Title

Cisplatin resistance in human cervical, ovarian and lung cancer cells

Publication Date

2015

Journal Title

Cancer Chemother Pharmacol

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).

Volume Number

75

Issue Number

6

Pages

1217-27

Document Type

Article

EPub Date

2015/04/22

Status

Faculty; Northwell Resident

Facility

School of Medicine; Northwell Health

Primary Department

Pathology and Laboratory Medicine

PMID

25894720

DOI

10.1007/s00280-015-2739-2