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Cisplatin Biochemical Mechanism of Action: From Cytotoxicity to Induction of Cell Death Through Interconnections Between Apoptotic and Necrotic Pathways
Abstract
Although cisplatin, cis-diamminedichloroplatinum(II), has been successfully used in the chemotherapy of cancer for more than 25 years, its biochemical mechanism of action is still unclear. The current accepted paradigm about cisplatin mechanism of action is that the drug induces its cytotoxic properties through binding to nuclear DNA and subsequent interference with normal transcription, and/or DNA replication mechanisms. If cisplatin-DNA adducts are not efficiently processed by cell machinery, cytotoxic processes eventually end up in cell death. However, before cisplatin enters the cell it may bind to phospholipids and phosphatidylserine in the cell membrane. In addition, in the cytoplasm many potential platinum-binding sites are also available, including RNA and sulfur-containing biomolecules. Moreover, there is much evidence suggesting that the cytotoxic effects induced by binding of cisplatin to non-DNA targets (especially proteins) may contribute to its biochemical mechanism of action. On the other hand, it has been found that several factors such as the dose of drug as well as the metabolic condition of the cell subjected to cisplatin aggression, may determine that cancer cells die through apoptosis or necrosis. In fact, it has recently been reported that both mechanisms of cell demise work in concert so that within a population of tumour cells there is a continuum of possible modes of cell death.
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“Platinum agents, such as cisplatin and carboplatin, form DNA-platinum adducts resulting in intra- and interstrand DNA crosslinks leading to increased double strand breaks and cell death (3).”
From Potentiation of carboplatin-mediated DNA damage by the Mdm2 modulator Nutlin-3a in a humanized orthotopic breast-to-lung metastatic model (2015) · cites this paper as [3]
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Metadata
- Authors
- Fuertes, M., Castilla, J., Alonso, C., & Pérez, J.
- Affiliations
- Universidad Autónoma de Madrid (ES)
- Corresponding author
- Castilla, J.
- Pérez, J.
- Venue
- Current Medicinal Chemistry
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2003-02-01
- Volume
- 10
- Issue
- 3
- Pages
- 257-266
- ISSN
- 0929-8673 (ISSN-L)
- OpenAlex
- W2146133266
- Cited by
- 432
- References
- 0
- Citations by year
- 2026: 3 · 2025: 14 · 2024: 31 · 2023: 38 · 2022: 21 · 2021: 14 · 2020: 17 · 2019: 13 · 2018: 15 · 2017: 21 · 2016: 22 · 2015: 15 · 2014: 30 · 2013: 28 · 2012: 27
- FWCI
- 5.98
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fundación Ramón Areces
- Topics
- Health Sciences › Medicine › Oncology › Metal complexes synthesis and properties
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
- Keywords
- cisplatin, mechanism of action, DNA adducts, phospholipid binding, phosphatidylserine, RNA binding, cytotoxicity, apoptosis, necrosis, cell death pathways, platinum-based chemotherapy
- MeSH terms
- Animals, Antineoplastic Agents, Binding Sites, Cisplatin, DNA Damage, DNA Repair, Humans, Necrosis, Neoplasms, Cell Death, Apoptosis
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