Ana-Maria Florea | Federal institute for risk assessment (original) (raw)
Papers by Ana-Maria Florea
![Research paper thumbnail of Targeting Intracellular Calcium Signaling ([Ca(2+)]i) to Overcome Acquired Multidrug Resistance of Cancer Cells: A Mini-Overview](https://attachments.academia-assets.com/88226196/thumbnails/1.jpg)
](Cancers, Jan 9, 2017
Cancer is a main public health problem all over the world. It affects millions of humans no matte... more Cancer is a main public health problem all over the world. It affects millions of humans no matter their age, gender, education, or social status. Although chemotherapy is the main strategy for the treatment of cancer, a major problem limiting its success is the intrinsic or acquired drug resistance. Therefore, cancer drug resistance is a major impediment in medical oncology resulting in a failure of a successful cancer treatment. This mini-overview focuses on the interdependent relationship between intracellular calcium ([Ca(2+)]i) signaling and multidrug resistance of cancer cells, acquired upon treatment of tumors with anticancer drugs. We propose that [Ca(2+)]i signaling modulates gene expression of multidrug resistant (MDR) genes which in turn can be modulated by epigenetic factors which in turn leads to modified protein expression in drug resistant tumor cells. A precise knowledge of these mechanisms will help to develop new therapeutic strategies for drug resistant tumors and...
Apoptosis : an international journal on programmed cell death, Jan 19, 2017
Inhibitors of apoptosis (IAPs) are a family of proteins that play a significant role in the contr... more Inhibitors of apoptosis (IAPs) are a family of proteins that play a significant role in the control of programmed cell death (PCD). PCD is essential to maintain healthy cell turnover within tissue but also to fight disease or infection. Uninhibited, IAPs can suppress apoptosis and promote cell cycle progression. Therefore, it is unsurprising that cancer cells demonstrate significantly elevated expression levels of IAPs, resulting in improved cell survival, enhanced tumor growth and subsequent metastasis. Therapies to target IAPs in cancer has garnered substantial scientific interest and as resistance to anti-cancer agents becomes more prevalent, targeting IAPs has become an increasingly attractive strategy to re-sensitize cancer cells to chemotherapies, antibody based-therapies and TRAIL therapy. Antagonism strategies to modulate the actions of XIAP, cIAP1/2 and survivin are the central focus of current research and this review highlights advances within this field with particular e...
Oncotarget, 2017
Neuroblastoma (NB) is a pediatric cancer treated with poly-chemotherapy including platinum comple... more Neuroblastoma (NB) is a pediatric cancer treated with poly-chemotherapy including platinum complexes (e.g. cisplatin (CDDP), carboplatin), DNA alkylating agents, and topoisomerase I inhibitors (e.g. topotecan (TOPO)). Despite aggressive treatment, NB may become resistant to chemotherapy. We investigated whether CDDP and TOPO treatment of NB cells interacts with the expression and function of proteins involved in regulating calcium signaling. Human neuroblastoma cell lines SH-SY5Y, IMR-32 and NLF were used to investigate the effects of CDDP and TOPO on cell viability, apoptosis, calcium homeostasis, and expression of selected proteins regulating intracellular calcium concentration ([Ca 2+ ] i). In addition, the impact of pharmacological inhibition of [Ca 2+ ] i-regulating proteins on neuroblastoma cell survival was studied. Treatment of neuroblastoma cells with increasing concentrations of CDDP (0.1−10 µM) or TOPO (0.1 nM−1 µM) induced cytotoxicity and increased apoptosis in a concentration-and time-dependent manner. Both drugs increased [Ca 2+ ] i over time. Treatment with CDDP or TOPO also modified mRNA expression of selected genes encoding [Ca 2+ ] i-regulating proteins. Differentially regulated genes included S100A6, ITPR1, ITPR3, RYR1 and RYR3. With FACS and confocal laser scanning microscopy experiments we validated their differential expression at the protein level. Importantly, treatment of neuroblastoma cells with pharmacological modulators of [Ca 2+ ] i-regulating proteins in combination with CDDP or TOPO increased cytotoxicity. Thus, our results confirm an important role of calcium signaling in the response of neuroblastoma cells to chemotherapy and suggest [Ca 2+ ] i modulation as a promising strategy for adjunctive treatment.
Oncotarget, Jan 12, 2016
Glioblastoma is the most aggressive brain tumor in adults with a median survival below 12 months ... more Glioblastoma is the most aggressive brain tumor in adults with a median survival below 12 months in population-based studies. The main reason for tumor recurrence and progression is constitutive or acquired resistance to the standard of care of surgical resection followed by radiotherapy with concomitant and adjuvant temozolomide (TMZ/RT→TMZ). Here, we investigated the role of microRNA (miRNA) alterations as mediators of alkylator resistance in glioblastoma cells. Using microarray-based miRNA expression profiling of parental and TMZ-resistant cultures of three human glioma cell lines, we identified a set of differentially expressed miRNA candidates. From these, we selected miR-138 for further functional analyses as this miRNA was not only upregulated in TMZ-resistant versus parental cells, but also showed increased expression in vivo in recurrent glioblastoma tissue samples after TMZ/RT→TMZ treatment. Transient transfection of miR-138 mimics in glioma cells with low basal miR-138 ex...
![Research paper thumbnail of Calcium ([Ca2+]i) signaling as a key-target for cancer treatment](https://a.academia-assets.com/images/blank-paper.jpg)
](![Research paper thumbnail of Cisplatin (CDDP) triggers cell death of MCF-7 cells following disruption of intracellular calcium ([Ca2+]i) homeostasis](https://attachments.academia-assets.com/88226130/thumbnails/1.jpg)
](The Journal of Toxicological Sciences, 2014
While arsenic compounds are known as environmental toxicants (especially in drinking water) and a... more While arsenic compounds are known as environmental toxicants (especially in drinking water) and as carcinogens, some arsenic compounds, like arsenic trioxide (As 2 O 3), are clinically used in humans to treat some forms of cancer (e.g. leukemia). Although arsenic compounds have been studied intensively, their interactions with living cells are still not fully elucidated. We have previously proposed that modulation of intracellular calcium ([Ca 2+ ] i) homeostasis induced by As 2 O 3 could be an important mechanism to induce cytotoxicity. Here we demonstrate, using human cell models (neuroblastoma (SY-5Y) or embryonic kidney cells (HEK)) and confocal microscopy in combination with the calcium sensitive dye fluo 4-AM, that As 2 O 3 interferes with calcium signaling at low (environmentally and clinically relevant concentrations of 100 pM to 1 M). Within this concentration range, As 2 O 3 had cell type specific cytotoxic effects, with neuroblastoma cells being more sensitive to As 2 O 3 than HEK 293. In addition, by staining with Hoechst 33347 and counting micronucleated cells as well as apoptotic nuclei, As 2 O 3 was found to increase the rate of apoptosis and DNA damage, which was also cell type specific. These results indicate that the As 2 O 3-induced cell death could be triggered or mediated by [Ca 2+ ] i signals and suggest that low concentrations of As 2 O 3 are able to interfere with specific physiological processes in diverse cell models.
Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell... more Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e.g., by interference with transcription and/or DNA replication mechanisms. Additionally, cisplatin damages tumors via induction of apoptosis, mediated by the activation of various signal transduction pathways, including calcium signaling, death receptor signaling, and the activation of mitochondrial pathways. Unfortunately, neither cytotoxicity nor apoptosis are exclusively induced in cancer cells, thus, cisplatin might also lead to diverse side-effects such as neuro-and/or renal-toxicity or bone marrow-suppression. Moreover, the binding of cisplatin to proteins and enzymes may modulate its biochemical mechanism of action. While a combination-chemotherapy with cisplatin is a cornerstone for the treatment of multiple cancers, the challenge is that cancer cells could become cisplatin-resistant. Numerous mechanisms of cisplatin resistance were described including changes in cellular uptake, drug efflux, increased detoxification, inhibition of apoptosis and increased DNA repair. To minimize cisplatin resistance, combinatorial therapies were developed and have proven more effective to defeat cancers. Thus, understanding of the biochemical mechanisms triggered by cisplatin in tumor cells may lead to the design of more efficient platinum derivates (or other drugs) and might provide new therapeutic strategies and reduce side effects.
Metals and metal compounds are part of our environment. Several metals are essential for physiolo... more Metals and metal compounds are part of our environment. Several metals are essential for physiological functions (e.g., zinc or magnesium); while the beneficial effects of others are uncertain (e.g., manganese), some metals are proven to be toxic (e.g., mercury, lead). Additionally there are organic metal compounds; some of them are extremely toxic (e.g., trimethyltin, methylmercury), but there is very little knowledge available how they are handled by organisms. Scientific evidence indicates that long-term exposure to (some) metallic compounds induces different forms of cancer, including breast cancer. On the other side, several metal compounds have clinical use in treating life-threatening diseases such as cancer. In this paper we discuss the recent literature that shows a correlation between metal exposure and breast cancer.
Journal of Local and Global Health Science, 2013
Breast cancer represents one of the most common cancers in women and is a major life threatening ... more Breast cancer represents one of the most common cancers in women and is a major life threatening illness found all over the world. Therapy approaches include irradiation and surgery, with chemotherapy considered an important strategy to treat breast cancer. Platinum based anticancer drugs, such as cisplatin (cis-di-amino-dichloride-platin, CDDP), carboplatin, orthoplatin, etc., have been successfully used in breast cancer therapy because they activate multiple mechanisms to induce apoptosis in tumor cells. Nevertheless, during chemotherapy, drug resistance frequently develops; this impairs the successful treatment of breast cancer and often leads to patients' decease. While combinations of anticancer drugs used in chemotherapy regimens reduced the occurrence of drug resistance (e.g. doxorubicin þ docetaxel, doxorubicin þ cyclophosphamide, docetaxel þ herceptin þ carboplatin) the molecular mechanism of those effects are not completely understood. Here we review possible mechanisms related to breast cancer treatment and resistance to current therapies as well as possible new therapeutic targets (e.g. calcium signaling) which could be used in the future.
Journal of Local and Global Health Science, 2013
Journal of Local and Global Health Science, 2013
Lead (Pb2+) is ubiquitously distributed in the environment and shows significant health effects i... more Lead (Pb2+) is ubiquitously distributed in the environment and shows significant health effects in humans, especially in the nervous system. In this review we illustrate how (Pb2+) neurotoxicity is associated with its ability to partially mimic the function of Ca2+ and modifies synaptic transmission pre- and post-synaptically. As Pb2+ binds to calcium-binding sites it alters their functionality, ranging from reduced currents through voltage and receptor gated channels, to modulation of ion-transporters and alterations of calcium-dependent signaling pathways. Overall Pb2+ exposure not only reduces pre-synaptically the transmitter release, but also post-synaptically the likelihood to generate a new action potential. This review will highlight the major-interactions with the different targets in schemes and short animated sequences to allow a general understanding of lead neurotoxicity to a wider audience; therefore, not all possible mechanisms will be mentioned or discussed.
NeuroToxicology, 2009
Arsenic trioxide and trimethyltin chloride (TMT) share a common mechanism: both trigger a Ca 2+ r... more Arsenic trioxide and trimethyltin chloride (TMT) share a common mechanism: both trigger a Ca 2+ release from the stores. .. .. . 806 5. While cisplatin and arsenic trioxide both increase [Ca 2+ ] i , their consecutive application further increases [Ca 2+ ] i and consequently elevates apoptosis .
Molecular Cancer Therapeutics, 2014
Glioblastoma is the most common malignant brain tumor in adults and characterized by a poor progn... more Glioblastoma is the most common malignant brain tumor in adults and characterized by a poor prognosis. Glioma cells expressing O6-methylguanine DNA methyltransferase (MGMT) exhibit a higher level of resistance toward alkylating agents, including the standard of care chemotherapeutic agent temozolomide. Here, we demonstrate that long-term glioma cell lines (LTL) as well as glioma-initiating cell lines (GIC) express receptors for the immune modulatory cytokine IFN-β and respond to IFN-β with induction of STAT-3 phosphorylation. Exposure to IFN-β induces a minor loss of viability, but strongly interferes with sphere formation in GIC cultures. Furthermore, IFN-β sensitizes LTL and GIC to temozolomide and irradiation. RNA interference confirmed that both IFN-β receptors, R1 and R2, are required for IFN-β–mediated sensitization, but that sensitization is independent of MGMT or TP53. Most GIC lines are highly temozolomide-resistant, mediated by MGMT expression, but nevertheless susceptible...
Materialwissenschaft und Werkstofftechnik, 2005
Journal of Neurochemistry, 2012
British Journal of Pharmacology, 2009
Brain, 2013
Thymosin beta 4 is a pleiotropic actin-sequestering polypeptide that is involved in wound healing... more Thymosin beta 4 is a pleiotropic actin-sequestering polypeptide that is involved in wound healing and developmental processes. Thymosin beta 4 gene silencing promotes differentiation of neural stem cells whereas thymosin beta 4 overexpression initiates cortical folding of developing brain hemispheres. A role of thymosin beta 4 in malignant gliomas has not yet been investigated. We analysed thymosin beta 4 staining on tissue microarrays and performed interrogations of the REMBRANDT and the Cancer Genome Atlas databases. We investigated thymosin beta 4 expression in seven established glioma cell lines and seven gliomainitiating cell lines and induced or silenced thymosin beta 4 expression by lentiviral transduction in LNT-229, U87MG and GS-2 cells to study the effects of altered thymosin beta 4 expression on gene expression, growth, clonogenicity, migration, invasion, self-renewal and differentiation capacity in vitro, and tumorigenicity in vivo. Thymosin beta 4 expression increased with grade of malignancy in gliomas. Thymosin beta 4 gene silencing in LNT-229 and U87MG glioma cells inhibited migration and invasion, promoted starvation-induced cell death in vitro and enhanced survival of glioma-bearing mice. Thymosin beta 4 gene silencing in GS-2 cells inhibited self-renewal and promoted differentiation in vitro and decreased tumorigenicity in vivo. Gene expression analysis suggested a thymosin beta 4-dependent regulation of mesenchymal signature genes and modulation of TGFb and p53 signalling networks. We conclude that thymosin beta 4 should be explored as a novel molecular target for anti-glioma therapy.
Cancers, Jan 9, 2017
Cancer is a main public health problem all over the world. It affects millions of humans no matte... more Cancer is a main public health problem all over the world. It affects millions of humans no matter their age, gender, education, or social status. Although chemotherapy is the main strategy for the treatment of cancer, a major problem limiting its success is the intrinsic or acquired drug resistance. Therefore, cancer drug resistance is a major impediment in medical oncology resulting in a failure of a successful cancer treatment. This mini-overview focuses on the interdependent relationship between intracellular calcium ([Ca(2+)]i) signaling and multidrug resistance of cancer cells, acquired upon treatment of tumors with anticancer drugs. We propose that [Ca(2+)]i signaling modulates gene expression of multidrug resistant (MDR) genes which in turn can be modulated by epigenetic factors which in turn leads to modified protein expression in drug resistant tumor cells. A precise knowledge of these mechanisms will help to develop new therapeutic strategies for drug resistant tumors and...
Apoptosis : an international journal on programmed cell death, Jan 19, 2017
Inhibitors of apoptosis (IAPs) are a family of proteins that play a significant role in the contr... more Inhibitors of apoptosis (IAPs) are a family of proteins that play a significant role in the control of programmed cell death (PCD). PCD is essential to maintain healthy cell turnover within tissue but also to fight disease or infection. Uninhibited, IAPs can suppress apoptosis and promote cell cycle progression. Therefore, it is unsurprising that cancer cells demonstrate significantly elevated expression levels of IAPs, resulting in improved cell survival, enhanced tumor growth and subsequent metastasis. Therapies to target IAPs in cancer has garnered substantial scientific interest and as resistance to anti-cancer agents becomes more prevalent, targeting IAPs has become an increasingly attractive strategy to re-sensitize cancer cells to chemotherapies, antibody based-therapies and TRAIL therapy. Antagonism strategies to modulate the actions of XIAP, cIAP1/2 and survivin are the central focus of current research and this review highlights advances within this field with particular e...
Oncotarget, 2017
Neuroblastoma (NB) is a pediatric cancer treated with poly-chemotherapy including platinum comple... more Neuroblastoma (NB) is a pediatric cancer treated with poly-chemotherapy including platinum complexes (e.g. cisplatin (CDDP), carboplatin), DNA alkylating agents, and topoisomerase I inhibitors (e.g. topotecan (TOPO)). Despite aggressive treatment, NB may become resistant to chemotherapy. We investigated whether CDDP and TOPO treatment of NB cells interacts with the expression and function of proteins involved in regulating calcium signaling. Human neuroblastoma cell lines SH-SY5Y, IMR-32 and NLF were used to investigate the effects of CDDP and TOPO on cell viability, apoptosis, calcium homeostasis, and expression of selected proteins regulating intracellular calcium concentration ([Ca 2+ ] i). In addition, the impact of pharmacological inhibition of [Ca 2+ ] i-regulating proteins on neuroblastoma cell survival was studied. Treatment of neuroblastoma cells with increasing concentrations of CDDP (0.1−10 µM) or TOPO (0.1 nM−1 µM) induced cytotoxicity and increased apoptosis in a concentration-and time-dependent manner. Both drugs increased [Ca 2+ ] i over time. Treatment with CDDP or TOPO also modified mRNA expression of selected genes encoding [Ca 2+ ] i-regulating proteins. Differentially regulated genes included S100A6, ITPR1, ITPR3, RYR1 and RYR3. With FACS and confocal laser scanning microscopy experiments we validated their differential expression at the protein level. Importantly, treatment of neuroblastoma cells with pharmacological modulators of [Ca 2+ ] i-regulating proteins in combination with CDDP or TOPO increased cytotoxicity. Thus, our results confirm an important role of calcium signaling in the response of neuroblastoma cells to chemotherapy and suggest [Ca 2+ ] i modulation as a promising strategy for adjunctive treatment.
Oncotarget, Jan 12, 2016
Glioblastoma is the most aggressive brain tumor in adults with a median survival below 12 months ... more Glioblastoma is the most aggressive brain tumor in adults with a median survival below 12 months in population-based studies. The main reason for tumor recurrence and progression is constitutive or acquired resistance to the standard of care of surgical resection followed by radiotherapy with concomitant and adjuvant temozolomide (TMZ/RT→TMZ). Here, we investigated the role of microRNA (miRNA) alterations as mediators of alkylator resistance in glioblastoma cells. Using microarray-based miRNA expression profiling of parental and TMZ-resistant cultures of three human glioma cell lines, we identified a set of differentially expressed miRNA candidates. From these, we selected miR-138 for further functional analyses as this miRNA was not only upregulated in TMZ-resistant versus parental cells, but also showed increased expression in vivo in recurrent glioblastoma tissue samples after TMZ/RT→TMZ treatment. Transient transfection of miR-138 mimics in glioma cells with low basal miR-138 ex...
The Journal of Toxicological Sciences, 2014
While arsenic compounds are known as environmental toxicants (especially in drinking water) and a... more While arsenic compounds are known as environmental toxicants (especially in drinking water) and as carcinogens, some arsenic compounds, like arsenic trioxide (As 2 O 3), are clinically used in humans to treat some forms of cancer (e.g. leukemia). Although arsenic compounds have been studied intensively, their interactions with living cells are still not fully elucidated. We have previously proposed that modulation of intracellular calcium ([Ca 2+ ] i) homeostasis induced by As 2 O 3 could be an important mechanism to induce cytotoxicity. Here we demonstrate, using human cell models (neuroblastoma (SY-5Y) or embryonic kidney cells (HEK)) and confocal microscopy in combination with the calcium sensitive dye fluo 4-AM, that As 2 O 3 interferes with calcium signaling at low (environmentally and clinically relevant concentrations of 100 pM to 1 M). Within this concentration range, As 2 O 3 had cell type specific cytotoxic effects, with neuroblastoma cells being more sensitive to As 2 O 3 than HEK 293. In addition, by staining with Hoechst 33347 and counting micronucleated cells as well as apoptotic nuclei, As 2 O 3 was found to increase the rate of apoptosis and DNA damage, which was also cell type specific. These results indicate that the As 2 O 3-induced cell death could be triggered or mediated by [Ca 2+ ] i signals and suggest that low concentrations of As 2 O 3 are able to interfere with specific physiological processes in diverse cell models.
Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell... more Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e.g., by interference with transcription and/or DNA replication mechanisms. Additionally, cisplatin damages tumors via induction of apoptosis, mediated by the activation of various signal transduction pathways, including calcium signaling, death receptor signaling, and the activation of mitochondrial pathways. Unfortunately, neither cytotoxicity nor apoptosis are exclusively induced in cancer cells, thus, cisplatin might also lead to diverse side-effects such as neuro-and/or renal-toxicity or bone marrow-suppression. Moreover, the binding of cisplatin to proteins and enzymes may modulate its biochemical mechanism of action. While a combination-chemotherapy with cisplatin is a cornerstone for the treatment of multiple cancers, the challenge is that cancer cells could become cisplatin-resistant. Numerous mechanisms of cisplatin resistance were described including changes in cellular uptake, drug efflux, increased detoxification, inhibition of apoptosis and increased DNA repair. To minimize cisplatin resistance, combinatorial therapies were developed and have proven more effective to defeat cancers. Thus, understanding of the biochemical mechanisms triggered by cisplatin in tumor cells may lead to the design of more efficient platinum derivates (or other drugs) and might provide new therapeutic strategies and reduce side effects.
Metals and metal compounds are part of our environment. Several metals are essential for physiolo... more Metals and metal compounds are part of our environment. Several metals are essential for physiological functions (e.g., zinc or magnesium); while the beneficial effects of others are uncertain (e.g., manganese), some metals are proven to be toxic (e.g., mercury, lead). Additionally there are organic metal compounds; some of them are extremely toxic (e.g., trimethyltin, methylmercury), but there is very little knowledge available how they are handled by organisms. Scientific evidence indicates that long-term exposure to (some) metallic compounds induces different forms of cancer, including breast cancer. On the other side, several metal compounds have clinical use in treating life-threatening diseases such as cancer. In this paper we discuss the recent literature that shows a correlation between metal exposure and breast cancer.
Journal of Local and Global Health Science, 2013
Breast cancer represents one of the most common cancers in women and is a major life threatening ... more Breast cancer represents one of the most common cancers in women and is a major life threatening illness found all over the world. Therapy approaches include irradiation and surgery, with chemotherapy considered an important strategy to treat breast cancer. Platinum based anticancer drugs, such as cisplatin (cis-di-amino-dichloride-platin, CDDP), carboplatin, orthoplatin, etc., have been successfully used in breast cancer therapy because they activate multiple mechanisms to induce apoptosis in tumor cells. Nevertheless, during chemotherapy, drug resistance frequently develops; this impairs the successful treatment of breast cancer and often leads to patients' decease. While combinations of anticancer drugs used in chemotherapy regimens reduced the occurrence of drug resistance (e.g. doxorubicin þ docetaxel, doxorubicin þ cyclophosphamide, docetaxel þ herceptin þ carboplatin) the molecular mechanism of those effects are not completely understood. Here we review possible mechanisms related to breast cancer treatment and resistance to current therapies as well as possible new therapeutic targets (e.g. calcium signaling) which could be used in the future.
Journal of Local and Global Health Science, 2013
Journal of Local and Global Health Science, 2013
Lead (Pb2+) is ubiquitously distributed in the environment and shows significant health effects i... more Lead (Pb2+) is ubiquitously distributed in the environment and shows significant health effects in humans, especially in the nervous system. In this review we illustrate how (Pb2+) neurotoxicity is associated with its ability to partially mimic the function of Ca2+ and modifies synaptic transmission pre- and post-synaptically. As Pb2+ binds to calcium-binding sites it alters their functionality, ranging from reduced currents through voltage and receptor gated channels, to modulation of ion-transporters and alterations of calcium-dependent signaling pathways. Overall Pb2+ exposure not only reduces pre-synaptically the transmitter release, but also post-synaptically the likelihood to generate a new action potential. This review will highlight the major-interactions with the different targets in schemes and short animated sequences to allow a general understanding of lead neurotoxicity to a wider audience; therefore, not all possible mechanisms will be mentioned or discussed.
NeuroToxicology, 2009
Arsenic trioxide and trimethyltin chloride (TMT) share a common mechanism: both trigger a Ca 2+ r... more Arsenic trioxide and trimethyltin chloride (TMT) share a common mechanism: both trigger a Ca 2+ release from the stores. .. .. . 806 5. While cisplatin and arsenic trioxide both increase [Ca 2+ ] i , their consecutive application further increases [Ca 2+ ] i and consequently elevates apoptosis .
Molecular Cancer Therapeutics, 2014
Glioblastoma is the most common malignant brain tumor in adults and characterized by a poor progn... more Glioblastoma is the most common malignant brain tumor in adults and characterized by a poor prognosis. Glioma cells expressing O6-methylguanine DNA methyltransferase (MGMT) exhibit a higher level of resistance toward alkylating agents, including the standard of care chemotherapeutic agent temozolomide. Here, we demonstrate that long-term glioma cell lines (LTL) as well as glioma-initiating cell lines (GIC) express receptors for the immune modulatory cytokine IFN-β and respond to IFN-β with induction of STAT-3 phosphorylation. Exposure to IFN-β induces a minor loss of viability, but strongly interferes with sphere formation in GIC cultures. Furthermore, IFN-β sensitizes LTL and GIC to temozolomide and irradiation. RNA interference confirmed that both IFN-β receptors, R1 and R2, are required for IFN-β–mediated sensitization, but that sensitization is independent of MGMT or TP53. Most GIC lines are highly temozolomide-resistant, mediated by MGMT expression, but nevertheless susceptible...
Materialwissenschaft und Werkstofftechnik, 2005
Journal of Neurochemistry, 2012
British Journal of Pharmacology, 2009
Brain, 2013
Thymosin beta 4 is a pleiotropic actin-sequestering polypeptide that is involved in wound healing... more Thymosin beta 4 is a pleiotropic actin-sequestering polypeptide that is involved in wound healing and developmental processes. Thymosin beta 4 gene silencing promotes differentiation of neural stem cells whereas thymosin beta 4 overexpression initiates cortical folding of developing brain hemispheres. A role of thymosin beta 4 in malignant gliomas has not yet been investigated. We analysed thymosin beta 4 staining on tissue microarrays and performed interrogations of the REMBRANDT and the Cancer Genome Atlas databases. We investigated thymosin beta 4 expression in seven established glioma cell lines and seven gliomainitiating cell lines and induced or silenced thymosin beta 4 expression by lentiviral transduction in LNT-229, U87MG and GS-2 cells to study the effects of altered thymosin beta 4 expression on gene expression, growth, clonogenicity, migration, invasion, self-renewal and differentiation capacity in vitro, and tumorigenicity in vivo. Thymosin beta 4 expression increased with grade of malignancy in gliomas. Thymosin beta 4 gene silencing in LNT-229 and U87MG glioma cells inhibited migration and invasion, promoted starvation-induced cell death in vitro and enhanced survival of glioma-bearing mice. Thymosin beta 4 gene silencing in GS-2 cells inhibited self-renewal and promoted differentiation in vitro and decreased tumorigenicity in vivo. Gene expression analysis suggested a thymosin beta 4-dependent regulation of mesenchymal signature genes and modulation of TGFb and p53 signalling networks. We conclude that thymosin beta 4 should be explored as a novel molecular target for anti-glioma therapy.