In vitro testing of drug combinations employing nilotinib and alkylating agents with regard to pretransplant conditioning treatment of advanced-phase chronic myeloid leukemia

Radujkovic, Aleksandar; Luft, Thomas; Dreger, Peter; Ho, Anthony D.; Zeller, W. Jens; Früehauf, Stefan; Topaly, Julian

doi:10.1007/s00280-014-2533-6

Cited by 2 publications

(2 citation statements)

References 21 publications

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“…P-gp is a surface glycoprotein which plays an important role in the development of multi-drug resistance ( Dewanjee et al, 2017 ). LAMA-84r cell line used in this study is characterized by an over-expression of BCR-ABL and increased the activity of P-gp ( Radujkovic et al, 2014 ), so metformin could decrease P-gp levels and have a cytotoxic activity in this cell line. Effects of metformin against resistant Ph + cells need to be further investigated with a focus on leukemia initiating cells.…”

Section: Discussionmentioning

confidence: 99%

Metformin and Thymoquinone Synergistically Inhibit Proliferation of Imatinib-Resistant Human Leukemic Cells

et al. 2022

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Chemotherapy resistance is one of the major challenges in cancer treatment, including leukemia. A massive array of research is evaluating combinations of drugs directed against different intracellular signaling molecules to overcome cancer resistance, increase therapy effectiveness, and decrease its adverse effects. Combining chemicals with proven safety profiles, such as drugs already used in therapy and active substances isolated from natural sources, could potentially have superior effects compared to monotherapies. In this study, we evaluated the effects of metformin and thymoquinone (TQ) as monotherapy and combinatorial treatments in chronic myeloid leukemia (CML) cell lines sensitive and resistant to imatinib therapy. The effects were also evaluated in primary monocytic acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) cells. Both compounds induced a dose- and time-dependent decrease of viability and proliferation in tested cells. Metformin had similar IC50 values in imatinib-sensitive and imatinib-resistant cell lines. IC50 values of TQ were significantly higher in imatinib-resistant cells, but with a limited resistance index (2.4). Synergistic effects of combinatorial treatments were observed in all tested cell lines, as well as in primary cells. The strongest synergistic effects were observed in the inhibition of imatinib-resistant cell line proliferation. Metformin and TQ inhibited the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling and induced apoptosis in tested cell lines and primary cells. The enhanced effects of combinatorial treatments on the induction of apoptosis were more dominant in imatinib-resistant compared to imatinib-sensitive CML cells. Primary cells were more sensitive to combinatorial treatments compared to cell lines. A combination of 1.25 mM metformin and 0.625 µM TQ increased the levels of cleaved poly (ADP-ribose) polymerase (PARP), decreased the levels of proliferation regulatory proteins, and inhibited protein kinase B (Akt) and NF-κB signaling in primary CLL cells. This study demonstrates that combinatorial treatments of imatinib-resistant malignant clones with metformin and TQ by complementary intracellular multi-targeting represents a promising approach in future studies.

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Section: Discussionmentioning

confidence: 99%

Metformin and Thymoquinone Synergistically Inhibit Proliferation of Imatinib-Resistant Human Leukemic Cells

et al. 2022

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“…Synergism assay. Synergism was determined by the isobologram and Fa-CI plot based on Chou and Talalay method (17,18). K562 cells seeded in a 96-well plate were exposed to DMSO (as control), idelalisib, imatinib or their combination at a fixed ratio of IC 50 idelalisib to IC 50 imatinib (390:1) for 48 h. Cell growth inhibition was determined using the MTT assay, and the IC 50 values were calculated.…”

Section: Flow Cytometric Analysis Of Apoptosis With Annexin V-fitc/ Pmentioning

confidence: 99%

Idelalisib induces G1 arrest and apoptosis in chronic myeloid leukemia K562 cells

et al. 2016

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Increasing resistance of imatinib, a BCR-ABL tyrosine kinase inhibitor, hinders its use in the therapy of chronic myeloid leukemia (CML). The PI3K pathway is known to be closely involved in BCR-ABL transformation and the tumorigenesis of CML, suggesting that PI3K may be a potential target for CML therapy. Idelalisib, a specific inhibitor of PI3K p110δ, has been approved for the treatment of chronic lymphocytic leukemia (CLL). However, the antileukemia effect of idelalisib on CML remains unknown. In the present study, the antileukemia activity of idelalisib alone or in combination with imatinib was investigated by use of K562 cells. Idelalisib inhibited K562 proliferation in a dose-dependent manner. G1 arrest was induced, in which upregulation of p27 and p21, as well as downregulation of cyclin D1 and p-pRb, may be involved. Furthermore, idelalisib induced apoptosis in the K562 cells, with increased expression of pro-apoptotic molecules such as Bad and Bax, cleavage of caspase-9, -8 and -3, and PARP, in contrast to downregulation of anti-apoptotic protein Bcl-2. Combination of idelalisib with imatinib led to a synergistic antiproliferative effect on K562 cells, together with enhanced activity of G1 arrest and apoptosis induction. In conclusion, idelalisib exhibited in vitro antitumor activity on CML K562 cells alone or in combination with imatinib, suggesting potential application in CML therapy.

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In vitro testing of drug combinations employing nilotinib and alkylating agents with regard to pretransplant conditioning treatment of advanced-phase chronic myeloid leukemia

Abstract: Our in vitro data warrant further investigation and may provide the basis for nilotinib-supplemented conditioning regimens for allo-SCT in advanced-phase CML.

Cited by 2 publications

References 21 publications

Metformin and Thymoquinone Synergistically Inhibit Proliferation of Imatinib-Resistant Human Leukemic Cells

Metformin and Thymoquinone Synergistically Inhibit Proliferation of Imatinib-Resistant Human Leukemic Cells

Idelalisib induces G1 arrest and apoptosis in chronic myeloid leukemia K562 cells

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