The radiation- and chemo-sensitizing capacity of diclofenac can be predicted by a decreased lactate metabolism and stress response
© 2024. The Author(s)..
BACKGROUND: An enhanced aerobic glycolysis ("Warburg effect") associated with an increase in lactic acid in the tumor microenvironment contributes to tumor aggressiveness and resistance to radiation and chemotherapy. We investigated the radiation- and chemo-sensitizing effects of the nonsteroidal anti-inflammatory drug (NSAID) diclofenac in different cancer cell types.
METHODS: The effects of a non-lethal concentration of diclofenac was investigated on c-MYC and Lactate Dehydrogenase (LDH) protein expression/activity and the Heat shock Protein (HSP)/stress response in human colorectal (LS174T, LoVo), lung (A549), breast (MDA-MB-231) and pancreatic (COLO357) carcinoma cells. Radiation- and chemo-sensitization of diclofenac was determined using clonogenic cell survival assays and a murine xenograft tumor model.
RESULTS: A non-lethal concentration of diclofenac decreases c-MYC protein expression and LDH activity, reduces cytosolic Heat Shock Factor 1 (HSF1), Hsp70 and Hsp27 levels and membrane Hsp70 positivity in LS174T and LoVo colorectal cancer cells, but not in A549 lung carcinoma cells, MDA-MB-231 breast cancer cells and COLO357 pancreatic adenocarcinoma cells. The impaired lactate metabolism and stress response in diclofenac-sensitive colorectal cancer cells was associated with a significantly increased sensitivity to radiation and 5Fluorouracil in vitro, and in a human colorectal cancer xenograft mouse model diclofenac causes radiosensitization.
CONCLUSION: These findings suggest that a decrease in the LDH activity and/or stress response upon diclofenac treatment predicts its radiation/chemo-sensitizing capacity.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:19 |
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| Enthalten in: |
Radiation oncology (London, England) - 19(2024), 1 vom: 16. Jan., Seite 7 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Schwab, Melissa [VerfasserIn] |
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| Links: |
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| Themen: |
144O8QL0L1 |
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| Anmerkungen: |
Date Completed 18.01.2024 Date Revised 19.01.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1186/s13014-024-02399-5 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM367196646 |
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| 100 | 1 | |a Schwab, Melissa |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The radiation- and chemo-sensitizing capacity of diclofenac can be predicted by a decreased lactate metabolism and stress response |
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| 500 | |a Date Revised 19.01.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2024. The Author(s). | ||
| 520 | |a BACKGROUND: An enhanced aerobic glycolysis ("Warburg effect") associated with an increase in lactic acid in the tumor microenvironment contributes to tumor aggressiveness and resistance to radiation and chemotherapy. We investigated the radiation- and chemo-sensitizing effects of the nonsteroidal anti-inflammatory drug (NSAID) diclofenac in different cancer cell types | ||
| 520 | |a METHODS: The effects of a non-lethal concentration of diclofenac was investigated on c-MYC and Lactate Dehydrogenase (LDH) protein expression/activity and the Heat shock Protein (HSP)/stress response in human colorectal (LS174T, LoVo), lung (A549), breast (MDA-MB-231) and pancreatic (COLO357) carcinoma cells. Radiation- and chemo-sensitization of diclofenac was determined using clonogenic cell survival assays and a murine xenograft tumor model | ||
| 520 | |a RESULTS: A non-lethal concentration of diclofenac decreases c-MYC protein expression and LDH activity, reduces cytosolic Heat Shock Factor 1 (HSF1), Hsp70 and Hsp27 levels and membrane Hsp70 positivity in LS174T and LoVo colorectal cancer cells, but not in A549 lung carcinoma cells, MDA-MB-231 breast cancer cells and COLO357 pancreatic adenocarcinoma cells. The impaired lactate metabolism and stress response in diclofenac-sensitive colorectal cancer cells was associated with a significantly increased sensitivity to radiation and 5Fluorouracil in vitro, and in a human colorectal cancer xenograft mouse model diclofenac causes radiosensitization | ||
| 520 | |a CONCLUSION: These findings suggest that a decrease in the LDH activity and/or stress response upon diclofenac treatment predicts its radiation/chemo-sensitizing capacity | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Diclofenac | |
| 650 | 4 | |a Radiation sensitization | |
| 650 | 4 | |a Stress response | |
| 650 | 4 | |a Tumor metabolism | |
| 650 | 7 | |a Diclofenac |2 NLM | |
| 650 | 7 | |a 144O8QL0L1 |2 NLM | |
| 650 | 7 | |a Lactates |2 NLM | |
| 700 | 1 | |a Dezfouli, Ali Bashiri |e verfasserin |4 aut | |
| 700 | 1 | |a Khosravi, Mohammad |e verfasserin |4 aut | |
| 700 | 1 | |a Alkotub, Bayan |e verfasserin |4 aut | |
| 700 | 1 | |a Bauer, Lisa |e verfasserin |4 aut | |
| 700 | 1 | |a Birgani, Mohammad Javed Tahmasebi |e verfasserin |4 aut | |
| 700 | 1 | |a Multhoff, Gabriele |e verfasserin |4 aut | |
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