Sayo Horibe1, Akira Matsuda2, Toshihito Tanahashi3, Jun Inoue4, Shoji Kawauchi4, Shigeto Mizuno4, Masaki Ueno2, Kyohei Takahashi2, Yusaku Maeda2, Tatsuya Maegouchi2, Yoshiki Murakami5, Ryoko Yumoto6, Junya Nagai6, Mikihisa Takano6. 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.
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 humanlung cancer cell line selected for cisplatin.