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Life Sci. 2015 Mar 1;124:31-40. doi: 10.1016/j.lfs.2015.01.011. Epub 2015 Jan 24.

Cisplatin resistance in human lung cancer cells is linked with dysregulation of cell cycle associated proteins.

Author information

1
Laboratory of Medicinal and Biochemical Analysis, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima 737-0112, Japan; Department of Medical Pharmaceutics, Kobe Pharmaceutical University, Kobe 658-8558, Japan.
2
Laboratory of Medicinal and Biochemical Analysis, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima 737-0112, Japan.
3
Department of Medical Pharmaceutics, Kobe Pharmaceutical University, Kobe 658-8558, Japan. Electronic address: tana@kobepharma-u.ac.jp.
4
Department of Medical Pharmaceutics, Kobe Pharmaceutical University, Kobe 658-8558, Japan.
5
Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan.
6
Department of Pharmaceutics and Therapeutics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan.

Abstract

AIMS:

Cisplatin (CDDP) is a platinum-based drug that is widely used in cancer chemotherapy, but the development of resistance in tumor cells is a major weakness of these treatments. Several mechanisms have been proposed to explain cisplatin resistance, and disruption of certain cellular pathways could modulate drug sensitivity to cisplatin. A lower level of cross-resistance to cisplatin leads to better outcomes in clinical use.

MAIN METHODS:

Cross-resistance was assessed using cisplatin resistant lung cancer cell line A549/CDDP. Cell cycle analysis was used to examine the effect of cisplatin on cell signaling pathways regulating G2/M transition in cisplatin resistant cells.

KEY FINDINGS:

A549/CDDP cells exhibited cross-resistance to carboplatin, but not oxaliplatin, which is often found in platinum analogues. Flow cytometry showed that nocodazole treatment caused a G2/M block in both A549/CDDP cells and cisplatin susceptible cells. However, A549/CDDP cells escaped the G2/M block following exposure to cisplatin. Activation of the Cdc2/CyclinB complex is required for transition from G2 to M phase, and the inactive form of phosphorylated Cdc2 is activated by Cdc25C dephosphorylation of Tyr15. In the cisplatin-treated susceptible cells, the levels of phosphorylated Cdc2 and Cdc25C were markedly decreased, leading to a loss of Cdc2 activity and G2/M arrest. In A549/CDDP cells, however, Cdc2 activity was supported by the expression of Cdc2 and Cdc25C after the addition of cisplatin, which resulted in G2/M progression.

SIGNIFICANCE:

The resistance phenotype of G2/M progression has been correlated with dysregulation of Cdc2 in a human lung cancer cell line selected for cisplatin.

KEYWORDS:

A549; Cdc2; Cdc25C; Cisplatin; Cross resistance; Drug resistance

PMID:
25625243
DOI:
10.1016/j.lfs.2015.01.011
[Indexed for MEDLINE]

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