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Cancer Chemotherapy and Pharmacology

Erschienen in:

01.06.2015 | Original Article

Cisplatin resistance in human cervical, ovarian and lung cancer cells

verfasst von: Jianli Chen, Charalambos Solomides, Hemant Parekh, Fiona Simpkins, Henry Simpkins

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 6/2015

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Abstract

Purpose

This study was performed to determine whether or not in cervical, ovarian and lung cancer cell lines, free radicals (ROS) play a role in cisplatin cytotoxicity and activation of the mitochondrial and JNK/p38 pathways. The role of the enzyme, dihydrodiol dehydrogenase (DDH1), in the activation/deactivation of this pathway and how this may be related to the development of resistance was also investigated.

Methods

Mitochondrial membrane potential and ROS analysis were performed by flow cytometry, P-JNK and P-p38 by western blotting and mRNA by RT-PCR. Dihydrodiol dehydrogenase (DDH1) and thioredoxin knockdowns were prepared by standard techniques.

Results

Cisplatin treatment of a cervical cancer cell line resulted in ROS production with mitochondrial membrane depolarization and phosphorylation of JNK and p38. N-acetyl-cysteine, a free radical scavenger, ameliorated these effects. Treatment of the sensitive cells with H₂O₂ produced similar effects but at shorter incubation times. Similar results were observed with an ovarian cell line. Downregulation of dihydrodiol dehydrogenase in the cisplatin-resistant cervical and lung cancer cell lines resulted in increased drug sensitivity with detectable production of ROS and activation of the JNK/p38 pathways; however, downregulation of thioredoxin in the cervical cells had minimal effect.

Conclusion

Dihydrodiol dehydrogenase appears to play a role in cisplatin resistance in cervical, ovarian and lung cancer cells which includes mitochondrial membrane depolarization, ROS production and activation of the JNK pathway. However, its mode of action cannot be mimicked by an ROS scavenger so its mechanism of action is more complex (a not unexpected finding considering its role in xenobiotic activation/countering oxidative stress).

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Titel: Cisplatin resistance in human cervical, ovarian and lung cancer cells
verfasst von: Jianli Chen
Charalambos Solomides
Hemant Parekh
Fiona Simpkins
Henry Simpkins
Publikationsdatum: 01.06.2015
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 6/2015
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-015-2739-2

Springer Medizin

Cisplatin resistance in human cervical, ovarian and lung cancer cells

Abstract

Purpose

Methods

Results

Conclusion

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Springer Medizin

Abstract

Purpose

Methods

Results

Conclusion

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