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

671 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

Fingerprint

Drug Resistance
Cisplatin
Pharmaceutical Preparations
Neoplasms
Apoptosis
Platinum
Death Domain Receptors
Calcium Signaling
Therapeutics
Combination Drug Therapy
DNA Replication
DNA Repair
Signal Transduction
Cell Death
Bone Marrow
Kidney
Enzymes

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

Cite this

Cisplatin as an anti-tumor drug : Cellular mechanisms of activity, drug resistance and induced side effects. / Florea, Ana Maria; Busselberg, Dietrich.

In: Cancers, Vol. 3, No. 1, 03.2011, p. 1351-1371.

Research output: Contribution to journalReview article

@article{9c769ef452e8463d87414d43f3a79f06,
title = "Cisplatin as an anti-tumor drug: Cellular mechanisms of activity, drug resistance and induced side effects",
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.",
keywords = "Apoptosis, Cancer, Cell death, Cisplatin, Combinatorial therapy, DNA damage and repair, Intracellular mechanisms, Multi drug resistance, ROS, ROS intracellular calcium, Toxicity",
author = "Florea, {Ana Maria} and Dietrich Busselberg",
year = "2011",
month = "3",
doi = "10.3390/cancers3011351",
language = "English",
volume = "3",
pages = "1351--1371",
journal = "Cancers",
issn = "2072-6694",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "1",

}

TY - JOUR

T1 - Cisplatin as an anti-tumor drug

T2 - Cellular mechanisms of activity, drug resistance and induced side effects

AU - Florea, Ana Maria

AU - Busselberg, Dietrich

PY - 2011/3

Y1 - 2011/3

N2 - 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.

AB - 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.

KW - Apoptosis

KW - Cancer

KW - Cell death

KW - Cisplatin

KW - Combinatorial therapy

KW - DNA damage and repair

KW - Intracellular mechanisms

KW - Multi drug resistance

KW - ROS

KW - ROS intracellular calcium

KW - Toxicity

UR - http://www.scopus.com/inward/record.url?scp=79953700297&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79953700297&partnerID=8YFLogxK

U2 - 10.3390/cancers3011351

DO - 10.3390/cancers3011351

M3 - Review article

C2 - 24212665

AN - SCOPUS:79953700297

VL - 3

SP - 1351

EP - 1371

JO - Cancers

JF - Cancers

SN - 2072-6694

IS - 1

ER -