment (p < 0.05). The results are representative of at least three similar experiments.

Mentions: B-NHL patients administered ibrutinib in clinical trials display reduced lymphadenopathy accompanied by substantial lymphocytosis, suggesting that the potential anti-adhesion activity of ibrutinib triggers B-lymphoid malignant cell mobilization from tumor tissues to the peripheral blood. To investigate possible effects of PLS-123 in active BCR- and chemokine-mediated adhesion, we analyzed anti-IgM- and chemokine CXCL12-induced adhesion to the extracellular matrix component fibronectin and the cellular adhesion molecule VCAM-1 in Namalwa cells. Compared with ibrutinib's inhibitory effects, our novel Btk inhibitor PLS-123 more significantly attenuated anti-IgM- and CXCL12-mediated adhesion to fibronectin and VCAM-1 in a dose-dependent manner (Figure 5A). Moreover, CXCL12 and its cognate receptor CXCR4 axis also appear to be crucial for migration and homing of malignant B cells via activation of BCR signal pathway [19]. In transwell culture system, PLS-123 also more efficiently blocked neoplastic cells migration toward chemokine CXCL12 through its dual-action inhibitory mode of Btk activation (Figure 5B & 5C).


Irreversible dual inhibitory mode: the novel Btk inhibitor PLS-123 demonstrates promising anti-tumor activity in human B-cell lymphoma.

Ding N, Li X, Shi Y, Ping L, Wu L, Fu K, Feng L, Zheng X, Song Y, Pan Z, Zhu J - Oncotarget (2015)

PLS-123 overcomes BCR- and chemokine-mediated lymphoma cell adhesion and migrationA.Namalwa cells pretreated with increasing concentrations of ibrutinib, PLS-123 (0.2, 0.5, 1, 2 and 5 μM) or vehicle were stimulated with anti-IgM or CXCL12 for 30 mins, and then tumor cells were subjected to adhesion assays on plates precoated with fibronectin or VCAM-1. B. Namalwa cells were treated with increasing concentration of ibrutinib, PLS-123 (0.2, 0.5, 1, 2 and 5 μM) or vehicle and subjected to a chemotaxis migration assay in transwell plates with filters coated with VCAM-1, and CXCL12 was added into the lower chamber as a chemoattractant. C. Namalwa cells were pretreated with 1 μM ibrutinib, 1 μM PLS-123 or vehicle for 1 hour and then stimulated or not with CXCL12 for 10 minutes. Whole cell extracts were probed by indicated antibodies for Western blot analysis. *Significantly decreased compared with ibrutinib treatment (p < 0.05). The results are representative of at least three similar experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4558140&req=5

Figure 5: PLS-123 overcomes BCR- and chemokine-mediated lymphoma cell adhesion and migrationA.Namalwa cells pretreated with increasing concentrations of ibrutinib, PLS-123 (0.2, 0.5, 1, 2 and 5 μM) or vehicle were stimulated with anti-IgM or CXCL12 for 30 mins, and then tumor cells were subjected to adhesion assays on plates precoated with fibronectin or VCAM-1. B. Namalwa cells were treated with increasing concentration of ibrutinib, PLS-123 (0.2, 0.5, 1, 2 and 5 μM) or vehicle and subjected to a chemotaxis migration assay in transwell plates with filters coated with VCAM-1, and CXCL12 was added into the lower chamber as a chemoattractant. C. Namalwa cells were pretreated with 1 μM ibrutinib, 1 μM PLS-123 or vehicle for 1 hour and then stimulated or not with CXCL12 for 10 minutes. Whole cell extracts were probed by indicated antibodies for Western blot analysis. *Significantly decreased compared with ibrutinib treatment (p < 0.05). The results are representative of at least three similar experiments.
Mentions: B-NHL patients administered ibrutinib in clinical trials display reduced lymphadenopathy accompanied by substantial lymphocytosis, suggesting that the potential anti-adhesion activity of ibrutinib triggers B-lymphoid malignant cell mobilization from tumor tissues to the peripheral blood. To investigate possible effects of PLS-123 in active BCR- and chemokine-mediated adhesion, we analyzed anti-IgM- and chemokine CXCL12-induced adhesion to the extracellular matrix component fibronectin and the cellular adhesion molecule VCAM-1 in Namalwa cells. Compared with ibrutinib's inhibitory effects, our novel Btk inhibitor PLS-123 more significantly attenuated anti-IgM- and CXCL12-mediated adhesion to fibronectin and VCAM-1 in a dose-dependent manner (Figure 5A). Moreover, CXCL12 and its cognate receptor CXCR4 axis also appear to be crucial for migration and homing of malignant B cells via activation of BCR signal pathway [19]. In transwell culture system, PLS-123 also more efficiently blocked neoplastic cells migration toward chemokine CXCL12 through its dual-action inhibitory mode of Btk activation (Figure 5B & 5C).

Bottom Line: Here we present a novel covalent irreversible Btk inhibitor PLS-123 with more potent anti-proliferative activity compared with ibrutinib in multiple cellular and in vivo models through effective apoptosis induction and dual-action inhibitory mode of Btk activation.The phosphorylation of BCR downstream activating AKT/mTOR and MAPK signal pathways was also more significantly reduced after treatment with PLS-123 than ibrutinib.Gene expression profile analysis further suggested that the different selectivity profile of PLS-123 led to significant downregulation of oncogenic gene PTPN11 expression, which might also offer new opportunities beyond what ibrutinib has achieved.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital and Institute, Beijing, China.

ABSTRACT
The B-cell receptor (BCR) signaling pathway has gained significant attention as a therapeutic target in B-cell malignancies. Recently, several drugs that target the BCR signaling pathway, especially the Btk inhibitor ibrutinib, have demonstrated notable therapeutic effects in relapsed/refractory patients, which indicates that pharmacological inhibition of BCR pathway holds promise in B-cell lymphoma treatment. Here we present a novel covalent irreversible Btk inhibitor PLS-123 with more potent anti-proliferative activity compared with ibrutinib in multiple cellular and in vivo models through effective apoptosis induction and dual-action inhibitory mode of Btk activation. The phosphorylation of BCR downstream activating AKT/mTOR and MAPK signal pathways was also more significantly reduced after treatment with PLS-123 than ibrutinib. Gene expression profile analysis further suggested that the different selectivity profile of PLS-123 led to significant downregulation of oncogenic gene PTPN11 expression, which might also offer new opportunities beyond what ibrutinib has achieved. In addition, PLS-123 dose-dependently attenuated BCR- and chemokine-mediated lymphoma cell adhesion and migration. Taken together, Btk inhibitor PLS-123 suggested a new direction to pharmacologically modulate Btk function and develop novel therapeutic drug for B-cell lymphoma treatment.

No MeSH data available.


Related in: MedlinePlus