Cisplatin as an anti-tumor drug: Cellular mechanisms of activity, drug resistance and induced side effects

Ana Maria Florea, Dietrich Busselberg

Research output: Contribution to journalReview article

695 Citations (Scopus)

Abstract

Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e.g., by interference with transcription and/or DNA replication mechanisms. Additionally, cisplatin damages tumors via induction of apoptosis, mediated by the activation of various signal transduction pathways, including calcium signaling, death receptor signaling, and the activation of mitochondrial pathways. Unfortunately, neither cytotoxicity nor apoptosis are exclusively induced in cancer cells, thus, cisplatin might also lead to diverse side-effects such as neuro- and/or renal-toxicity or bone marrow-suppression. Moreover, the binding of cisplatin to proteins and enzymes may modulate its biochemical mechanism of action. While a combination-chemotherapy with cisplatin is a cornerstone for the treatment of multiple cancers, the challenge is that cancer cells could become cisplatin-resistant. Numerous mechanisms of cisplatin resistance were described including changes in cellular uptake, drug efflux, increased detoxification, inhibition of apoptosis and increased DNA repair. To minimize cisplatin resistance, combinatorial therapies were developed and have proven more effective to defeat cancers. Thus, understanding of the biochemical mechanisms triggered by cisplatin in tumor cells may lead to the design of more efficient platinum derivates (or other drugs) and might provide new therapeutic strategies and reduce side effects.

Original languageEnglish
Pages (from-to)1351-1371
Number of pages21
JournalCancers
Volume3
Issue number1
DOIs
Publication statusPublished - Mar 2011

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Keywords

  • Apoptosis
  • Cancer
  • Cell death
  • Cisplatin
  • Combinatorial therapy
  • DNA damage and repair
  • Intracellular mechanisms
  • Multi drug resistance
  • ROS
  • ROS intracellular calcium
  • Toxicity

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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