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  • 1.
    Chatzakos, Vicky
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Studies of bioactive lipids in cancer2012Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Lipids are a broad class of molecules that, besides being a major form of energy storage and components of cell membranes, act as bioactive signalling molecules. N-acyl taurines are structurally related to endocannabinoids that are known to exert antiproliferative actions in a variety of cancer cells. We have evaluated the cytotoxicity of N-oleoyl taurine and N-arachidonoyl taurine and found N-acyl taurines to reduce proliferation of prostate cancer cells.

    The sphingolipids ceramide and sphingosine act as tumour suppressors. We found selenite treatment to cause reduced viability, induction of neutral sphingomyelinase activity and accumulation of ceramide in the liver cancer cells. Inhibition of sphingosine kinase 1 (SK1) sensitized the cells to selenite treatment with regards to ceramide accumulation, arrest of cells in the G1/S phases of the cell cycle and formation of reactive oxygen species. Whereas combined selenite treatment and SK1 inhibition synergistically reduced the number of viable cells, the non-tumorigenic hepatocyte cell line, remained unaffected.

    Furthermore, we studied the involvement of sphingolipid metabolism in bladder cancer cells treated with Bacillus Calmette-Guérin (BCG), and found BCG to induce formation of nitric oxide and upregulation of nitric oxide synthase 2 as well as SK1 protein levels. Additionally, pharmacological inhibition of SK1 enhanced the viability reduction, ceramide accumulation and induction of apoptosis observed following BCG treatment.

    In conclusion, our findings have shown that N-acyl taurines exert antiproliferative effects on prostate cancer cells. Furthermore, sphingolipids were shown to be involved in cytotoxic treatment with selenite and BCG in liver cancer and bladder cancer cells respectively, and inhibition of SK1 increased the cytotoxicity. Our findings raise the possibility that modulation of ceramide-metabolizing enzymes could be used to enhance the effects of selenite and BCG in these cancer cell types.

  • 2.
    Chatzakos, Vicky
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Rothlind, Emmie
    Karolinska Institutet.
    Izza Hamzo, Maria
    Karolinska Institutet.
    Wiklund, Peter
    Karolinska Institutet.
    Flygare, Jenny
    Karolinska Institutet.
    De Verdier, Petra
    Karolinska Institutet.
    Bacillus Calmette-Guérin treatment specifically induces SK1 protein expression inurothelial bladder-cancer cellsManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Bladder instillation with Bacillus Calmétte-Guerin (BCG) is an established treatmentmodality for superficial high-risk urinary bladder-cancer and carcinoma in situ (CIS), but theanti-tumor mechanisms following BCG-instillations remain largely unknown. In this study weexamined the effects of BCG-treatment on SK1 protein expression in the murine bladdercancer cell line MBT2. To simulate in vivo BCG-instillations, where the immune systemplays a vital role for successful BCG-treatment, we also stimulated MBT2 cells withsupernatant from BCG-treated (SupBCG) or un-treated Raw 264.7 macrophages. BCGtreatment as well as SupBCG treatment induced SK1 protein expression. Treatment with thesphingosine-kinase 1 (SK1) inhibitor 2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole (SK1-II) induced reduced viability in a dose dependent manner. However, combined treatment withBCG diminished this viability reduction suggesting a protective effect of BCG, but not ofSup-BCG, from SK1-II induced toxicity. Apoptosis was detected, as PARP-cleavage, in cellstreated with SupBCG whereas BCG-only or supernatant from untreated macrophages did notinduce apoptosis. A substantial increase in ceramides C18, C18:1 and C20:1 was observedafter BCG-treatment. These ceramide subspecies, as well as ceramides C14, C16, C20, C22and C22:1, were also induced by 20 or 30M of SK1-II, but the induction was abrogated byco-treatement with BCG. Following treatment with Sup-BCG, the levels of all the abovementioned ceramide subspecies were increased. Levels of ceramides C14, C16, C18, C18:1,C20, C20:1, C22 and C22:1 were more than two times higher in response to combinedtreatment with Sup-BCG and 10M of SK1-II as compared to treatment with Sup-BCG orSK1-II alone. Taken together these data suggest the sphingolipid metabolism as an importantpathway in the response to BCG-therapy.

  • 3.
    Chatzakos, Vicky
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Rundlöf, Anna-Klara
    Karolinska Institutet.
    Ahmed, Dilruba
    Karolinska Institutet.
    De Verdier, Petra J.
    Karolinska Institutet.
    Flygare, Jenny
    Karolinska Institutet.
    Inhibition of sphingosine kinase 1 enhances cytotoxicity, ceramide levels and ROS formation in liver cancer cells treated with selenite2012Ingår i: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 84, nr 5, s. 712-721Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    High doses of selenite have been shown to induce cell death in acute myeloid leukemia and lung cancercells. In this study, we combined selenite treatment with modulators of sphingolipid metabolism in thehepatocellular carcinoma cell line Huh7. Treatment with 20 mM of selenite reduced the viability of Huh7cells by half and increased the levels of long chain C14-, C16-, C18- and C18:1- ceramides by two-fold.Inhibition of neutral sphingomyelinase with 3-O-methylsphingosine significantly reduced the cytotoxiceffect of selenite. In line with this result, selenite caused a 2.5-fold increase in the activity of neutralsphingomyelinase. The sphingosine kinase 1 (SK1) inhibitor 2-(p-hydroxyanilino)-4-(p-chlorophe-nyl)thiazole (SK1-II) sensitized the cells to the cytotoxic effects of selenite. Preincubation with 10 mM ofSK1-II prior to treatment with 10 mM of selenite caused induction of apoptosis and gave rise to a 2.5-foldincrease in C14-, C16-, C18- and C18:1- ceramides. Instead, 50 mM of SK1-II combined with 10 mM ofselenite caused accumulation of cells in G1/S phases, but less apoptosis and accumulation of ceramides.The formation of reactive oxygen species (ROS) after treatment with 10 mM of selenite was maximallyenhanced by 1 mM of SK1-II. Moreover, combined treatment with SK1-II and 10 mM of selenitesynergistically reduced the number of viable Huh7 cells, while the non-tumorigenic hepatocyte cell lineMIHA remained unaffected by the same treatment. These results raise the possibility that a combinationof selenite and SK1 inhibitors could be used to treat liver cancer cells, that are regarded as drug resistant,at doses that are non-toxic to normal liver cells.

  • 4.
    Chatzakos, Vicky
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Slätis, Katharina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Djureinovic, Tatjana
    Helleday, Thomas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Hunt, Mary C.
    N-Acyl Taurines are Anti-Proliferative in Prostate Cancer Cells2012Ingår i: Lipids, ISSN 0024-4201, E-ISSN 1558-9307, Vol. 47, nr 4, s. 355-361Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Endocannabinoids have been implicated in cancer development and cause heterogenous effects in tumor cells, by inducing apoptosis, reducing migration, causing anti-angiogenic activity and alterations in the cell cycle resulting in growth arrest. Recently, several novel amides of fatty acids that are structurally related to endocannabinoids have been isolated from mammalian sources, although the functions of these fatty amides are not well studied. One group of these novel fatty acid amides are the N-acyl taurines (fatty acids conjugated to the amino acid taurine). This study examined if N-acyl taurines, specifically N-arachidonoyl taurine and N-oleoyl taurine could function in a similar way to endocannabinoids and result in cell cycle alterations or growth arrest in the human prostate adenocarcinoma cell line PC-3. PC-3 cells were treated with various concentrations of N-arachidonoyl taurine and N-oleoyl taurine and cell proliferation and viability was measured using resazurin and colony formation assays. Effects of N-acyl taurines on the cell cycle was measured using FACS analysis. Treatment with N-arachidonoyl taurine and N-oleoyl taurine resulted in a significant reduction in proliferation of PC-3 cells, even at concentrations as low as 1 mu M. Treatment with N-oleoyl taurine resulted in an increased number of cells in the subG1 population, suggesting apoptosis, and a lower number of cells in S-phase of the cell cycle. In summary, our results show that novel biologically active lipids, the N-acyl taurines, result in reduced proliferation in PC-3 cells.

  • 5.
    Issaeva, Natalia
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Thomas, Huw D.
    Djurenovic, Tatjana
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Jaspers, Janneke E.
    Stoimenov, Ivaylo
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Kyle, Suzanne
    Pedley, Nicholas
    Gottipati, Ponnari
    Zur, Rafal
    Sleeth, Kate
    Chatzakos, Vicky
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Mulligan, Evan A.
    Lundin, Cecilia
    Gubanova, Evgenia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Kersbergen, Ariena
    Harris, Adrian L.
    Sharma, Ricky A.
    Rottenberg, Sven
    Curtin, Nicola J.
    Helleday, Thomas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    6-Thioguanine Selectively Kills BRCA2-Defective Tumors and Overcomes PARP Inhibitor Resistance2010Ingår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, nr 15, s. 6268-6276Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Familial breast and ovarian cancers are often defective in homologous recombination (HR) due to mutations in the BRCA1 or BRCA2 genes. Cisplatin chemotherapy or poly(ADP-ribose) polymerase (PARP) inhibitors were tested for these tumors in clinical trials. In a screen for novel drugs that selectively kill BRCA2-defective cells, we identified 6-thioguanine (6TG), which induces DNA double-strand breaks (DSB) that are repaired by HR. Furthermore, we show that 6TG is as efficient as a PARP inhibitor in selectively killing BRCA2-defective tumors in a xenograft model. Spontaneous BRCA1-defective mammary tumors gain resistance to PARP inhibitors through increased P-glycoprotein expression. Here, we show that 6TG efficiently kills such BRCA1-defective PARP inhibitor-resistant tumors. We also show that 6TG could kill cells and tumors that have gained resistance to PARP inhibitors or cisplatin through genetic reversion of the BRCA2 gene. Although HR is reactivated in PARP inhibitor-resistant BRCA2-defective cells, it is not fully restored for the repair of 6TG-induced lesions. This is likely to be due to several recombinogenic lesions being formed after 6TG. We show that BRCA2 is also required for survival from mismatch repair-independent lesions formed by 6TG, which do not include DSBs. This suggests that HR is involved in the repair of 6TG-induced DSBs as well as mismatch repair-independent 6TG-induced DNA lesion. Altogether, our data show that 6TG efficiently kills BRCA2-defective tumors and suggest that 6TG may be effective in the treatment of advanced tumors that have developed resistance to PARP inhibitors or platinum-based chemotherapy. Cancer Res; 70(15); 6268-76. (C) 2010 AACR.

  • 6.
    Thiel, Tomas
    et al.
    Karolinska Institutet.
    Ryk, Charlotta
    Chatzakos, Vicky
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Hallén Grufman, Katarina
    Karolinska Institutet.
    Bavand-Chobot, Nasrin
    Karolinska Institutet.
    Flygare, Jenny
    Karolinska Institutet.
    Wiklund, N. Peter
    Karolinska Institutet.
    De Verdier, Petra J.
    Karolinska Institutet.
    Secondary stimulation from Bacillus Calmette-Guérin induced macrophages upregulatesNOS2 protein in bladder cancer cellsManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Treatment with Bacillus Calmette-Guérin (BCG) bladder instillations is an established treatment modality for superficial urinary bladder cancer and carcinoma in situ (CIS), but the anti-tumor mechanisms following BCG-instillations remain largely unknown. Previous data show increased nitric oxide (NO) concentrations in the urinary bladder from patients treated with BCG suggesting that NO-formation may be involved in the BCG-mediated effect. Using immunohistochemistry we have previously shown nitric oxide synthase 2 (NOS2/iNOS) protein expression in both immune cells and in urothelial cells in bladder cancer patient biopsies. In this study we analysed the influence of macrophage- (RAW 264.7) secreted factors on NO production by stimulating urothelial carcinoma cells (MBT2) with supernatant from BCG-treated macrophages as well as supernatant from untreated macrophages. Using real-time PCR, western blot and chemiluminescence, we found no effect of BCG when added straight to the culture medium of urothelial carcinoma cells. However, when 40% of the culture medium of the bladder cancer cells was substituted with supernatant from BCGstimulated macrophages, we found increased NOS2 mRNA and protein expression as well as increased levels of NO. In addition we found increased cell death only in bladder cancer cells stimulated with supernatant from BCG-treated macrophages, as visualized by cell cycle analysis and PARP cleavage. These results suggest that simultaneous targeting of the microenvironment and subsequent stimulation of adaptive responses can improve conventional BCG-therapy.

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