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  • 1
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    Springer
    Keywords: pharmacology ; molecular ; molecular pharmacology
    Type of Publication: Book chapter
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  • 2
    Keywords: Rb ; PKB/AKT ; lipid ; mechanism of action ; erufosine ; synergistic combinations ; pAkt ; BCR-ABL ; CML ; caspases ; KINASE INHIBITOR ; LEVEL ; INCREASE ; SUBSTRATE ; AGENT ; signaling ; CASPASE ; INHIBITORS ; protein expression ; MAMMALIAN-CELLS ; PROTEIN-KINASE-C ; leukemia ; FUSION ; LINE ; MEMBRANE ; SIGNAL-TRANSDUCTION ; COMPONENT ; ALKYLPHOSPHOCHOLINES ; ANTILEUKEMIC EFFICACY ; CELL-LINE ; chemotherapy ; cell lines ; p27 ; ENTRY ; HEALTH ; ASSAY ; PROGRESSION ; SIGNAL ; treatment ; TYROSINE KINASE INHIBITOR ; CYCLE ; CELL-LINES ; CELL-CYCLE ; cell cycle ; PROTEIN-KINASE ; signal transduction ; INDUCTION ; REDUCTION ; TYROSINE KINASE ; COMBINATION ; KINASE ; PATHWAY ; THERAPY ; PATHWAYS ; CELL ; INHIBITOR ; APOPTOSIS ; EXPRESSION ; CELLS ; DISEASE ; NEW-YORK ; LINES ; cell line ; DRUG ; PROTEINS ; PROTEIN ; TRANSDUCTION ; cell signaling ; MECHANISM ; PATIENT
    Abstract: The ether lipid analog erufosine (erucylphospho-N,N,N,- trimethylpropylammonium, ErPC3) has high activity against leukemic cells without affecting the normal hematopoiesis. It belongs to the group of alkylphosphocholines (APC) that are inhibitors of protein kinase C and phospholipase C. However, the mechanism of action of erufosine remains rather unclear. We focused on combination effects with the tyrosine kinase inhibitor imatinib mesylate (gleevec, former STI-571 or CGP-57148) against two chronic myeloid leukemia (CML)-derived cell lines (K-562 and BV-173). The influence of erufosine on proteins involved in the phosphatidylinositol-3-phosphate pathway and on expression of the retinoblastoma protein Rb was studied, the latter being a key component for cell cycle entry and progression in mammalian cells. The consecutive treatment of K-562 and BV-173 cells with erufosine (2.5, 5, 15, 30 mu M) and imatinib mesylate (0.05, 0.1 mu M) led to synergism as measured by the MTT-dye reduction assay and this is reason to hypothesize that such combinations could be beneficial for relapsed patients with drug-resistant disease. Whole cell lysates from K-562 and BV-173 were investigated for the expression of Rb, PKB/Akt, pAkt, and p27 by Western blot. Erufosine caused decreases of pAkt and CML fusion protein p210 (BCR-ABL) protein expression, but induced the Rb protein expression in K-562 cells. A parallel increase in p27 level was observed after 24 and 48 h treatment. These alterations in signal transduction could be an explanation for the drug interaction found. Furthermore, Rb is a substrate of caspases and is cleaved during apoptosis as already evidenced for BV-173 cells. Our experimental findings suggest that erufosine acts through induction of changes in protein signaling and especially through Rb induction. This unique mode of action makes it an attractive partner for combination therapies, for example, in combination with imatinib mesylate for treatment of CML
    Type of Publication: Book chapter
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  • 3
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    Springer
    Keywords: molecular pharmacology ; AGENT ; molecular ; pharmacology ; AGENTS
    Type of Publication: Book chapter
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  • 4
    Keywords: APOPTOSIS ; CANCER ; CELLS ; GROWTH ; INHIBITOR ; proliferation ; CELL ; COMBINATION ; INHIBITION ; PATHWAY ; PATHWAYS ; TOXICITY ; transcription ; cell line ; LINES ; MICE ; TRANSDUCTION ; PATIENT ; NF-KAPPA-B ; ACTIVATION ; TRANSCRIPTION FACTOR ; REDUCTION ; CELL-LINES ; signal transduction ; SIGNAL ; ANTITUMOR-ACTIVITY ; BONE-MARROW ; culture ; LYMPHOMA ; GLUTATHIONE ; CHROMOSOMAL-ABERRATIONS ; EFFICACY ; SIGNAL-TRANSDUCTION ; CELL-LINE ; chemotherapy ; leukemia ; LINE ; ABERRATIONS ; NF-kappa B ; CISPLATIN ; curcumin ; FACTOR-I ; cell lines ; CANCER-THERAPY ; MULTIPLE-MYELOMA ; CYTOTOXICITY ; ARREST ; multiple myeloma ; INCREASE ; LEVEL ; ASSAYS ; CANCERS ; ENGLAND ; aberration ; antineoplasic effect ; antitumor activity ; bendamustine ; chemoprotection ; clastogenic effect ; GSH level ; myeloma ; ACAD
    Abstract: Curcumin is the pigment of turmeric and has been reported as a signal transduction modulator and inhibitor of transcription factors, for example, NF-kappa B. In our article we found a concentration-dependent cytotoxic activity of curcumin in a panel of eight leukemic cell lines (SKW-3, CEM, U-937, HL-60, HL-60/Dox, K-562, LAMA-84, and AR-230). Additive to synergistic interactions was recorded for combinations with bendamustine and idarubicine in SKW-3 and LAMA-84 cells. Noteworthy, in multiple myeloma cells (RPMI-8226 and U-266) a potentiation of the efficacy of bendamustine by curcumin application was found. Moreover, curcumin increased the bendamustine cytotoxicity in cultures of cells isolated from the bone marrow of a patient with non-Hodgkin's lymphoma (NHL). The increased bendamustine efficacy could be explained by NF-kappa B inhibition, because this factor is activated in many cancers, especially leukemia and multiple myeloma. Curcumin is characterized by low toxicity and was described to have a chemoprotective activity. Therefore, the level of reduced glutathione (GSH) was measured and a concentration-dependent increase of GSH levels was recorded in AR-230 and SKW-3 cells (concentration range 5-25 mu M). Experiments with mice showed significant protection against cisplatin-induced chromosomal aberrations (clastogenic effect) and inhibition of mitoses in bone marrow cells. Curcumin alone caused reduction of the mitotic index. In combination with cisplatin, however, this parameter was increased when compared to cisplatin alone. Our data indicate that curcumin has pleiotropic effects on signal transduction by inhibiting transcription thus exerting antitumor activity. In addition, curcumin has protective and anticlastogenic activity by enhancing the scavenging of free radicals
    Type of Publication: Journal article published
    PubMed ID: 17404048
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  • 5
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; tumor ; CELL ; Germany ; EXPOSURE ; PROTEIN ; DRUG ; cell line ; LINES ; MECHANISM ; SUFFICIENT ; MR ; CELL-LINES ; treatment ; NO ; ASSAY ; EFFICACY ; ALKYLPHOSPHOCHOLINES ; ANTILEUKEMIC EFFICACY ; CELL-LINE ; chemotherapy ; LINE ; MODULATION ; p53 ; BETA ; Jun ; sensitivity ; cell lines ; ONCOLOGY ; RE ; TUMOR-SUPPRESSOR ; LEVEL ; ASSAYS ; SUPPRESSOR ; technique ; USA ; UNIT ; mechanism of action ; Rb ; antisense ; ANTINEOPLASTIC ACTIVITY ; chronic myeloid leukemia (CML) ; cytotoxic efficacy ; erucylphospho-N,N,N-trimethylpropylammonium (erufosine)
    Abstract: The alkylphosphocholine erucylphospho-N,N,N-trimethylpropylammonium (ErPC3) is a promising new drug for treating various types of cancer. Its mechanism of action is no yet fully understood but is related to the Rb tumor suppressor protein. In the present study. we investigated the role of decreased Rb expression levels for the antileukemic efficacy of ErPC3 in BV-173 and K-562 CML-derived cell lines. We used antisense technique to knock down Rb levels in the two cell lines in addition to ErPC3 treatment. Cells with reduced Rb expression showed a diminished sensitivity to ErPC3 exposure, as determinec by MTT (BV 173 and K-562) and clonogenicity assays (K-562 only), if concentration. below the IC50 were used. The feasibility of Rb knockdown varied between BV-173 and K-562 cells, with the former being distinctly more sensitive than the latter. We conclude that sufficient Rb levels are important for the cytotoxic and anticlonogenic effects of ErPC; at levels below the IC50, but that higher concentrations of ErPC3 are less dependent or Rb status
    Type of Publication: Journal article published
    PubMed ID: 17495525
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  • 6
    Keywords: 3, ACTIVATION, ALKYLPHOSPHOCHOLINES, ANTILEUKEMIC EFFICACY, APOPTOSIS, ASSAY, CASPASE ACTIVATION, CA
    Abstract: Multiple myeloma (MM) is a frequent hematological malignancy that is incurable despite recent developments, such as proteasome and angiogenic inhibitors. Erucylphospho-N,N,N-trimethylpropylammonium (erufosine) is an i.v. injectable alkylphosphocholine with antineoplastic activity based on an unusual mode of action and is currently undergoing clinical trials in leukemia patients. The aim of this investigation was to evaluate the efficacy of erufosine in MM cells and to study the modulation of cell-death pathways. The cytotoxicity of erufosine against three MM cell lines (RPMI-8226, U-266, and OPM-2) was determined by the 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide-dye reduction assay. All MM cell lines responded to erufosine, RPMI-8226 cells being most and U-266 being least sensitive. The respective IC50 values were 3.2 and 16.2 mu mol/L. Various cell-death characteristics were studied in response to erufosine, such as morphological changes, oligonucleosomal DNA fragmentation, caspase activation, and poly (ADP)-ribose polymerase cleavage. Erufosine was found to cause cell shrinkage, chromatin condensation, and caspase-8 and -3 activation. Taken together, our data indicate that erufosine is a potential antimyeloma drug eliciting specific features of apoptotic cell death in vitro
    Type of Publication: Journal article published
    PubMed ID: 19723075
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  • 7
    Keywords: APOPTOSIS ; IN-VITRO ; PHASE-I ; ALKYLPHOSPHOCHOLINES ; drug resistance ; MULTIPLE-MYELOMA ; CYTOTOXICITY ; multiple myeloma ; INTERLEUKIN-6 ; OSTEOPONTIN ; BONE ; BREAST-CANCER CELLS ; erufosine ; PERIFOSINE ; MEK INHIBITORS ; AKT INHIBITOR ; MEK1/2 INHIBITOR ; Raf/MEK/ERK
    Abstract: Alkylphosphocholines are highly active against multiple myeloma (MM) cells in vitro and are devoid of myelotoxicity. Little is known about the determinants of MM cell responsiveness or resistance to these drugs. In this study we investigated the effects of disease-relevant cytokines, such as interleukin-6 (IL-6) and osteopontin (OPN), on the in vitro antimyeloma activity of erufosine and perifosine. The role of the Raf/MEK/ERK pathway was also studied. Exogenous IL-6 reduced the cytotoxicity of erufosine against OPM-2 cells and, to a smaller extent, against U-266 cells. This was accompanied by inhibition of apoptosis in OPM-2 cells. The efficacy of perifosine was similarly affected, but to a greater extent. IL-6 slightly enhanced the sensitivity of RPMI-8226 cells to erufosine, thus emphasizing the heterogeneity of MM. Induced overexpression of OPN isoforms made OPM-2 cells less sensitive to erufosine. In all cases of IL-6- or OPN-induced resistance, the effective concentrations of erufosine were still within the clinically achievable range. Like other alkylphosphocholines, erufosine enhanced Raf/MEK/ERK signaling in MM cells but in some cases this contributed to cytotoxicity.
    Type of Publication: Journal article published
    PubMed ID: 22421411
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  • 8
    Keywords: IN-VITRO ; NF-KAPPA-B ; BREAST-CANCER ; MULTIPLE-MYELOMA ; MYCOSIS-FUNGOIDES ; LEUKEMIA-CELLS ; SEZARY-SYNDROME ; BONE-MARROW-CELLS ; AKT INHIBITOR ; XENOGRAFT MODEL
    Abstract: While most patients with early-stage cutaneous T-cell lymphomas (CTCL) have a very good prognosis, the survival of patients with extensive tumour stage and visceral involvement remains extremely poor and necessitates the development of more effective treatment modalities. In this study, we evaluated the in vitro effects of two alkylphosphocholines (APCs, miltefosine and erufosine) and the polyphenolic compound curcumin on 5 human CTCL cell lines (Hut-78, HH, MJ, My-La CD4(+) and My-La CD8(+)). All tested drugs showed considerable cytotoxic activity, as determined by the MU dye reduction assay. The IC50 values of both APCs ranged from the low micromolar level (Hut-78 cells) to 60-80 mu M (HH cells). The IC50 values of curcumin ranged from 12 to 24 mu M. All tested drugs induced apoptosis, as ascertained by morphological changes, DNA fragmentation and activation of caspase cascades. Miltefosine and erufosine induced dephosphorylation of Akt in My-La CD8(+) cells and phosphorylation of JNK in Hut-78 and My-La CD8(+) cells. APCs increased the level of the autophagic marker LC3B in Hut-78 and MJ cells. Results from co-treatment with autophagy modulators suggested that the cytotoxicity of APCs in CTCL cells is mediated, at least in part, by induction of autophagy.
    Type of Publication: Journal article published
    PubMed ID: 24225136
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  • 9
    Keywords: TUMOR-CELLS ; NF-KAPPA-B ; TRANSCRIPTION FACTORS ; CARCINOMA-CELLS ; SEZARY-SYNDROME ; T-CELL LYMPHOMA ; BIOLOGICAL-ACTIVITIES ; HUMAN MULTIPLE-MYELOMA ; FREE-RADICAL REACTIONS ; INFLAMMATORY PATHWAYS
    Abstract: The unfavorable safety of existing anticancer medications and the issue of multidrug resistance have fuelled the search for novel plant compounds as potential antineoplastic agents. One of the used approaches for identifying perspective candidates is based on ethnopharmacology. Curcumin is the yellow pigment of curry and has being employed in traditional Indian medicine. Within the EU it has the status of food ingredient (E100) and remains in many food additives. It is isolated from Curcuma longa L. and has been reported as NF-kappa B inhibitor and apoptosis inducer with antioxidant, cholesterol lowering, anti-inflammatory, anti-parasitic, antibacterial and antitumor potential. Curcumin has been shown to exert a wide spectrum of pleiotropic activities including antitumor effects and protection of the normal bone marrow. It possesses antineoplastic activity in various malignant cell lines in vitro, such as cutaneous T cell lymphoma, acute myeloid leukemia and urinary bladder cancer cells. In lymphoma and leukemia cell lines curcumin induces apoptosis as evidenced by caspase activation, PARP cleavage and oligonucleosomal DNA fragmentation. Expression of the myeloid marker CD13 (aminopeptidase N) is associated with faster apoptosis induction. In addition, curcumin causes concentration-dependent glutathione level increase. Application of curcumin in vivo resulted in protection against cisplatin-induced chromosomal aberrations (anticlastogenic effect). This finding reveals curcumin as preferable partner for combinations with antineoplastic agents in order to potentiate their activity and ameliorate the adverse effects. There is a clear need for new curcumin formulations because of its low bioavailability after oral intake. Cutaneous and intravesical curcumin applications remain a possibility for successful clinical use of curcumin.
    Type of Publication: Journal article published
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  • 10
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