Table 3.
Candidate molecules and compounds for the protection against cisplatin induced-hearing loss.
| Molecule or compound | IUPAC name | Natural occurrence | Direct effect on cancer cells | Modulation of cisplatin anti-cancer cytotoxicity | Known adverse effects in humans | Use in human trials |
|---|---|---|---|---|---|---|
| 3-MA | 3-Methylpentane | A structural isomer of hexane | No data available | No data available | Irritation, headache, drowsiness, dizziness, loss of coordination, convulsions, and coma57 | Technically possible |
| Apocynin | 1-(4-hydroxy-3-methoxyphenyl)ethanone | Apocynin is a natural polyphenolic compound isolated from various plants such as Apocynum cannabinum, Picrorhiza kurroa | Apocynin inhibits the NF-kB activation in androgen-independent rat prostate cancer cell lines58 | No data available | Irritating to eyes, respiratory system and skin59 | No data available |
| Astaxanthin (ATX) | 3,3'-Dihydroxy-beta,beta-carotene-4,4'-dione | Astaxanthin is a keto-carotenoid in the terpenes class of chemical compounds. It is classified as a xanthophyll but it is a carotenoid with no vitamin A activity. It is found in the majority of aquatic organisms with red pigment. | Enhances CTL activity and IFN-gamma production against Meth-A tumor cells in parallel to suppression of tumor growth60 | No data available | Doses of up to 50 mg have been tolerated. An upper toxicity limit is not known61 | Technically possible |
| Benzamil | 3,5-diamino-N-(N'-benzylcarbamimidoyl)-6-chloropyrazine-2-carboxamide | Synthetic molecule | No data available | Amiloride (10, 30, and 100 μmol/L) concentration-dependently potentiated erlotinib-induced inhibition of cell proliferation and colony formation in the four pancreatic cancer cell lines62 | Irritating to eyes, respiratory system and skin63 | Technically possible |
| CHCP1 | Not available | Not available | Not available | Not available | Not available | No data available |
| CHCP2 | Not available | Not available | Not available | Not available | Not available | No data available |
| CLEFMA | (Z)-4-[(3E,5E)-3,5-bis[(2-chlorophenyl)methylidene]-4-oxopiperidin-1-yl]-4-oxobut-2-enoic acid | Synthetic molecule | IC50 for the human lung carcinoma A549 cell line measured by MTT test - 13.82 µM (24 h ) and 16.05 (48 h) | Decreases the cisplatin-induced ROS production, decreases the motility of cancer cells in the presence of cisplatin36 | No data available | No data available |
| CYM-5478 | 2-[[4-[5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl]-2,3-dihydro-1H-inden-1-yl]amino]ethanol | No data available | No data available | No data available | No data available | No data available |
| Dexamethasone | (8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-3-one | Dexamethasone is a synthetic adrenal corticosteroid | Induction of apoptosis and enhancement chemosensitivity of GRα-rich colon cancer cell lines64 | Dexamethasone reduces cisplatin efficiency in different human NSCLC cell lines in a p53-dependent manner65 | Vertigo, acne, insomnia, increased appetite, irritability, muscle weakness, impaired wound healing, amnesia increased blood sugar levels66 | Technically possible |
| Dexmedetomidine | 5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole | Dexmedetomidine is an imidazole derivate and active d-isomer of medetomidine | Dexmedetomidine promots cell proliferation, migration and upregulats antiapop- totic protein in human lung carcinoma and neuroglioma cell lines67 | no data available | low or high blood pressure (hypotension or hypertension), slow heart rate (bradycardia), nausea, dry mouth, irregular heartbeat, fever, vomiting, low blood plasma68 | technically possible |
| Dimethyl sulfoxide (DMSO) | Methylsulfinylmethane | Synthetic molecule | DMSO inhibits the tumor volume growth in breast cancer bearing mice (except for 0.25 mg/g) in a time and dose-dependent way.37 | DMSO did not have any effect on cisplatin's cytoxicity on human cervical (KB-3-1) or colorectal (DLD-1) carcinoma cells69 | Garlic-like taste (a few minutes after instillation), odor on breath 70 | Technically possible |
| D-methionine | (2R)-2-amino-4-methylsulfanylbutanoic acid | D-methionine is an optically active form of methionine having D-configuration. It is a methionine and a D-alpha-amino acid | No data available | No data available | No data available | Technically possible |
| E6 Berbamine | (20,21,25-trimethoxy-15,30-dimethyl-7,23-dioxa-15,30-diazaheptacyclo[22.6.2.23,6.18,12.114,18.027,31.022,33]hexatriaconta-3(36),4,6(35),8,10,12(34),18,20,22(33),24,26,31-dodecaen-9-yl) 4-nitrobenzoate | Berbamine is a natural compound derived from the Berberis amurensis plant, E6 Berbamine is a synthetic molecule | Induction of apoptosis in breast cancer and lung cancer cell lines71 | No data available | Jaundice, stomach upset, lethargy, nose bleed, skin and eye irritation, kidney irritation72 | Technically possible |
| Edaravone | 5-methyl-2-phenyl-4H-pyrazol-3-one | Not available | Lack of cytostatic effect in colon carcinoma cells73 | No data available | Bruising, gait disturbance, headache,skin inflammation or rash, eczema, respiratory disorder,oxygen deficiency74 | Technically possible |
| EF24 | (3E,5E)-3,5-bis[(2-fluorophenyl)methylidene]piperidin-4-one | Synthetic molecule | Cytostatic effect75 | Decreases the cisplatin-induced ROS production, decreases the motility of cancer cells in the presence of cisplatin36 | No data available | No data available |
| Flubendazole (Flu, microtubule assembly blocker) | Methyl N-[6-(4-fluorobenzoyl)-1H-benzimidazol-2-yl]carbamate | Flubendazole is a member of the class of mebendazole. The benzoyl group is replaced by a p-fluorobenzoyl group | Flubendazole inhibited breast cancer cells proliferation in dose- and time-dependent manner50 | No data available | Abdominal pain, headache, dizziness, diarrhoea76 | Technically possible |
| FUT-175 | (6-carbamimidoylnaphthalen-2-yl) 4-(diaminomethylideneamino)benzoate;methanesulfonic acid | Nafamostat Mesylate (MN) is the mesylate salt form of nafamostat | NM significantly inhibits proliferation, migration, and invasion in MDA-MB231 triple-negative breast cancer (TNBC) cells77 | No data available | Nausea, vomiting, itching and eruption78 | Technically possible |
| KR-22335 | 3-Amino-3-(4-fluoro-phenyl)-1H-quinoline-2,4-dione | Synthetic molecule | No data available | KR-22332 does not appear to interfere with the antitumor effect of chemotherapeutic37 | No data available | No data available |
| Leupeptin | N-Acetyl-L-leucyl-L-leucyl-L-argininal hemisulfate salt | Organic compound produced by actinomycetes | No data vailable | No data availabe | No data available | Technically possible |
| L-serine | (S)-2-Amino-3-hydroxypropanoic acid H-Ser-OH; | Serine is a nonessential amino acid derived from glycine. L-serine is the L-enantiomer of serine. | No data available |
L-serine inhibits the antitumor effect of cisplatin in human gastric cancer cell lines SGC7901, BGC823, and MGC803 in a dose-dependent manner79 | Tiredness, anxiety, chronic fatigue, neurotoxicity, depression80 | Technically possible |
| Mdivi-1 | 3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanylidene-1H-quinazolin-4-one | Synthetic molecule | No data available | Synergistic action with cisplatin81 | No data available | No data available |
| NAC | N-Acetyl-L-cysteine ((2R)-2-acetamido-3-sulfanylpropanoic acid) | NAC is an essentially prodrug that is converted to cysteine (in the intestine by the enzyme aminoacylase 1) and absorbed in the intestine into the blood stream. Cysteine is a key constituent to glutathione and hence administration of acetylcysteine replenishes glutathione stores. | Growth inhibition of several cancers82 | No data available | Unlikely cause of clinically apparent liver injury83 | Technically possible |
| ORC-13661 | (1R,8S)-4-[(4-chlorophenyl)carbamoylamino]-11-methyl-5-thia-11-azatricyclo[6.2.1.02,6]undeca-2(6),3-diene-3-carboxamide | No data available | No data available | No data available | No data available | No data available |
| Quercetin | 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxychromen-4-one | Quercetin is a flavonoid widely distributed in many plants, vegetables and fruits | Growth inhibition in the human breast carcinoma cell line58 | Synergistic action with cisplatin against human oral squamous cell carcinoma (OSCC) (cell lines Tca-8113 and SCC-15)84 | Headache (oral use), numbness and tingling (oral use), shortness of breath (intravenous use), nausea and vomiting (intravenous use), kidney damage (intravenous use greater than 945 mg/m2)85 | Technically possible |
| Quinine | (R)-[(2S,4S,5R)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methanol | Quinine is a quinidine alkaloid isolated from the bark of the cinchona tree | Quinine possess cytotoxic effect on laryngeal cancer cells (147.58 μM/mL for 24 h and 123.74 μM/mL for 48 h)86 | No data available | Headache, ringing in the ears, trouble seeing, and sweating, deafness, low blood platelets, an irregular heartbeat, during pregnancy is harm to the baby87 | Technically possible |
| Quinoxaline | Quinoxaline | Synthetic molecule | Cytostatic effect88 | No data available | No data available | No data available |
| Rapamycin | (1R,9S,12S,15R,16E,18R,19R,21R,23S,24Z,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]propan-2-yl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone | Isolated from Streptomyces hygroscopicus found in an Easter Island soil sample | Used for therapy of carcinoma89 leukemia (B-CLL)90 melanoma91 | Synergistic action with cisplatin against various types of cancer92,93 | Stomatitis, behavioral disturbance, rash, pyrexia, pneumonia, gastroenteritis, aggression, agitation, amenorrhea, hypercholesterolemia, elevated partial thromboplastin time, neutropenia, infectiorapa94 | Technically possible |
| Salvianolic acid B (Sal B) | (2R)-2-[(E)-3-[(2R,3R)-3-[(1R)-1-carboxy-2-(3,4-dihydroxyphenyl)ethoxy]carbonyl-2-(3,4-dihydroxyphenyl)-7-hydroxy-2,3-dihydro-1-benzofuran-4-yl]prop-2-enoyl]oxy-3-(3,4-dihydroxyphenyl)propanoic acid | Sal B is a compound extracted from Salvia miltiorrhiza (Danshen) | Slows the growth of breast cancer cells95 and and lung cancer cells96 | No data available | Allergy, dizziness, headache, mild GI symptoms, and reversible thrombocytopenia97 | Technically possible |
| SRT1720 (small-molecule activator of the sirtuin subtype SIRT1) | N-[2-[3-(piperazin-1-ylmethyl)imidazo[2,1-b][1,3]thiazol-6-yl]phenyl]quinoxaline-2-carboxamide;2,2,2-trifluoroacetic acid | No data available | Cytostatic effects on various cancer88 | No data available | Stomatitis, behavioral disturbance, rash, pyrexia, pneumonia, gastroenteritis, aggression, agitation, amenorrhea, hypercholesterolemia, elevated partial thromboplastin time, neutropenia, infection | Technically possible |
| Z-LLF-CHO | Benzyl N-[(2S)-4-methyl-1-[[(2S)-4-methyl-2-[(1-oxo-3-phenylpropan-2-yl)amino]pentanoyl]amino]-1-oxopentan-2-yl]carbamate | No data available | Z-LLF-CHO induces early tumor regression and a delay in tumor progression in a murine model of Burkitt's lymphoma98 | No data available | No data available | No data available |