Human NQO1 as a Selective Target for Anticancer Therapeutics and Tumor Imaging
Abstract
:1. Introduction
2. NQO1 Gene, Expression, Cellular Functions, and Anticancer Bioreductive Catalysis
2.1. Scavenging of Superoxide Radicals
2.2. Reduction and Activation of Quinone Compounds and Futile Redox Cycling
2.3. Preservation of Endogenous Antioxidants like Ubiquinone and α-Tocopherol
2.4. Stabilization of Tumor Suppressor Proteins p53 and p73
2.5. Cytotoxic Mechanisms of NQO1 Bioactivating Compounds
2.6. Differential Expression of NQO1 in Normal vs. Malignant Cells
2.7. NQO1 Bioreductive Quinone Substrates Eliciting Cytotoxicity
2.8. Inhibitors of NQO1 Catalytic Activity
2.9. β-Lapachone and Deoxynyboquinone, Two Potent Futile Cycling Substrates of NQO1
2.10. Clinical Advances of β-Lapachone
3. Overview and Brief Descriptions of NQO1-Activatable Fluorescent Probes for Imaging Cancer Cells/Tissues
3.1. General Design and Approaches of Molecular Probes for NQO1 Sensing, Quantitation, and Imaging
3.2. NQO1 Fluorescent Probes with Emission Wavelengths in the Visible Spectrum
3.3. NIR/IR Probes for NQO1 Activity Imaging
3.4. Chemiluminescent Probes for NQO1
3.5. Bioluminescent Probes for NQO1 and NQO1-Deliverable Anticancer Drug Strategy
3.6. Biomedical Applications of NIR-ASM, a Superior Nontoxic NQO1-Imaging Agent
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Compound | Structure | Properties/Limitations to Therapy | Reference(s) |
---|---|---|---|
β-Lapachone | Well-characterized, excellent futile substrate, complex structure, solubility problems, potent efficacy in vitro and in preclinical cancer models; however, anemia was a prominent adverse effect in a single clinical trial. | [44,69,75,80,81,82] | |
Deoxynyboquinone | Natural product, has also been synthesized, more potent than β-lapachone as a futile cycle substrate and for induction of tumor cell killing, insoluble, limited data on anticancer efficacy. | [83,84] | |
GNQ-9 | Synthetic quinone substrate, BBB-permeable, strong cytotoxicity in cancer cell lines, eliminated glioblastoma in orthotopic xenografts. Some evidence indicates immunogenic cell death may play a part. | [79] | |
Phenothiazinium redox cyclers | Robust induction of oxidative stress, and cell death in NQO1 stably transfected MCF-7 cells was demonstrated. | [85] | |
RH1 | RH1 is similar to mitomycin, activation by NQO1 and similar enzymes leads to the formation of cytotoxic species, which then alkylate and crosslink the DNA. Phase I clinical trial indicated bone marrow suppression in patients. | [52,86] | |
Combretastatin A-4 prodrug | CA-4 is an anti-microtubule and anti-angiogenesis drug. NQO1-mediated release of CA-4 was reported in a prodrug approach. Selective killing of NQO1-rich cells was indicated. | [87] | |
Podophyllotoxin prodrug | Podophyllotoxin derivatives inhibit topoisomerase II. Prodrug 3 of the study induced greater cell kill in NQO1-positive cells and suppressed the growth of HepG2 xenografts. | [88] | |
Steptonigrin (STN) | A quinone antibiotic, has been reported to induce NQO1-dependent and dicumarol-sensitive cell death. | [89,90] | |
Geldanamycin AAG | The hydroquinone resulting from NQO1 action on Gelda-AAG inactivates HSP-90, leading to apoptosis. Thus, these cytotoxic quinones exhibit synthetic lethality with NRF2 inducers. | [39] | |
Mitomycin C (MMC) | Mitomycin C (MMC), an established clinically used antitumor antibiotic, can be activated by NQO1 to alkylate DNA and generate crosslinks. Other enzymes have also been implicated in MMC conversion to semiquinone species. | [67,68,91,92] | |
EO9 | EO9 was engineered as an NQO1-targeted drug; however, it penetrates the cancers poorly and is rapidly eliminated, thus hindering its antitumor efficacy. | [66,93,94,95] | |
5 FU prodrug | A tripartite prodrug composed of a trigger group, a self-immolative linker, and 5-FU was synthesized. The prodrug had a cytotoxicity similar to 5-FU and may have a better safety profile. | [96] |
Reagent Number | Original Designation | Structure | Reference |
---|---|---|---|
1 | NMPABA | [138,146] | |
2 | Q3NI | [146] | |
3 | Q3PA | [146] | |
4 | QMeNN | [147] | |
5 | Q3PA Rhodamine fluorophore | [148] | |
6 | Q3MJSNR | [149] | |
7 | 6-Hydroxyl phenolprobe-13 | [150] | |
8 | 4-Methylumbelliferone (4-MU), probe-14 | [151] | |
9 | 7-Nitro-2,1,3-benzoxadiazole, probe-16 | [152] | |
10 | Aminoacetyl-naphthalene, probe,18-TPQ | [153] | |
11 | Hydroxylphenylpolyenyl pyridinium, probe 19-QBMP | [154] | |
12 | 7-Ethyl-10-hydroxycamptothecinprobe-24 | [155] | |
13 | NQ-DCM | [156] | |
14 | Triphenylphosphoniumprobe-21 | [157] |
Reagent Number | Designation | Structure | Reference |
---|---|---|---|
15 | Q3STCY | [164] | |
16 | NIR-ASM | [165] | |
17 | HCYSN | [166] | |
18 | LET-10 | [167] | |
19 | NQO-Iml | [168] |
Reagent Number | Chemiluminescent Probes for NQO1 | Structure | Reference |
---|---|---|---|
20 | NIR CL probe | [175] | |
21 | LET-10 | [176] | |
22 | Luciferin probe 1 (Bioluminescent) | [177] | |
23 | Luciferin probe 2 (Bioluminescent) | [177] | |
24 | SN-38 conjugate | [178] | |
25 | Phenalenone conjugate | [165] | |
26 | Prodrug for detecting DT-diaphorase | [161] |
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Khan, A.E.M.A.; Arutla, V.; Srivenugopal, K.S. Human NQO1 as a Selective Target for Anticancer Therapeutics and Tumor Imaging. Cells 2024, 13, 1272. https://doi.org/10.3390/cells13151272
Khan AEMA, Arutla V, Srivenugopal KS. Human NQO1 as a Selective Target for Anticancer Therapeutics and Tumor Imaging. Cells. 2024; 13(15):1272. https://doi.org/10.3390/cells13151272
Chicago/Turabian StyleKhan, A. E. M. Adnan, Viswanath Arutla, and Kalkunte S. Srivenugopal. 2024. "Human NQO1 as a Selective Target for Anticancer Therapeutics and Tumor Imaging" Cells 13, no. 15: 1272. https://doi.org/10.3390/cells13151272