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Resistance to cisplatin
S Akiyama1, Z S Chen, T Sumizawa
1Department of Cancer Chemotherapy, Faculty of Medicine, Kagoshima University, Japan. akiyamas@khosp2.kufm.kagoshima-u.ac.jp
Abstract:
Resistance to cis-diamminedichloroplatinum(II) (cisplatin), a DNA damaging agent, is a major obstacle for its clinical effectiveness. Multiple mechanisms may be involved in cisplatin resistance. Frequently cited mechanisms include reduced accumulation, elevated levels of glutathione (GSH) and metallothionein, and enhanced DNA repair. Alterations in oncogene expression and in signal transduction pathways involved in apoptosis have been associated with cisplatin resistance. Of these mechanisms, decreased accumulation of cisplatin is the most common finding. Efflux of cisplatin by an organic anion transporter has been proposed, and one of the organic anion transporters, canalicular multispecific organic anion transporter, is associated with cisplatin resistance. Sensitivity to cisplatin has been increased by inhibitors of DNA repair, agents that increase accumulation of cisplatin and depletion of GSH. None of the agents tested that modulate cisplatin sensitivity completely reverses cisplatin resistance. These observations indicate that multiple mechanisms of resistance arise in the same cell line when cells are selected in vitro.
Insights
Cisplatin resistance in cancer is a significant challenge, often caused by reduced drug accumulation. While various mechanisms exist, no single intervention fully overcomes this resistance, highlighting the complexity of platinum-based chemotherapy.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Cisplatin is a crucial DNA-damaging chemotherapy agent.
- Resistance to cisplatin limits its clinical efficacy in cancer treatment.
- Understanding resistance mechanisms is vital for improving chemotherapy outcomes.
Purpose of the Study:
- To review and summarize the known mechanisms of cisplatin resistance.
- To highlight the commonality of reduced cisplatin accumulation as a resistance factor.
- To discuss strategies for overcoming cisplatin resistance.
Main Methods:
- Literature review of studies investigating cisplatin resistance mechanisms.
- Analysis of frequently cited factors contributing to resistance.
- Evaluation of agents that modulate cisplatin sensitivity.
Main Results:
- Reduced cellular accumulation is the most frequent cisplatin resistance mechanism.
- Other mechanisms include elevated glutathione (GSH), metallothionein, and enhanced DNA repair.
- Organic anion transporters, such as the canalicular multispecific organic anion transporter, are implicated in cisplatin efflux.
- Inhibitors of DNA repair, GSH depletion, and agents increasing cisplatin accumulation can enhance sensitivity.
- No single agent completely reverses cisplatin resistance, indicating multifactorial resistance.
Conclusions:
- Cisplatin resistance is complex and multifactorial.
- Reduced drug accumulation is a primary mechanism.
- Targeting multiple resistance pathways may be necessary for effective treatment.
- In vitro selection can lead to cells with multiple resistance mechanisms simultaneously.