Table 1.
Anticancer drugs or agents that directly or indirectly modulate reactive oxygen species in human malignancies
| Name of the drug or agent | Mechanism of the action or their target | Human malignancies | Status | References |
|---|---|---|---|---|
| Targeting antioxidant system, lipid ROS and ferroptosis | ||||
| Buthionine sulfoximine (BSO) | Block synthesis of GSH, induce lipid ROS | Ovarian cancer, breast cancer, melanoma, rhabdomyosarcoma | Approved | [51, 54, 55 177, 178, 182, 184] |
| Sulfasalazine (SSZ) | Inhibition of system Xc-, Induction of ferroptosis | Glioma, pancreatic carcinoma, lung carcinoma | Approved | [52, 54, 55, 194–196] |
| Artesunate (ART) | Induce ferroptosis through iron metabolism mediated lethal lipid ROS | Pancreatic carcinoma, ovarian cancer, lung carcinoma, head and neck cancer | Phase I/II | [51, 52, 54, 55, 192, 193] |
| Erastin | Inhibit VDAC2/VDAC3, block GSH synthesis, increase lipid peroxidation and lipid ROS | Fibrosarcoma, lung carcinoma, prostate cancer, osteosarcoma | Phase I/II/III | [51, 52, 54, 55, 184, 197] |
| Sorafenib | Inhibition of system Xc-, deplete GSH leading to accumulation of lipid ROS | Hepatocellular carcinoma | FDA Approved | [51, 54, 55, 191] |
| Cisplatin | Suppress GSH and GPX levels | Ovarian cancer, colon cancer | FDA Approved | [54, 200, 249, 250, 253, 254] |
| RSL-3 | Inhibit GPX4 and deplete GSH to induce ROS | Lung carcinoma, colon cancer | Clinical | [52, 54, 55] |
| ML-162 | Inhibit GPX4, enhances ROS production | Colon cancer, melanoma | [51, 54, 55, 202] | |
| ML-210 | Inhibit GPX4, increased ROS production | Lung carcinoma, colon cancer | [51, 54, 55, 202] | |
| FIN56 | Degrade GPX4 or inhibit the function GPX4 | Fibrosarcoma and transformed human fibroblast cells | [51, 53–55, 58, 59] | |
| FINO2 | Inhibit GPX4 | Fibrosarcoma, renal cell carcinoma | [51, 53, 54, 58] | |
| Lanperisone | Inhibition of system Xc-, enhance ROS production | Lung carcinoma, Kras-mutant mouse embryonic fibroblast | FDA Approved | [201, 202] |
| Artenimol | Promotes iron metabolism and ROS-mediated ferroptosis | Colon cancer, lung carcinoma | [51, 54, 55, 190] | |
| Salinomycin and Ionomycin | Iron-mediated ROS production | Breast cancer, colon cancer | FDA Approved | [202, 203] |
| Cotylenin A (CN-A) | Induces ferroptosis by increasing ROS | Pancreatic carcinoma | [54, 208] | |
| N-acetyl-l-cysteine (NAC) | Inhibit ROS production and ferroptosis via oxidative pathway | Fibrosarcoma, colon cancer, breast cancer | FDA Approved | [51, 55, 85, 182, 205, 206, 236] |
| Vitamin E | Inhibit ferroptosis via suppression of LOX | Knockout Gpx4 murine model | [54, 55, 205, 209] | |
| Ferrostatin | Inhibit ferroptosis via ROS generation from lipid peroxidation | Fibrosarcoma, murine embryonic fibroblast | [54, 56, 204, 205] | |
| Liproxstatin | Inhibit ferroptosis via ROS generation from lipid peroxidation | Murine hippocampal, fibrosarcoma | [54, 56, 204, 205] | |
| EUK-134 | SOD mimetic, inhibit H2O2 | Lung carcinoma, breast cancer | [1, 54, 180] | |
| NOV-002 | Modulate of intracellular GSSG/GSH ratio and increase oxidative stress, glutathione disulfide mimetic | Breast cancer, lung carcinoma | Phase I/II | [1, 7, 37, 180, 181] |
| DZNep (EZH2 inhibitor) | Silence thioredoxin and increases ROS | Acute myeloid leukemia | Phase I | [186] |
| All-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) | Inhibit translocation of NRF2, enhance ROS | Leukemia, breast cancer, ovarian cancer | FDA Approved | [187, 188] |
| AEM1 | Repress transcriptional activation of NRF2 | Lung carcinoma | [189] | |
| Auranofin | Inhibitor of thioredoxin | Head and neck cancer, ovarian cancer, rhabdomyosarcoma | Phase I/II | [182–185] |
| Targeting mitochondrial and mitochondrial ROS | ||||
| Mitoquinone (MitoQ) | Mitochondrial respiratory chain complexes I, III, and IV to enhance ROS production | Renal cell carcinoma, Kras model of pancreatic carcinoma | [85, 157] | |
| MitoTEMPO | Activate SOD2 and inhibit mitochondrial superoxide | Renal cell carcinoma | [85, 157] | |
| Arsenic trioxide (AS2O3) | Enhance ROS production, inhibit the mitochondrial respiratory function | A promyelocytic leukemia, lung carcinoma, myeloma | FDA Approved | [217–220] |
| Paclitaxel | Increased mitochondria ROS that results in activation of STAT3 signaling | Lung Carcinoma, breast cancer | [117] | |
| Ivosidenib | Specific inhibitors for IDH1/2 mutant and target mROS for the anticancer effect | Acute myeloid Leukemia and Glioblastoma | FDA Approved | [215] |
| Enasidenib | Specific inhibitors for IDH1/2 mutant and target mROS for the anticancer effect | Acute myeloid Leukemia and Glioblastoma | FDA Approved | [215] |
| Disulfiram | Inhibit mitochondrial ALDH activity, activate the p38 pathway and ROS | Glioblastoma | FDA Approved | [146, 216] |
| 2-Deoxyglucose | Induce oxidative stress via accumulation of glutathione disulfide and NADP + /NADPH | Pancreatic carcinoma, Prostate cancer, cervical carcinoma | Phase I/II trials | [221–223] |
| Metformin | Mitochondrial complex I inhibitor, Inhibition of oxygen consumption, activate AMPK signaling | Hepatocellular carcinoma, murine cancer models (B16 for melanoma; MC38 for colon adenocarcinoma) | FDA Approved | [159–161] |
| Nutraceuticals | ||||
| Epigallocatechin-3-gallate (EGCG) | Modulation of ROS production, inhibition of NF-κB, regulation of MAPKs | Pancreatic carcinoma, colon cancer, breast cancer, lung carcinoma | Phase I/II | [227, 230] |
| Phenylethyl isothiocyanate (PEITC) | Deplete GPX and induce ROS | Bladder cancer, renal cell carcinoma, prostate cancer | In clinical trials | [179, 208] |
| Benzyl isothiocyanate (BITC) | Increase ROS production, activate JNK and p38 pathways | Pancreatic carcinoma, breast cancer, lung carcinoma | Phase I | [231, 234] |
| Vitamin A | Enhance ROS production | Ovarian cancer | [224] | |
| Vitamin C | Attenuated tumor growth in mutant Kras (G12D)/Apc murine models | Colorectal carcinoma, pancreatic carcinoma | In clinical trials | [225] |
| Vitamin D | Alteration in the ratio of GSSG and GSH, regulate thioredoxin-interacting protein | Endometrial cancer, breast cancer, colorectal carcinoma | In clinical trials | [226] |
| Bromelain | Downregulate CoA ligase 4, induce ROS in lipid membranes | KRAS mutant colon cancer | [207] | |
| Pancratistatin | Mitochondrial permeabilization increases ROS | Leukemia, colon cancer | Phase I | [239] |
| Aminoflavone | Enhance intracellular ROS by degenerating mitochondrial membrane potential | Pancreatic carcinoma, breast cancer, colorectal carcinoma | Phase II | [236] |
| Curcumin | Enhance intracellular ROS by increasing the potential of mitochondrial membrane | Almost all cancers | Phase II/III | [240, 241] |
| Nimbolide | Modulation of GSH/GSSG ratio leads to ROS production, inhibit STAT3 pathway | [242, 243] | ||
| β-Caryophyllene oxide | Suppress tumor growth and support apoptosis by suppressing ROS-mediated activation of MAPKs | Prostate cancer colon cancer Leukemia, lung carcinoma, multiple myeloma, Prostate cancer | [75, 244] | |
| Chemotherapeutic agents | ||||
| Doxorubicin, daunorubicin | Block DNA synthesis and topoisomerase II activity; inhibit complex I/II leading to an increase in the production of mitochondrial ROS | Acute myeloid leukemia, acute lymphocytic leukemia, breast cancer, chronic myelogenous leukemia, lymphoma, bladder cancer, Kaposi's sarcoma | FDA Approved | [245, 246] |
| Salvicine (SAL) | Inhibit topoisomerase II, GSH depletion trigger H2O2 production, DNA double-strand breaks | Gastric carcinoma, leukemia, cervical carcinoma | Phase I/II | [247, 248] |
| Carboplatin | Maintain very high levels of ROS to induce cell death | Breast cancer, ovarian cancer, lung carcinoma | FDA approved | [249, 250] |
| Oxaliplatin | Retain DACH by the formation of platinum–DNA adducts, block DNA replication | Colon carcinoma, Ovarian cancer, lung carcinoma | FDA approved | [249, 250] |
| Temozolomide (TMZ) | Inhibit autophagy, induces cell death via the accumulation of lipid ROS | Glioblastoma stem cells | FDA approved | [190, 197, 198] |
| PARP inhibitors (Olaparib, niraparib, rucaparib) | Inhibit the activity of PARP enzyme, enhance ROS mediated DNA damage | Breast cancer, ovarian cancer, pancreatic carcinoma, prostate carcinoma, lung carcinoma |
FDA approved European Medicines Agency |
[253–255] |
| 5-Fluorouracil (5-FU) | Inhibit thymidylate synthetase, block DNA and RNA synthesis, increase ROS | Colorectal carcinoma, breast cancer, pancreatic carcinoma | FDA approved | [251] |
| Vorinostat | Suppress SLC7A11, enhance ROS lead to DNA damage | FDA approved | [252] | |