Effects of arsenic trioxide and hypoxia in multidrug-resistant neuroblastoma
(2005) In Lund University Faculty of Medicine Doctoral Dissertation Series- Abstract
- Neuroblastoma is a childhood tumour derived from the sympathetic nervous system. Although most children with neuroblastoma initially respond to treatment, approximately 50% of these patients relapse with multidrug-resistant tumours. Arsenic trioxide (As2O3) has been used for centuries to treat different clinical disorders including malignancies. This drug has now attracted new attention since it has been proven efficient for treatment of patients with relapsed acute promyelocytic leukaemia. We have demonstrated that As2O3 is toxic to neuroblastoma cells at clinically relevant concentrations, including cells that are resistant to treatment with cytotoxic drugs commonly used in neuroblastoma therapy. As2O3 is also efficient to cells grown... (More)
- Neuroblastoma is a childhood tumour derived from the sympathetic nervous system. Although most children with neuroblastoma initially respond to treatment, approximately 50% of these patients relapse with multidrug-resistant tumours. Arsenic trioxide (As2O3) has been used for centuries to treat different clinical disorders including malignancies. This drug has now attracted new attention since it has been proven efficient for treatment of patients with relapsed acute promyelocytic leukaemia. We have demonstrated that As2O3 is toxic to neuroblastoma cells at clinically relevant concentrations, including cells that are resistant to treatment with cytotoxic drugs commonly used in neuroblastoma therapy. As2O3 is also efficient to cells grown under hypoxic conditions, an import feature since neuroblastoma is a solid tumour with frequent regions of hypoxia. As2O3 - induced cell death does not depend on activation of a classical apoptotic cell death, since inhibition of caspases did not affect the death. However, proteolytic activation of Bax seems to be of importance for As2O3 - induced cell death, since inhibition of Bax cleavage was associated with a reduction in cell death. The cleaved and activated Bax (p18 Bax) was only found in a nuclear fraction in As2O3-treated cells.
In order to mimic growth conditions in a solid tumour, neuroblastoma cells were grown at hypoxia in presence or absence of glucose. Growth in absence of glucose induced cell death at normoxia conditions, but growth at hypoxic conditions could inhibit the glucose-deficiency induced cell death. Hypoxic growth conditions seem to rescue the cells through inhibiting glucose-deficiency induced activation of caspases and through induced expression of survival-promoting factors signalling through the MAPK-pathway. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/544953
- author
- Karlsson, Jenny LU
- supervisor
-
- Sven Påhlman LU
- opponent
-
- Associate Professor Shoshan, Maria, Dept of Oncology and Pathology, Cancer Center Karolinska, Stockholm
- organization
- publishing date
- 2005
- type
- Thesis
- publication status
- published
- subject
- keywords
- Klinisk biologi, Clinical biology, neuroblastoma, multidrug resistance, hypoxia, glucose-deficiency, cell death, Bax, Apoptosis, arsenic trioxide
- in
- Lund University Faculty of Medicine Doctoral Dissertation Series
- pages
- 115 pages
- publisher
- Lund University: Faculty of Medicine
- defense location
- Main lecture hall, Pathology building, Malmö university hospital
- defense date
- 2005-06-03 09:15:00
- ISSN
- 1652-8220
- ISBN
- 91-85439-54-1
- language
- English
- LU publication?
- yes
- additional info
- Jenny Karlsson, Ingrid Øra, Isabella Pörn-Ares and Sven Påhlman. 2004. Arsenic trioxide-induced death of neuroblastoma cells involves activation of Bax and does not require p53. Clinical Cancer Research, vol 10 pp 3179-3188.Jenny Karlsson, Alexander Pietras, Siv Beckman, Christer Larsson and Sven Påhlman. . Arsenic trioxide-induced neuroblastoma cell death is accompanied by proteolytic activation of nuclear Bax. (manuscript)Jenny Karlsson, Anders Edsjö, Sven Påhlman and Helen M. Pettersson. . Multidrug-resistant neuroblastoma cells are responsive to arsenic trioxide at both normoxia and hypoxia. Mol Cancer Ther, (accepted)Jenny Karlsson, Hélen Nilsson, Marie Ovenberger, Erik Fredlund and Sven Påhlman. . Hypoxia rescues neuroblastoma cells from glucose deficiency-induced cell death. (manuscript)The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Molecular Medicine (013031200)
- id
- 6b92eb7e-ef78-489c-90c2-453600796ff3 (old id 544953)
- date added to LUP
- 2016-04-01 16:59:27
- date last changed
- 2019-11-19 13:49:08
@phdthesis{6b92eb7e-ef78-489c-90c2-453600796ff3, abstract = {{Neuroblastoma is a childhood tumour derived from the sympathetic nervous system. Although most children with neuroblastoma initially respond to treatment, approximately 50% of these patients relapse with multidrug-resistant tumours. Arsenic trioxide (As2O3) has been used for centuries to treat different clinical disorders including malignancies. This drug has now attracted new attention since it has been proven efficient for treatment of patients with relapsed acute promyelocytic leukaemia. We have demonstrated that As2O3 is toxic to neuroblastoma cells at clinically relevant concentrations, including cells that are resistant to treatment with cytotoxic drugs commonly used in neuroblastoma therapy. As2O3 is also efficient to cells grown under hypoxic conditions, an import feature since neuroblastoma is a solid tumour with frequent regions of hypoxia. As2O3 - induced cell death does not depend on activation of a classical apoptotic cell death, since inhibition of caspases did not affect the death. However, proteolytic activation of Bax seems to be of importance for As2O3 - induced cell death, since inhibition of Bax cleavage was associated with a reduction in cell death. The cleaved and activated Bax (p18 Bax) was only found in a nuclear fraction in As2O3-treated cells.<br/><br> <br/><br> In order to mimic growth conditions in a solid tumour, neuroblastoma cells were grown at hypoxia in presence or absence of glucose. Growth in absence of glucose induced cell death at normoxia conditions, but growth at hypoxic conditions could inhibit the glucose-deficiency induced cell death. Hypoxic growth conditions seem to rescue the cells through inhibiting glucose-deficiency induced activation of caspases and through induced expression of survival-promoting factors signalling through the MAPK-pathway.}}, author = {{Karlsson, Jenny}}, isbn = {{91-85439-54-1}}, issn = {{1652-8220}}, keywords = {{Klinisk biologi; Clinical biology; neuroblastoma; multidrug resistance; hypoxia; glucose-deficiency; cell death; Bax; Apoptosis; arsenic trioxide}}, language = {{eng}}, publisher = {{Lund University: Faculty of Medicine}}, school = {{Lund University}}, series = {{Lund University Faculty of Medicine Doctoral Dissertation Series}}, title = {{Effects of arsenic trioxide and hypoxia in multidrug-resistant neuroblastoma}}, year = {{2005}}, }