Oxidative Medicine and Cellular Longevity / 2018 / Article / Tab 1

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 targetDDR inhibitorsROS-inducing treatments (direct/indirect mode of action)ReferencesCombinatory therapy
Preclinical studies and clinical trials

PARPOlaparibRadiotherapyOS increase by mitochondrial dysfunction[146]NCT01460888
Cisplatin + RadiotherapyROS increase via NADPH oxidase[141143]NCT01562210
(♦)(♦)
Cetuximab + RadiotherapyGlutamine transport inhibition, GSH decrease[163, 164]NCT01758731
(♦)(♦)
ErlotinibEGFR inhibition, ROS-mediated apoptosis[173, 174][172]

PARPVeliparib (ABT-888)Temozolomide + Carboplatin + PaclitaxelROS increase, AKT–mTOR signaling disruption[144]NCT01506609
ROS increase via NADPH oxidase[147]
ROS induction[148]
BevacizumabROS and apoptosis increase[165167]NCT02305758
RituximabCD20 binding in B-lymphocytes, O2 generation[170, 171][169]
AuranofinH2O2 and ROS increase by thioredoxin reductase inhibition[191][192]
BortezomibROS increase by ER stress[178, 180, 181][179]
LapatinibROS increases[176][176]
BerberineOS/NOS decrease[177][177]

PARPRucaparibCarboplatin(♦)(♦)NCT01009190

PARPNiraparibBevacizumabCysteine and GSH level reduction[165167]NCT02354131
4-Iodo-3-nitrobenzamideButhionine sulphoximineInhibition of glutamate–cysteine ligase complex in GSH synthesis[187189][190]

RPAMCI13ECisplatin(♦)(♦)[149]

RAD51B02IRMitomycin C + CisplatinStress-mediated ER cell apoptosis by ROS generation[151][150]
(♦)(♦)

APE-1MethoxyaminePemetrexed + CisplatinMitochondrial dysfunction, ROS increase[161]NCT02535312
(♦)(♦)

ATMKU-55933Radiotherapy(♦)(♦)[155]
Doxorubicin + RadiotherapyROS increase by enzymatic/nonenzymatic pathways[157][156]
(♦)(♦)

ATRNU-6027Cisplatin(♦)(♦)[152]
HydroxyureaIncreased O2 production[153][152]
VX-970TopotecanROS increase[182]NCT02487095
Cisplatin + Gemcitabine(♦)(♦)NCT02567409
ROS increase, mitochondria alterations[154]
Carboplatin + Gemcitabine(♦)(♦)NCT02627443
(♦)(♦)

DNA-PKcsNU-7441EtoposideROS increase, GSH depletion, mitochondrial alterations[182, 183][185]
KU-60648Etoposide + Doxorubicin(♦)(♦)[160]
(♦)(♦)
VX-984Doxorubicin(♦)(♦)NCT02644278
UCN-015-FluorouracileCellular O2•− increase(♦)NCT00045747

Chk1/Chk2LY2603618Pemetrexed(♦)(♦)NCT00988858
Cisplatin + Pemetrexed(♦)(♦)NCT01139775
(♦)(♦)
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 (♦).

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