Arsenic accumulation decreased in metallothionein null Cisplatin-resistant cell lines
Toshihiro Suzuki1, Shigeki Ohata, Tadayasu Togawa
1Department of Analytical Biochemistry, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan. tssuzuki@my-pharm.ac.jp
Abstract:
Metallothionein (MT) is known to play an important role in the resistance of tumor cells to cis-diamminedichloroplatinum (II) (cisplatin). To identify non-MT factors of cisplatin resistance, we characterized cisplatin-resistant cell lines derived from MT-null cells. All of the cisplatin-resistant MT- null cell lines, namely MKCr-1, -3, -4, -12, and -13, showed strong cisplatin resistance and decreased platinum accumulation. Some multidrug resistance proteins (MRPs) have been reported to contribute to cisplatin resistance. However, no significant difference of the MRPs was observed in any of these cell lines. The MKCrs showed cross-resistance to other metals such as arsenite, arsenate, cadmium and antimony. The arsenate and arsenite sensitivities were highly correlated with sensitivity to cisplatin. In addition, the degree of arsenite accumulation was correlated with the degree of cisplatin accumulation. These results suggest that the cisplatin resistance was strongly correlated with the arsenite transport mechanism in these cells.
Insights
Metallothionein-null cells resistant to cisplatin show decreased platinum accumulation. Cisplatin resistance in these cells is strongly linked to the arsenite transport mechanism, not multidrug resistance proteins.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Metallothionein (MT) is implicated in tumor cell resistance to cisplatin, a key chemotherapy drug.
- This study investigates non-MT factors contributing to cisplatin resistance by analyzing MT-null cell lines.
- Previous research suggests multidrug resistance proteins (MRPs) may play a role in cisplatin resistance.
Discussion:
- MT-null cisplatin-resistant cell lines (MKCrs) exhibit reduced platinum accumulation.
- These cell lines show cross-resistance to various metals, including arsenite, arsenate, cadmium, and antimony.
- No significant differences in MRP expression were found in the resistant cell lines.
Key Insights:
- Cisplatin resistance in MT-null cells strongly correlates with arsenite sensitivity.
- Arsenite accumulation levels mirror cisplatin accumulation levels in these resistant cells.
- The findings suggest a shared transport mechanism for cisplatin and arsenite.
Outlook:
- Further research into the specific arsenite transporter involved could reveal novel therapeutic targets.
- Understanding this transport mechanism may lead to strategies to overcome cisplatin resistance.
- This work opens new avenues for developing more effective platinum-based cancer therapies.
