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Tirapazamine Cytotoxicity for Neuroblastoma Is p53 Dependent
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| Zeitschriftentitel: | Clinical Cancer Research |
|---|---|
| Personen und Körperschaften: | , |
| In: | Clinical Cancer Research, 11, 2005, 7, S. 2774-2780 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Association for Cancer Research (AACR)
|
| Schlagwörter: |
| author_facet |
Yang, Bo Reynolds, C. Patrick Yang, Bo Reynolds, C. Patrick |
|---|---|
| author |
Yang, Bo Reynolds, C. Patrick |
| spellingShingle |
Yang, Bo Reynolds, C. Patrick Clinical Cancer Research Tirapazamine Cytotoxicity for Neuroblastoma Is p53 Dependent Cancer Research Oncology |
| author_sort |
yang, bo |
| spelling |
Yang, Bo Reynolds, C. Patrick 1078-0432 1557-3265 American Association for Cancer Research (AACR) Cancer Research Oncology http://dx.doi.org/10.1158/1078-0432.ccr-04-2382 <jats:title>Abstract</jats:title> <jats:p>Relapse of neuroblastoma commonly occurs in hypoxic tissues, and is associated with an acquired and sustained high-level drug resistance, often due to p53 loss of function. Abrogating p53 function with HPV 16 E6 transduction in drug-sensitive neuroblastoma cell lines caused high-level drug resistance. Tirapazamine (TPZ) is a bioreductive agent that forms a toxic free radical in hypoxia. We determined in six neuroblastoma cell lines the cytotoxicity of TPZ using DIMSCAN, a digital imaging fluorescence assay, apoptosis and mitochondrial membrane potential (ΔΨm) by flow cytometry, and protein expression by immunoblotting. TPZ exhibited high cytotoxicity, especially in hypoxia (2% O2), for all four p53-functional neuroblastoma cell lines, achieving &gt;3 logs of cell kill (LC99 ≤ 0.7 μg/mL). In p53-nonfunctional neuroblastoma cell lines, all TPZ LC99 values were &gt;3.0 μg/mL (average clinically achievable level). TPZ (24 hours) induced apoptosis in &gt;46% of cells in p53-functional cell lines but failed to cause apoptosis in p53 nonfunctional cell lines. Induction of p53 and p21 expression by TPZ was observed in a p53-functional cell line (SMS-SAN) but not in a p53-nonfunctional cell line (CHLA-90). Significant ΔΨm loss and glutathione (GSH) depletion in response to TPZ was observed in p53-functional cell lines (SMS-SAN, SMS-SAN EV, and CHLA-15) but not in p53-nonfunctional cell lines (SMS-SAN E6 and CHLA-90). N-Acetylcysteine inhibited TPZ-mediated ΔΨm loss and GSH depletion, but neither N-acetylcysteine nor Boc-d-fmk inhibited apoptosis caused by TPZ. In response to TPZ, ΔΨm loss preceded apoptosis. Thus, TPZ cytotoxicity for neuroblastoma cell lines in hypoxia occurred via a p53-dependent mitochondrial pathway that caused induction of p53 and p21, ΔΨm decrease, GSH depletion, and apoptosis. These data further define the mechanism of action of TPZ and suggest that as a single agent, TPZ would only have clinical activity against p53-functional neuroblastomas.</jats:p> Tirapazamine Cytotoxicity for Neuroblastoma Is p53 Dependent Clinical Cancer Research |
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| title |
Tirapazamine Cytotoxicity for Neuroblastoma Is p53 Dependent |
| title_unstemmed |
Tirapazamine Cytotoxicity for Neuroblastoma Is p53 Dependent |
| title_full |
Tirapazamine Cytotoxicity for Neuroblastoma Is p53 Dependent |
| title_fullStr |
Tirapazamine Cytotoxicity for Neuroblastoma Is p53 Dependent |
| title_full_unstemmed |
Tirapazamine Cytotoxicity for Neuroblastoma Is p53 Dependent |
| title_short |
Tirapazamine Cytotoxicity for Neuroblastoma Is p53 Dependent |
| title_sort |
tirapazamine cytotoxicity for neuroblastoma is p53 dependent |
| topic |
Cancer Research Oncology |
| url |
http://dx.doi.org/10.1158/1078-0432.ccr-04-2382 |
| publishDate |
2005 |
| physical |
2774-2780 |
| description |
<jats:title>Abstract</jats:title>
<jats:p>Relapse of neuroblastoma commonly occurs in hypoxic tissues, and is associated with an acquired and sustained high-level drug resistance, often due to p53 loss of function. Abrogating p53 function with HPV 16 E6 transduction in drug-sensitive neuroblastoma cell lines caused high-level drug resistance. Tirapazamine (TPZ) is a bioreductive agent that forms a toxic free radical in hypoxia. We determined in six neuroblastoma cell lines the cytotoxicity of TPZ using DIMSCAN, a digital imaging fluorescence assay, apoptosis and mitochondrial membrane potential (ΔΨm) by flow cytometry, and protein expression by immunoblotting. TPZ exhibited high cytotoxicity, especially in hypoxia (2% O2), for all four p53-functional neuroblastoma cell lines, achieving &gt;3 logs of cell kill (LC99 ≤ 0.7 μg/mL). In p53-nonfunctional neuroblastoma cell lines, all TPZ LC99 values were &gt;3.0 μg/mL (average clinically achievable level). TPZ (24 hours) induced apoptosis in &gt;46% of cells in p53-functional cell lines but failed to cause apoptosis in p53 nonfunctional cell lines. Induction of p53 and p21 expression by TPZ was observed in a p53-functional cell line (SMS-SAN) but not in a p53-nonfunctional cell line (CHLA-90). Significant ΔΨm loss and glutathione (GSH) depletion in response to TPZ was observed in p53-functional cell lines (SMS-SAN, SMS-SAN EV, and CHLA-15) but not in p53-nonfunctional cell lines (SMS-SAN E6 and CHLA-90). N-Acetylcysteine inhibited TPZ-mediated ΔΨm loss and GSH depletion, but neither N-acetylcysteine nor Boc-d-fmk inhibited apoptosis caused by TPZ. In response to TPZ, ΔΨm loss preceded apoptosis. Thus, TPZ cytotoxicity for neuroblastoma cell lines in hypoxia occurred via a p53-dependent mitochondrial pathway that caused induction of p53 and p21, ΔΨm decrease, GSH depletion, and apoptosis. These data further define the mechanism of action of TPZ and suggest that as a single agent, TPZ would only have clinical activity against p53-functional neuroblastomas.</jats:p> |
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| description | <jats:title>Abstract</jats:title> <jats:p>Relapse of neuroblastoma commonly occurs in hypoxic tissues, and is associated with an acquired and sustained high-level drug resistance, often due to p53 loss of function. Abrogating p53 function with HPV 16 E6 transduction in drug-sensitive neuroblastoma cell lines caused high-level drug resistance. Tirapazamine (TPZ) is a bioreductive agent that forms a toxic free radical in hypoxia. We determined in six neuroblastoma cell lines the cytotoxicity of TPZ using DIMSCAN, a digital imaging fluorescence assay, apoptosis and mitochondrial membrane potential (ΔΨm) by flow cytometry, and protein expression by immunoblotting. TPZ exhibited high cytotoxicity, especially in hypoxia (2% O2), for all four p53-functional neuroblastoma cell lines, achieving &gt;3 logs of cell kill (LC99 ≤ 0.7 μg/mL). In p53-nonfunctional neuroblastoma cell lines, all TPZ LC99 values were &gt;3.0 μg/mL (average clinically achievable level). TPZ (24 hours) induced apoptosis in &gt;46% of cells in p53-functional cell lines but failed to cause apoptosis in p53 nonfunctional cell lines. Induction of p53 and p21 expression by TPZ was observed in a p53-functional cell line (SMS-SAN) but not in a p53-nonfunctional cell line (CHLA-90). Significant ΔΨm loss and glutathione (GSH) depletion in response to TPZ was observed in p53-functional cell lines (SMS-SAN, SMS-SAN EV, and CHLA-15) but not in p53-nonfunctional cell lines (SMS-SAN E6 and CHLA-90). N-Acetylcysteine inhibited TPZ-mediated ΔΨm loss and GSH depletion, but neither N-acetylcysteine nor Boc-d-fmk inhibited apoptosis caused by TPZ. In response to TPZ, ΔΨm loss preceded apoptosis. Thus, TPZ cytotoxicity for neuroblastoma cell lines in hypoxia occurred via a p53-dependent mitochondrial pathway that caused induction of p53 and p21, ΔΨm decrease, GSH depletion, and apoptosis. These data further define the mechanism of action of TPZ and suggest that as a single agent, TPZ would only have clinical activity against p53-functional neuroblastomas.</jats:p> |
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| spelling | Yang, Bo Reynolds, C. Patrick 1078-0432 1557-3265 American Association for Cancer Research (AACR) Cancer Research Oncology http://dx.doi.org/10.1158/1078-0432.ccr-04-2382 <jats:title>Abstract</jats:title> <jats:p>Relapse of neuroblastoma commonly occurs in hypoxic tissues, and is associated with an acquired and sustained high-level drug resistance, often due to p53 loss of function. Abrogating p53 function with HPV 16 E6 transduction in drug-sensitive neuroblastoma cell lines caused high-level drug resistance. Tirapazamine (TPZ) is a bioreductive agent that forms a toxic free radical in hypoxia. We determined in six neuroblastoma cell lines the cytotoxicity of TPZ using DIMSCAN, a digital imaging fluorescence assay, apoptosis and mitochondrial membrane potential (ΔΨm) by flow cytometry, and protein expression by immunoblotting. TPZ exhibited high cytotoxicity, especially in hypoxia (2% O2), for all four p53-functional neuroblastoma cell lines, achieving &gt;3 logs of cell kill (LC99 ≤ 0.7 μg/mL). In p53-nonfunctional neuroblastoma cell lines, all TPZ LC99 values were &gt;3.0 μg/mL (average clinically achievable level). TPZ (24 hours) induced apoptosis in &gt;46% of cells in p53-functional cell lines but failed to cause apoptosis in p53 nonfunctional cell lines. Induction of p53 and p21 expression by TPZ was observed in a p53-functional cell line (SMS-SAN) but not in a p53-nonfunctional cell line (CHLA-90). Significant ΔΨm loss and glutathione (GSH) depletion in response to TPZ was observed in p53-functional cell lines (SMS-SAN, SMS-SAN EV, and CHLA-15) but not in p53-nonfunctional cell lines (SMS-SAN E6 and CHLA-90). N-Acetylcysteine inhibited TPZ-mediated ΔΨm loss and GSH depletion, but neither N-acetylcysteine nor Boc-d-fmk inhibited apoptosis caused by TPZ. In response to TPZ, ΔΨm loss preceded apoptosis. Thus, TPZ cytotoxicity for neuroblastoma cell lines in hypoxia occurred via a p53-dependent mitochondrial pathway that caused induction of p53 and p21, ΔΨm decrease, GSH depletion, and apoptosis. These data further define the mechanism of action of TPZ and suggest that as a single agent, TPZ would only have clinical activity against p53-functional neuroblastomas.</jats:p> Tirapazamine Cytotoxicity for Neuroblastoma Is p53 Dependent Clinical Cancer Research |
| spellingShingle | Yang, Bo, Reynolds, C. Patrick, Clinical Cancer Research, Tirapazamine Cytotoxicity for Neuroblastoma Is p53 Dependent, Cancer Research, Oncology |
| title | Tirapazamine Cytotoxicity for Neuroblastoma Is p53 Dependent |
| title_full | Tirapazamine Cytotoxicity for Neuroblastoma Is p53 Dependent |
| title_fullStr | Tirapazamine Cytotoxicity for Neuroblastoma Is p53 Dependent |
| title_full_unstemmed | Tirapazamine Cytotoxicity for Neuroblastoma Is p53 Dependent |
| title_short | Tirapazamine Cytotoxicity for Neuroblastoma Is p53 Dependent |
| title_sort | tirapazamine cytotoxicity for neuroblastoma is p53 dependent |
| title_unstemmed | Tirapazamine Cytotoxicity for Neuroblastoma Is p53 Dependent |
| topic | Cancer Research, Oncology |
| url | http://dx.doi.org/10.1158/1078-0432.ccr-04-2382 |