Oxidative Medicine and Cellular Longevity / 2017 / Article / Tab 1

Review Article

Reactive Oxygen Species-Mediated Mechanisms of Action of Targeted Cancer Therapy

Table 1

The most important redox-associated targeted cancer therapy compounds with EMA-approved indications for the treatment of solid tumours or lymphomas. All indications are for metastatic or inoperable carcinomas if not otherwise mentioned.

DrugEMA-approved indication in solid tumoursMain targetsRole in redox system

AfatinibEGFR-mutated NSCLCEGFRChronic oxidative stress associated with resistance.

AxitinibRCCVEGFR1–3, PDGFR, c-KitOxidative stress-mediated genotoxic effects.

BevacizumabCRC
Breast cancer
NSCLC
Ovarian cancer
Peritoneal cancer
RCC
VEGFIncreases ROS levels.
Combined with autophagy inhibitor enhances ROS levels and apoptosis.

CetuximabHNSCC
CRC
EGFRReduces the amount of GSH by internalizing EGFR and glutamine transport.
Decreases Nox1 and Nox1-related effect of oxaliplatin.

CrizotinibALK-positive NSCLCALK, c-METIncreased O2•− production linked with cardiotoxicity. Prx II up-regulation associated with resistance.

ErlotinibEGFR-mutated NSCLC Pancreatic cancerEGFRIncreases ROS-mediated apoptosis in HNSCC and NSCLC.

GefitinibEGFR-mutated NSCLCEGFRIncreases oxidative stress linked to EMT and cardiotoxicity. NFE2L2/Keap1-axis related to treatment resistance.

ImatinibGISTsPDGFRα, KIT, ABL, CSF-1 receptorInduces ROS-dependent apoptosis in melanoma.

LapatinibHER2-positive breast cancerHER1, HER2Increases ROS; low ROS levels linked with resistance, which may be overcome with antioxidant mimics.

PazopanibRCC, sarcomasVarious kinases, for example, VEGFR1–3, (PDGFR-α and PDGFR-β), c-Kit, FGFR-1, and FGFR-3May induce oxidative DNA damage-mediated erythrocyte apoptosis.

RituximabNon-Hodgkin’s lymphomaCD-20CD20 stimulation leads to the production of O2•−.

SorafenibHCC, RCC, radioiodine-refractory thyroid cancerVarious kinases, for example, VEGFR-2 and VEGFR-3, PDGFR-β, and RAF-kinasesIncreases oxidative stress, which possibly is a predictive factor for sorafenib

SunitinibGISTs, pancreatic NET, RCCVarious kinases, for example, VEGFR1–3, (PDGFR-α and PDGFR-β), c-KitEnhances antioxidant defence, decreases NOS activity and expression.

TrastuzumabHER2-positive breast cancer and HER2-positive gastric cancerHER2 dimerizationRegulatory loop with NFE2L2
NFE2L2 increases trastuzumab resistance.

VemurafenibBRAF (V600E) mutated melanomaBRAF V600EIncreases NO and O2•− production increases depolarization of mitochondrial membranes. Induces PGC1α