Oxidative Medicine and Cellular Longevity

Review Article

Targeting Oxidatively Induced DNA Damage Response in Cancer: Opportunities for Novel Cancer Therapies

Table 1

DNA damage response (DDR) inhibitors in combination with ROS-inducing treatments for cancer therapy.


DDR target	DDR inhibitors	ROS-inducing treatments (direct/indirect mode of action)		References	Combinatory therapy Preclinical studies and clinical trials

PARP	Olaparib	Radiotherapy	OS increase by mitochondrial dysfunction	[146]	NCT01460888
		Cisplatin + Radiotherapy	ROS increase via NADPH oxidase	[141–143]	NCT01562210
		Cisplatin + Radiotherapy	(♦)	(♦)
		Cetuximab + Radiotherapy	Glutamine transport inhibition, GSH decrease	[163, 164]	NCT01758731
		Cetuximab + Radiotherapy	(♦)	(♦)
		Erlotinib	EGFR inhibition, ROS-mediated apoptosis	[173, 174]	[172]

PARP	Veliparib (ABT-888)	Temozolomide + Carboplatin + Paclitaxel	ROS increase, AKT–mTOR signaling disruption	[144]	NCT01506609
			ROS increase via NADPH oxidase	[147]
			ROS induction	[148]
		Bevacizumab	ROS and apoptosis increase	[165–167]	NCT02305758
		Rituximab	CD20 binding in B-lymphocytes, O₂⁻ generation	[170, 171]	[169]
		Auranofin	H₂O₂ and ROS increase by thioredoxin reductase inhibition	[191]	[192]
		Bortezomib	ROS increase by ER stress	[178, 180, 181]	[179]
		Lapatinib	ROS increases	[176]	[176]
		Berberine	OS/NOS decrease	[177]	[177]

PARP	Rucaparib	Carboplatin	(♦)	(♦)	NCT01009190

PARP	Niraparib	Bevacizumab	Cysteine and GSH level reduction	[165–167]	NCT02354131
PARP	4-Iodo-3-nitrobenzamide	Buthionine sulphoximine	Inhibition of glutamate–cysteine ligase complex in GSH synthesis	[187–189]	[190]

RPA	MCI13E	Cisplatin	(♦)	(♦)	[149]

RAD51	B02IR	Mitomycin C + Cisplatin	Stress-mediated ER cell apoptosis by ROS generation	[151]	[150]
RAD51	B02IR	Mitomycin C + Cisplatin	(♦)	(♦)

APE-1	Methoxyamine	Pemetrexed + Cisplatin	Mitochondrial dysfunction, ROS increase	[161]	NCT02535312
APE-1	Methoxyamine	Pemetrexed + Cisplatin	(♦)	(♦)

ATM	KU-55933	Radiotherapy	(♦)	(♦)	[155]
		Doxorubicin + Radiotherapy	ROS increase by enzymatic/nonenzymatic pathways	[157]	[156]
		Doxorubicin + Radiotherapy	(♦)	(♦)

ATR	NU-6027	Cisplatin	(♦)	(♦)	[152]
	NU-6027	Hydroxyurea	Increased O₂⁻ production	[153]	[152]
	VX-970	Topotecan	ROS increase	[182]	NCT02487095
		Cisplatin + Gemcitabine	(♦)	(♦)	NCT02567409
		Cisplatin + Gemcitabine	ROS increase, mitochondria alterations	[154]
		Carboplatin + Gemcitabine	(♦)	(♦)	NCT02627443
		Carboplatin + Gemcitabine	(♦)	(♦)

DNA-PKcs	NU-7441	Etoposide	ROS increase, GSH depletion, mitochondrial alterations	[182, 183]	[185]
	KU-60648	Etoposide + Doxorubicin	(♦)	(♦)	[160]
		Etoposide + Doxorubicin	(♦)	(♦)	[160]
	VX-984	Doxorubicin	(♦)	(♦)	NCT02644278
	UCN-01	5-Fluorouracile	Cellular O₂^•− increase	(♦)	NCT00045747

Chk1/Chk2	LY2603618	Pemetrexed	(♦)	(♦)	NCT00988858
		Cisplatin + Pemetrexed	(♦)	(♦)	NCT01139775
		Cisplatin + Pemetrexed	(♦)	(♦)
	Prexasertib (LY2606368)	Cisplatin + Cetuximab + Pemetrexed + 5-Fluorouracile	(♦)	(♦)	NCT02124148
			(♦)	(♦)
			(♦)	(♦)
			(♦)	(♦)
		Cisplatin + Radiotherapy + Cetuximab	(♦)	(♦)	NCT02555644
			(♦)	(♦)
			(♦)	(♦)

APE1 = AP endonuclease 1; ATM = ataxia telangiectasia-mutated protein; ATR = ATM- and Rad3-related; CHK = checkpoint kinase; DNA-PKcs = DNA-dependent protein kinase catalytic subunit; PARP = poly (ADPribose) polymerase; RPA = replication protein A. References in brackets; clinical trial identifiers (NCT). The effect of the single ROS-inducing drugs is indicated one time, and the following times is indicated with (♦).