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.

Drug	EMA-approved indication in solid tumours	Main targets	Role in redox system
Afatinib	EGFR-mutated NSCLC	EGFR	Chronic oxidative stress associated with resistance.
Axitinib	RCC	VEGFR1–3, PDGFR, c-Kit	Oxidative stress-mediated genotoxic effects.
Bevacizumab	CRC; Breast cancer; NSCLC; Ovarian cancer; Peritoneal cancer; RCC	VEGF	Increases ROS levels.; Combined with autophagy inhibitor enhances ROS levels and apoptosis.
Cetuximab	HNSCC; CRC	EGFR	Reduces the amount of GSH by internalizing EGFR and glutamine transport.; Decreases Nox1 and Nox1-related effect of oxaliplatin.
Crizotinib	ALK-positive NSCLC	ALK, c-MET	Increased O2^•− production linked with cardiotoxicity. Prx II up-regulation associated with resistance.
Erlotinib	EGFR-mutated NSCLC Pancreatic cancer	EGFR	Increases ROS-mediated apoptosis in HNSCC and NSCLC.
Gefitinib	EGFR-mutated NSCLC	EGFR	Increases oxidative stress linked to EMT and cardiotoxicity. NFE2L2/Keap1-axis related to treatment resistance.
Imatinib	GISTs	PDGFRα, KIT, ABL, CSF-1 receptor	Induces ROS-dependent apoptosis in melanoma.
Lapatinib	HER2-positive breast cancer	HER1, HER2	Increases ROS; low ROS levels linked with resistance, which may be overcome with antioxidant mimics.
Pazopanib	RCC, sarcomas	Various kinases, for example, VEGFR1–3, (PDGFR-α and PDGFR-β), c-Kit, FGFR-1, and FGFR-3	May induce oxidative DNA damage-mediated erythrocyte apoptosis.
Rituximab	Non-Hodgkin’s lymphoma	CD-20	CD20 stimulation leads to the production of O2^•−.
Sorafenib	HCC, RCC, radioiodine-refractory thyroid cancer	Various kinases, for example, VEGFR-2 and VEGFR-3, PDGFR-β, and RAF-kinases	Increases oxidative stress, which possibly is a predictive factor for sorafenib
Sunitinib	GISTs, pancreatic NET, RCC	Various kinases, for example, VEGFR1–3, (PDGFR-α and PDGFR-β), c-Kit	Enhances antioxidant defence, decreases NOS activity and expression.
Trastuzumab	HER2-positive breast cancer and HER2-positive gastric cancer	HER2 dimerization	Regulatory loop with NFE2L2; NFE2L2 increases trastuzumab resistance.
Vemurafenib	BRAF (V600E) mutated melanoma	BRAF V600E	Increases NO^• and O2^•− production increases depolarization of mitochondrial membranes. Induces PGC1α