| 1. |
- Myhre, Louise, et al.
(författare)
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Different cell cycle kinetic effects of N1,N11-diethylnorspermine-induced polyamine depletion in four human breast cancer cell lines.
- 2008
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Ingår i: Anti-Cancer Drugs. - 0959-4973. ; 19:4, s. 359-368
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Tidskriftsartikel (refereegranskat)abstract
- Polyamine analogues are presently undergoing clinical evaluation in the treatment of cancer. To better understand under what circumstances treatment with a polyamine analogue will yield beneficial results, we have investigated the effect of N,N-diethylnorspermine (DENSPM) on cell cycle kinetics of the human breast cancer cell lines SK-BR-3, MCF-7, HCC1937, and L56Br-C1. A bromodeoxyuridine-DNA flow cytometry method was used to evaluate the treatment with 10 micromol/l DENSPM on cell cycle kinetics. A correlation between polyamine pool size after DENSPM treatment and cell cycle kinetic effects was found. The most sensitive cell cycle phase was the S phase, followed by an effect on the G2+M phase and then the G1/S transition. The levels of a number of cell cycle regulatory proteins such as cyclin E1, cyclin A2, and cyclin B1 were lowered by DENSPM treatment, which may explain the effects on cell cycle kinetics. The two cell lines that were most sensitive to DENSPM treatment belong to the basal-like subtype of breast cancer and they were deficient with respect to p53, BRCA1, and RB1.
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| 2. |
- Myhre, Louise, et al.
(författare)
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Normal-like breast cells, but not breast cancer cells, recovered from treatment with N ',N ''-diethylnorspermine
- 2009
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Ingår i: Anti-Cancer Drugs. - 0959-4973. ; 20:4, s. 230-237
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Tidskriftsartikel (refereegranskat)abstract
- A number of polyamine analogs are currently used in various clinical trials as cancer treatment and it is important to investigate their effects not only on cancer cells but also on normal cells. Treatment with polyamine analogs depletes cells of polyamines and inhibits cell proliferation, but the analogs cannot take over the normal function of the natural polyamines in the cell. In this study, the normal-like breast epithelial cell line MCF-10A was treated with the polyamine analog N',N ''-diethylnorspermine (DENSPM). The cells were then studied using a bromodeoxyuridine-DNA flow cytometry method as well as western blot. The ability of both normal-like and breast cancer cells to recover from DENSPM treatment was also studied. DENSPM treatment of MCF-10A cells resulted in a prolongation of the S and G(2) + M phases, followed by a G(1)/S block. The p53/p21/RB1 pathway was involved in the G(1)/S block as shown by increased levels of p53 and p21 detected by western blot. Decreased levels of cyclin E1, cyclin A2, and cyclin B1 in DENSPM-treated cells can explain the prolongation of cell cycle phases that occurred before the G(1)/S block. We also show that MCF-10A cells rapidly recover from DENSPM-induced growth inhibition in contrast to four human breast cancer cell lines. The goal of cancer treatment is to cause minimal and reversible damage to normal cells, while cancer cells should be eliminated. Altogether, the data show that treatment with polyamine analogs spares normal cells, while negatively affecting the cancer cells. Anti-Cancer Drugs 20:230-237 (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.
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| 3. |
- Myhre, Louise
(författare)
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The Polyamine Dependence of Cell Cycle Progression-Application in Breast Cancer Treatment
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In the normal functioning organism, there is a balance between cell proliferation, cell differentiation, and cell death. An imbalance in these processes results in different diseases. This thesis concerns the imbalance where there is too little cell death and cell differentiation with increased cell proliferation. The result is uncontrolled cell proliferation resulting in the development of cancer. Polyamines are essential for normal cell cycle proliferation and polyamine levels are often elevated in cancer cells. The general aim of my thesis was to achieve a better understanding of the role of the polyamines in cell cycle progression and how to apply this to manipulate the breast cancer cell cycle. In one model system we investigated cell cycle progression in Chinese hamster ovary cells expressing different types of an enzyme involved in polyamine biosynthesis resulting in different polyamine pool levels. In the second model system we depleted the polyamines in four breast cancer cell lines with different genetic profiles to resemble the reality of breast cancer disease, and in one normal-like breast epithelial cell line. The substances we used to deplete the polyamines were: alpha-difluoromethylornithine, 4-amidinoindan-1-one 2'-amidinohydrazone, and, N1, N11-diethylnorspermine. Cell cycle kinetics was affected in both model systems by manipulation of the polyamine pools. The different cell lines responded differently to the same kind of treatment and different signaling pathways were induced. This resulted in different responses in cell cycle kinetics such as S phase prolongation and G1/S block. The cell cycle kinetic effects were correlated to changes in the levels of cell cycle regulatory proteins. The responses in the human cell lines can be reflected in their different genetic makeup. Altogether these data show the importance of finding biomarkers for the efficient use of compounds that affect the polyamine pools in the treatment of breast cancer. The result show that DENSPM treatment and almost certainly other spermine analogues may be effective in certain types of familial breast cancer sub groups while ineffective in other types of breast cancer.
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| 4. |
- Nasizadeh, Sima, et al.
(författare)
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Importance of polyamines in cell cycle kinetics as studied in a transgenic system.
- 2005
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 1090-2422 .- 0014-4827. ; 308:May 26, s. 254-264
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Tidskriftsartikel (refereegranskat)abstract
- Polyamines are organic cations, which are considered essential for normal cell cycle progression. This view is based on results from numerous studies using a variety of enzyme inhibitors or polyamine analogues interfering with either the metabolism or the physiological functions of the polyamines. However, the presence of non-specific effects may be hard to rule out in such studies. In the present study, we have for the first time used a transgenic cell system to analyze the importance of polyamines in cell growth. We have earlier shown that expression of trypanosomal ODC in an ODC-deficient variant of CHO cells (C55.7) supported growth of these otherwise polyamine auxotrophic cells. However, one of the transgenic cell lines grew much slower than the others. As shown in the present study, the level of ODC activity was much lower in these cells, and that was reflected in a reduction of cellular polyamine levels. Analysis of cell cycle kinetics revealed that reduction of growth was correlated to prolongation of the G(1), S, and G(2) + M phases in the cells. Providing exogenous putrescine to the cells resulted in a normalization of polyamine levels as well as cell cycle kinetics indicating a causal relationship.
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| 5. |
- Oredsson, Stina, et al.
(författare)
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Inhibition of cell proliferation and induction of apoptosis by N(1),N(11)-diethylnorspermine-induced polyamine pool reduction
- 2007
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Ingår i: Biochemical Society Transactions. - 0300-5127. ; 35:2, s. 405-409
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Tidskriftsartikel (refereegranskat)abstract
- Reduction of cellular polyamine pools results in inhibition of cell proliferation and sometimes in induction of cell death. Reduction of cellular polyamine pools can be achieved by several strategies involving all the mechanisms of polyamine homoeostasis, i.e. biosynthesis, catabolism and transport across the cell membrane. In the present paper, we concentrate on results achieved using the polyamine analogue DENSPM (N(1),N(11)-diethylnorspermine) on different cell lines. We discuss polyamine levels in DENSPM-treated cells in relation to effects on cell cycle kinetics and induction of apoptosis. To really understand the role of polyamines in cell cycle regulation and apoptosis, we believe it is now time to go through the vast polyamine literature in a meta-analysis-based manner. This short review does not claim to be such a study, but it is our hope to stimulate such studies in the polyamine field. Such work is especially important from the viewpoint of introducing drugs that affect polyamine homoeostasis in the treatment of various diseases such as cancer.
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