Dasatinib can enhance paclitaxel and gemcitabine inhibitory activity in human pancreatic cancer cells

Ma, Ling; Wei, Jia; Su, Gloria H.; Lin, Jiayuh

doi:10.1080/15384047.2019.1579956

Cited by 27 publications

(18 citation statements)

References 42 publications

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“…Treatment with the combination of dasatinib with gemcitabine also resulted in synergistic growth inhibition of four HPCCLs, including those established from patients with a primary pancreatic tumor (e.g., Bx-PC-3) or liver metastasis (e.g., Capan-1). Consistent with the results of a present study, the latter combination has been reported to have synergistic effect in two other HPCCLs ( 46 , 47 ). Although, dasatinib and gemcitabine combination has been shown to promote stable disease and to induce a partial response in patients with pancreatic cancer ( 48 ), it failed to improve patient survival in a phase II trial setting due to increased toxicity of such a combination ( 49 ).…”

Section: Discussionsupporting

confidence: 93%

Synergistic activity of agents targeting growth factor receptors, CDKs and downstream signaling molecules in a panel of pancreatic cancer cell lines and the identification of antagonistic combinations: Implications for future clinical trials in pancreatic cancer

et al. 2020

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Pancreatic cancer is one of the most aggressive, heterogeneous and fatal type of human cancers for which more effective therapeutic agents are urgently needed. Here, we investigated the sensitivity of a panel of seven human pancreatic cancer cell lines (HPCCLs) to treatment with various tyrosine kinase inhibitors (TKIs), cyclin-dependent kinase (CDK) inhibitors, an inhibitor of STAT3 stattic, and a cytotoxic agent gemcitabine both as single agents and in combination. The membranous expression of various receptors and the effect of selected agents on cell cycle distribution, cell signaling pathways and migration was determined using flow cytometry, western blot analysis and scratch wound healing assays, respectively. While the expression of both HER-3 and HER-4 was low or negative, the expression of EGFR and HER2 was high or intermediate in all HPCCLs. Of all the agents examined, the CDK1/2/5/9 inhibitor, dinacicilib, was the most potent agent which inhibited the proliferation of all seven HPCCLs with IC 50 values of ≤10 nM, followed by SRC targeting TKI dasatinib (IC 50 of ≤258 nM), gemcitabine (IC 50 of ≤330 nM), stattic (IC 50 of ≤2 µM) and the irreversible pan-HER TKI afatinib (IC 50 of ≤2.95 µM). Treatment with afatinib and dasatinib inhibited the ligand-induced phosphorylation of EGFR and SRC respectively. Statistically significant associations were found between HER2 expression and response to treatment with the ALK/IGF-IR/InsR inhibitor ceritinib and fibroblast growth factor receptor (FGFR)1/2/3 inhibitor AZD4547, HER3 and IGF-IR expression and their response to treatment with TKIs targeting HER family members (erlotinib and afatinib), and c-MET and ALK7 expression and their response to treatment with stattic. Interestingly, treatment with a combination of afatinib with dasatinib and gemcitabine with dasatinib resulted in synergistic tumor growth inhibition in all HPCCLs examined. In contrast, the combination of afatinib with dinaciclib was found to be antagonistic. Finally, the treatment with afatinib, dasatinib and dinaciclib strongly inhibited the migration of all HPCCLs examined. In conclusion, the CDK1/2/5/9 inhibitor dinaciclib, irreversible pan-HER TKI afatinib and SRC targeting TKI dasatinib were most effective at inhibiting the proliferation and migration of HPCCLs and the combination of afatinib with dasatinib and gemcitabine with dasatinib led to synergistic tumor growth inhibition in all HPCCLs examined. Our results support further investigation on the therapeutic potential of these combinations in future clinical trials in pancreatic cancer.

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Section: Discussionsupporting

confidence: 93%

Synergistic activity of agents targeting growth factor receptors, CDKs and downstream signaling molecules in a panel of pancreatic cancer cell lines and the identification of antagonistic combinations: Implications for future clinical trials in pancreatic cancer

et al. 2020

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“…Several kinases consistently identified as differentially active across multiple pipelines, cell lines, or final combinatorial analyses recapitulate kinases previously identified as playing well-established roles in a variety of human cancer pathologies. These kinases include insulin receptor (INSR) kinase [ 37 , 38 ] ( Figure 2 and Figure 3 , Table 3 and Table 4 ), EPHA2 kinase [ 29 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ] ( Figure 2 and Figure 3 , Table 4 ), platelet-derived growth factor receptor alpha (PDGFRA) kinase [ 47 , 48 , 49 , 50 , 51 ] ( Figure 2 and Figure 3 , Table 1 , Table 2 , Table 3 and Table 4 ), SRC kinase [ 26 , 27 , 52 , 53 , 54 , 55 , 56 , 57 ] ( Figure 2 and Figure 3 , Table 1 , Table 2 , Table 3 and Table 4 ), and tyrosine kinase nonreceptor 2 (TNK2) kinase [ 58 , 59 , 60 , 61 , 62 , 63 , 64 ...…”

Section: Discussionmentioning

confidence: 99%

Kinome Array Profiling of Patient-Derived Pancreatic Ductal Adenocarcinoma Identifies Differentially Active Protein Tyrosine Kinases

Creeden

Alganem

Imami

et al. 2020

IJMS

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Pancreatic cancer remains one of the most difficult malignancies to treat. Minimal improvements in patient outcomes and persistently abysmal patient survival rates underscore the great need for new treatment strategies. Currently, there is intense interest in therapeutic strategies that target tyrosine protein kinases. Here, we employed kinome arrays and bioinformatic pipelines capable of identifying differentially active protein tyrosine kinases in different patient-derived pancreatic ductal adenocarcinoma (PDAC) cell lines and wild-type pancreatic tissue to investigate the unique kinomic networks of PDAC samples and posit novel target kinases for pancreatic cancer therapy. Consistent with previously described reports, the resultant peptide-based kinome array profiles identified increased protein tyrosine kinase activity in pancreatic cancer for the following kinases: epidermal growth factor receptor (EGFR), fms related receptor tyrosine kinase 4/vascular endothelial growth factor receptor 3 (FLT4/VEGFR-3), insulin receptor (INSR), ephrin receptor A2 (EPHA2), platelet derived growth factor receptor alpha (PDGFRA), SRC proto-oncogene kinase (SRC), and tyrosine kinase non receptor 2 (TNK2). Furthermore, this study identified increased activity for protein tyrosine kinases with limited prior evidence of differential activity in pancreatic cancer. These protein tyrosine kinases include B lymphoid kinase (BLK), Fyn-related kinase (FRK), Lck/Yes-related novel kinase (LYN), FYN proto-oncogene kinase (FYN), lymphocyte cell-specific kinase (LCK), tec protein kinase (TEC), hemopoietic cell kinase (HCK), ABL proto-oncogene 2 kinase (ABL2), discoidin domain receptor 1 kinase (DDR1), and ephrin receptor A8 kinase (EPHA8). Together, these results support the utility of peptide array kinomic analyses in the generation of potential candidate kinases for future pancreatic cancer therapeutic development.

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“…The Tec kinase inhibitor LFM-A13 suppresses LPS-evoked TNF-α, IL-6, and IL-1β levels but not P38 signaling via regulation of JNK phosphorylation in human neutrophils [42]. The combination of dasatinib with other anti-cancer drugs has been reported to prevent AKT and ERK signaling to suppress cancer cell migration or the proliferation of pancreatic and ovarian cancer cells [43, 44]. In addition, dasatinib alone exhibits anti-tumor efficacy by inhibiting ERK/AKT signaling in nasopharyngeal carcinoma cells [45].…”

Section: Discussionmentioning

confidence: 99%

Dasatinib regulates LPS-induced microglial and astrocytic neuroinflammatory responses by inhibiting AKT/STAT3 signaling

Ryu

Lee

Woo

et al. 2019

J Neuroinflammation

119

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BackgroundThe FDA-approved small-molecule drug dasatinib is currently used as a treatment for chronic myeloid leukemia (CML). However, the effects of dasatinib on microglial and/or astrocytic neuroinflammatory responses and its mechanism of action have not been studied in detail.MethodsBV2 microglial cells, primary astrocytes, or primary microglial cells were treated with dasatinib (100 or 250 nM) or vehicle (1% DMSO) for 30 min or 2 h followed by lipopolysaccharide (LPS; 200 ng/ml or 1 μg/ml) or PBS for 5.5 h. RT-PCR, real-time PCR; immunocytochemistry; subcellular fractionation; and immunohistochemistry were subsequently conducted to determine the effects of dasatinib on LPS-induced neuroinflammation. In addition, wild-type mice were injected with dasatinib (20 mg/kg, intraperitoneally (i.p.) daily for 4 days or 20 mg/kg, orally administered (p.o.) daily for 4 days or 2 weeks) or vehicle (4% DMSO + 30% polyethylene glycol (PEG) + 5% Tween 80), followed by injection with LPS (10 mg/kg, i.p.) or PBS. Then, immunohistochemistry was performed, and plasma IL-6, IL-1β, and TNF-α levels were analyzed by ELISA.ResultsDasatinib regulates LPS-induced proinflammatory cytokine and anti-inflammatory cytokine levels in BV2 microglial cells, primary microglial cells, and primary astrocytes. In BV2 microglial cells, dasatinib regulates LPS-induced proinflammatory cytokine levels by regulating TLR4/AKT and/or TLR4/ERK signaling. In addition, intraperitoneal injection and oral administration of dasatinib suppress LPS-induced microglial/astrocyte activation, proinflammatory cytokine levels (including brain and plasma levels), and neutrophil rolling in the brains of wild-type mice.ConclusionsOur results suggest that dasatinib modulates LPS-induced microglial and astrocytic activation, proinflammatory cytokine levels, and neutrophil rolling in the brain.Electronic supplementary materialThe online version of this article (10.1186/s12974-019-1561-x) contains supplementary material, which is available to authorized users.

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Dasatinib can enhance paclitaxel and gemcitabine inhibitory activity in human pancreatic cancer cells

Cited by 27 publications

References 42 publications

Synergistic activity of agents targeting growth factor receptors, CDKs and downstream signaling molecules in a panel of pancreatic cancer cell lines and the identification of antagonistic combinations: Implications for future clinical trials in pancreatic cancer

Synergistic activity of agents targeting growth factor receptors, CDKs and downstream signaling molecules in a panel of pancreatic cancer cell lines and the identification of antagonistic combinations: Implications for future clinical trials in pancreatic cancer

Kinome Array Profiling of Patient-Derived Pancreatic Ductal Adenocarcinoma Identifies Differentially Active Protein Tyrosine Kinases

Dasatinib regulates LPS-induced microglial and astrocytic neuroinflammatory responses by inhibiting AKT/STAT3 signaling

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