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  • S. Karger AG  (4)
  • 1
    Online Resource
    Online Resource
    Ceritinib Enhances the Efficacy of Substrate Chemotherapeutic Agent in Human ABCB1-Overexpressing Leukemia Cells In Vitro, In Vivo and Ex-Vivo
    S. Karger AG ; 2018
    In:  Cellular Physiology and Biochemistry Vol. 46, No. 6 ( 2018), p. 2487-2499
    Details
    In: Cellular Physiology and Biochemistry, S. Karger AG, Vol. 46, No. 6 ( 2018), p. 2487-2499
    Abstract: Background/Aims: Multidrug resistance (MDR) triggered by ATP binding cassette (ABC) transporters, such as ABCB1, ABCC1, and ABCG2, is a key obstacle for successful cancer chemotherapy. There is currently no FDA-approved MDR modulator that can be used in clinic. Ceritinib, a selective ALK inhibitor, has been approved as the second-line treatment for ALK-positive non-small cell lung cancer. Here, we examined the role of ceritinib in leukemia associated MDR in therapy. Methods: The cell proliferation was detected by MTT assay. The flow cytometry was used to detect the expression of cell surface protein and to detect the accumulation and efflux of rhodamine 123 (Rh123) or doxorubicin (Dox) in cells. The RT-PCR and Western blot were performed to detect the gene expression and protein expression levels, respectively. Results: We found that ceritinib enhanced the efficacy of substrate chemotherapeutic agent in ABCB1-overexpressing K562/adr leukemia cells both in vitro and in vivo models, but neither in sensitive parental K562 leukemia cells nor in ABCC1-overexpressing HL-60/adr leukemia cells. Mechanistically, ceritinib significantly increased the intracellular accumulation of Rh123 or Dox but did neither alter ABCB1 expressions at both protein and mRNA levels nor block the phosphorylations of AKT and ERK1/2 at the concentration of MDR reversal. Importantly, ceritinib also increased the intracellular accumulation of Dox and enhanced the efficacy of Dox in primary leukemia cells in ex-vivo. Conclusion: Our results suggested that ceritinib enhanced the efficacy of substrate chemotherapeutic agent on inhibition of leukemia cell growth in vitro, in vivo and ex-vivo, which linked to block ABCB1 function, pumping out its substrate conventional chemotherapeutic agent, thereby increasing the intracellular accumulation. These suggest the combination of ceritinib and substrate chemotherapeutic drugs maybe an effective treatment of resistant leukemia patients with ABCB1-mediated MDR.
    Type of Medium: Online Resource
    ISSN: 1015-8987 , 1421-9778
    URL: Article
    DOI: 10.1159/000489655
    Language: English
    Publisher: S. Karger AG
    Publication Date: 2018
    detail.hit.zdb_id: 1482056-0
    SSG: 12
    SSG: 15,3
    Location Call Number Limitation Availability
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    Online Resource
  • 2
    Online Resource
    Online Resource
    PCI29732, a Bruton’s Tyrosine Kinase Inhibitor, Enhanced the Efficacy of Conventional Chemotherapeutic Agents in ABCG2-Overexpressing Cancer Cells
    S. Karger AG ; 2018
    In:  Cellular Physiology and Biochemistry Vol. 48, No. 6 ( 2018), p. 2302-2317
    Details
    In: Cellular Physiology and Biochemistry, S. Karger AG, Vol. 48, No. 6 ( 2018), p. 2302-2317
    Abstract: Background/Aims: Multidrug resistance (MDR) induced by the ABC transporter subfamily B member 1 (ABCB1) and subfamilyG member 2 (ABCG2) limits successful cancer chemotherapy and no commercially available MDR modulator is used in the clinic. In the current study, we aimed to investigate the effects of PCI29732 on the enhancement of chemotherapeutic agents. Methods: Cell cytotoxicity and reversal effect were measured with MTT assay. Additionally, flow cytometry was employed to detect the accumulation and efflux of the drugs. We investigated the interaction of PCI29732 and the substrate binding sites of ABCG2 was investigated via the photo-labeling of ABCG2 with the [125I] iodoarylazidoprazosin. The vanadate-sensitive ATPase activity of ABCG2 was measured to identify whether the drug affected the ATPase activity. RT-PCR and Western blot were utilized to analyze mRNA and protein expression respectively. Results: Here, we found that PCI29732 significantly enhanced the efficacy of substrate chemotherapeutic agents in ABCG2-overexpressing cells and also in xenografts harboring the H460/MX20 cell that overexpress ABCG2, but not in their parental sensitive cells and ABCB1-overexpressing cells. Mechanistically, the intracellular accumulations of doxorubicin and Rhodamine 123 were increased in ABCG2-overexpressing S1-MI-80 cells with the presence of PCI29732. PCI29732 stimulated the ATPase activity of ABCG2 at low concentrations. However at the high concentrations, PCI29732 inhibited the ATPase activity, and competed with [125I]-iodoarylazidoprazosin for photo-affinity labeling of ABCG2. PCI29732 did neither alter the mRNA or protein expression levels of ABCG2 nor the phosphorylation levels of AKT and ERK1/2. Conclusion: Our study demonstrates that PCI29732 inhibits the function of ABCG2 by competitively binding to the ATP-binding site of ABCG2 and enhances the anti-tumor efficacy of substrate chemotherapeutic agents, This findings encourages the development of combinational chemotherapy for the treatment of ABCG2- overexpressing cancer patients.
    Type of Medium: Online Resource
    ISSN: 1015-8987 , 1421-9778
    URL: Article
    DOI: 10.1159/000492647
    Language: English
    Publisher: S. Karger AG
    Publication Date: 2018
    detail.hit.zdb_id: 1482056-0
    SSG: 12
    SSG: 15,3
    Location Call Number Limitation Availability
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    Online Resource
  • 3
    Online Resource
    Online Resource
    TheBDKRB2 +9/-9 Polymorphisms Influence Pro-Inflammatory Cytokine Levels in Knee Osteoarthritis by Altering TLR-2 Expression: Clinical and in Vitro Studies
    S. Karger AG ; 2016
    In:  Cellular Physiology and Biochemistry Vol. 38, No. 3 ( 2016), p. 1245-1256
    Details
    In: Cellular Physiology and Biochemistry, S. Karger AG, Vol. 38, No. 3 ( 2016), p. 1245-1256
    Abstract: Background/Aims: The bradykinin B2 receptor (BDKRB2) +9/-9 gene polymorphisms have been shown to be associated with the susceptibility and severity of osteoarthritis (OA); however, the underlying mechanisms are unclear. In this study, we investigated the correlation between the BDKRB2 +9/-9 polymorphisms and pro-inflammatory cytokine levels in OA and the molecular mechanisms involved. Methods: A total of 156 patients with primary knee OA and 121 healthy controls were enrolled. The BDKRB2 +9/-9 polymorphisms were genotyped. The tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8 levels were determined using Enzyme-linked immunosorbent assay (ELISA). The toll-like receptor (TLR)-2 and TLR-4 mRNA levels were determined by quantitative real-time PCR. The basal and bradykinin-stimulated pro-inflammatory cytokine secretion in human OA synoviocytes and the involvement of TLR-2 and mitogen-activated protein kinases (MAPKs) were investigated. Results: The presence of -9 bp genotype is associated with higher TNF-α, IL-6, and IL-8 levels and higher TLR-2 expression in OA patients. The basal and bradykinin-induced TLR-2 expressions in human OA synoviocytes were significantly reduced by specific inhibitors of p38, JNK1/2, and ERK1/2. Both the B2 receptor antagonist MEN16132 and TLR-2 silencing inhibited IL-6 and IL-8 secretion in human OA synoviocytes. Conclusion: The data suggested that the BDKRB2 +9/-9 polymorphisms influence pro-inflammatory cytokine levels in knee osteoarthritis by altering TLR-2 expression.
    Type of Medium: Online Resource
    ISSN: 1015-8987 , 1421-9778
    URL: Article
    DOI: 10.1159/000443072
    Language: English
    Publisher: S. Karger AG
    Publication Date: 2016
    detail.hit.zdb_id: 1482056-0
    SSG: 12
    SSG: 15,3
    Location Call Number Limitation Availability
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    Online Resource
  • 4
    Online Resource
    Online Resource
    The Interleukin-1 Receptor-Associated Kinase M Selectively Inhibits the Alternative, Instead of the Classical NFκB Pathway
    S. Karger AG ; 2009
    In:  Journal of Innate Immunity Vol. 1, No. 2 ( 2009), p. 164-174
    Details
    In: Journal of Innate Immunity, S. Karger AG, Vol. 1, No. 2 ( 2009), p. 164-174
    Abstract: The innate immunity signaling process is controlled by numerous positive and negative regulators. The interleukin-1 receptor-associated kinase M (IRAK-M) is one of the negative regulators that contribute to the attenuation of NFκB activation. The molecular mechanism involved, however, is poorly defined. In this report, we observed that IRAK-M selectively suppresses the NIK-IKKα-mediated alternative NFκB pathway. Deletion of IRAK-M led to NIK stabilization, favored the formation of the IKKα/IKKα homodimer instead of the IKKα/IKKβ heterodimer, and enhanced RelB nuclear distribution. In contrast, p65 nuclear localization and phosphorylation was not affected by IRAK-M deficiency. IRAK-M-deficient cells exhibited increased expression of selected cytokines such as IL-6 and GM-CSF, as well as quickened resynthesis of IκBα. The increased expression of IL-6 and GM-CSF was ablated when RelB expression was knocked down using specific siRNA. We also demonstrated that the observed inhibitory effect of IRAK-M was primarily limited to the TLR2 ligand, instead of TLR4. Taken together, our findings suggest that IRAK-M negatively regulates the alternative NFκB pathway in a ligand-specific manner.
    Type of Medium: Online Resource
    ISSN: 1662-811X , 1662-8128
    URL: Article
    DOI: 10.1159/000158541
    Language: English
    Publisher: S. Karger AG
    Publication Date: 2009
    detail.hit.zdb_id: 2455818-7
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