The New Face of a Well-Known Antibiotic: A Review of the Anticancer Activity of Enoxacin and Its Derivatives
Abstract
:Simple Summary
Abstract
1. Introduction
2. Enoxacin as a Small-Molecule Enhancer of microRNA (SMER)
2.1. The miRNA Biogenesis
2.2. The Effect on Cancer Cells
2.2.1. TRBP-Dependent Cytotoxicity
2.2.2. PIWIL-3-Dependent Cytotoxicity
2.2.3. Other Consequences of Enoxacin-Mediated miRNA Dysregulation
2.3. The Effects on Non-Cancer Cells
miRNA | Conc. [µM] | Effect | Expression Change | Cell Line | Ref. |
---|---|---|---|---|---|
[↑/↓] | Change-Fold | ||||
Cancer cells | |||||
let-7b-5p, miR-146a-5p, miR-689 | 50 | ↓ | 0.5–1 | 4T1 (miRNA from EV), | [49] |
miR-100 | 124 | ↓ | 0.5–1 | primary ESFT spheres | [37] |
miR-141, miR-191 | 124 | ↓ | 1.5–2 | DU145, LNcap, | [38] |
miR-21-5p, miR-30a-3p, miR-30a-5p, miR-100-5p, miR-204-5p, miR-221-3p | 124 | ↑ | <1.5 | Cal62, STA-ET-8.2, TPC1 | [39] |
Let-7f, miR-26a, | 124 | ↑ | <1.5 | A673, SW1736 | [37] |
miR-21 | 100 | ↑ | 1.5–2 | MCF7 | [41] |
miR-16, miR-18a*, miR-21, miR-26a, miR-29b, miR-29c, miR-31, miR-193a, | 124 | ↑ | 1.5–2 | HCT-116 | [36] |
let-7f, miR-26a, miR-99a, miR-100, miR-143, miR-145, | 124 | ↑ | 1.5–2 | A673, STA-ET-8.2, TC252, primary ESFT spheres | [37] |
miR-21-5p, miR-30a-3p, miR-100-5p, miR-146b-5p, miR-221-3p, | 124 | ↑ | 1.5–2 | Cal62, SW1736, TPC1 | [39] |
miR-17 *, miR29b, miR-132, miR-146a, miR-191 miR-449a, | 124 | ↑ | 1.5–2 | DU145 LNcap, | [38] |
miR-214-3p | 50 | ↑ | 2–2.5 | 4T1 (cytosolic miRNA), | [49] |
miR-145 | 100 | ↑ | 2–2.5 | MCF7 | [41] |
miR-7, miR-16, miR-18a*, miR-29c, miR-101, miR-128, miR-181a, miR-212 | 124 | ↑ | 2–2.5 | HCT-116, RKO | [36] |
miR-100-5p, miR-146b-5p | 124 | ↑ | 2–2.5 | SW1736, TPC1 | [39] |
miR-34a, miR-449a | 124 | ↑ | 2–2.5 | DU145, LNcap | [38] |
let-7f, miR-99a, miR-100, miR-145 | 124 | ↑ | 2–2.5 | A673, STA-ET-8.2, TC252, primary ESFT spheres | [37] |
miR-7, miR-26a, miR-29b, miR-30a, miR-101, miR-122, miR-125a, miR-125b, miR-126, miR-128, miR-143, miR-181b, miR-205 | 124 | ↑ | 2.5–3 | HCT-116, RKO | [36] |
miR-100, miR-145 | 124 | ↑ | 2.5–3 | A673, TC252 | [37] |
miR-29b | 124 | ↑ | 2.5–3 | LNcap | [38] |
let-7a, let-7b, miR-30a, miR-31, miR-126, miR-181b, miR-193a, miR-193b, | 124 | ↑ | 3–3.5 | HCT-116, RKO | [36] |
let-7f, miR-143, miR-181a, | 124 | ↑ | 3–3.5 | A673, STA-ET-8.2, primary ESFT spheres | [37] |
miR-181a, miR-193b | 124 | ↑ | 3.5–4 | HCT-116 | [36] |
let-7b, miR-143, miR-205 | 124 | ↑ | 4–4.5 | HCT-116, RKO | [36] |
miR-143 | 124 | ↑ | 4–4.5 | TC252 | [37] |
miR-125a | 124 | ↑ | ca. 5 | HCT-116 | [36] |
miR-214-3p | 50 | ↑ | ca. 22 | 4T1 (miRNA from EV) | [49] |
Non-cancer cells | |||||
miR-128-1 | 60 | ↓ | 0.5–1 | dnTGFβRII T cells | [65] |
let-7i, miR-128 | 50 | ↓ | 1.5–2 | HEK293 | [35] |
let-7b, miR-23a, miR-30e, miR-96, miR-99a, miR-125a, miR-146, miR-190, miR-199a*, | 50 | ↑ | 1.5–2 | HEK293 | [35] |
miR-124a, miR-139, miR-152, miR-199b | 50 | ↑ | 2–2.5 | HEK293 | [35] |
miR-29b-1, miR-145a-5p, miR-326-3p | 60 | ↑ | 2–2.5 | dnTGFβRII T cells | [65] |
miR-181a | 60 | ↑ | 2.5–3 | dnTGFβRII T cells | [65] |
miR-346-5 | 60 | ↑ | 3–3.5 | dnTGFβRII T cells | [65] |
miRNA | Dose | Effect | Expression Change: | Tissue | Ref. |
---|---|---|---|---|---|
[↑/↓] | Change-Fold | ||||
miR-124 | 10 mg/kg 25 mg/kg | ↑ | ca. 4. ca. 6 | rat frontal cortex | [66] |
let-7a, miR-125a-5p | 10 mg/kg 25 mg/kg | ↑ | ca. 11. ca. 20 | ||
miR-132 | 10 mg/kg 25 mg/kg | ↑ | ca. 19 (for both doses) | ||
miR-30a-5p, miR-146b-5 | 15 mg/kg | ↑ | 1.5–2 | human orthotopic thyroid tumor from Cal62-luc mouse | [39] |
mIR-100-5p, miR-30-3p, miR-204-5 | 15 mg/kg | ↑ | 2–2.5 | human orthotopic thyroid tumor from Cal62-luc mouse | [39] |
miR-16, miR-18a*, miR-21, miR-26a, miR-29b, miR-29c, miR-31, miR-101, miR-193a | 10 mg/kg | ↑ | 1.5–2 | tumor from HCT-116 mouse xenograft | [36] |
miR-16, miR-29c, miR-31, miR-101, miR-181a | 10 mg/kg | ↑ | 1.5–2 | tumor from RKO mouse xenograft | [36] |
miR-128, miR-212 | 10 mg/kg | ↑ | 2–2.5 | tumor from HCT-116 mouse xenograft | [36] |
miR-18a*, miR-21, miR-26a, miR-29b, miR-30a, miR-128 | 10 mg/kg | ↑ | 2–2.5 | tumor from RKO mouse xenograft | [36] |
let-7b, miR-7, miR-143, miR-181b, miR-125b | 10 mg/kg | ↑ | 2.5–3 | tumor from HCT-116 mouse xenograft | [36] |
let-7a, miR-7, miR-122, miR-125a, miR-125b, miR-126, miR-181b, miR-193a, miR-193b, miR-205, miR-212 | 10 mg/kg | ↑ | 2.5–3 | tumor from RKO mouse xenograft | [36] |
let-7a, miR-30a, miR-122, miR-126 | 10 mg/kg | ↑ | 3–3.5 | tumor from HCT-116 mouse xenograft | [36] |
miR-143 | 10 mg/kg | ↑ | 3–3.5 | tumor from RKO mouse xenograft | [36] |
miR-125a, miR-181a, miR-193b | 10 mg/kg | ↑ | 3.5–4 | tumor from HCT-116 mouse xenograft | [36] |
let-7b | 10 mg/kg | ↑ | 4.5–5 | tumor from RKO mouse xenograft | [36] |
miR-205 | 10 mg/kg | ↑ | 4.5–5 | tumor from HCT-116 mouse xenograft | [36] |
3. Cytotoxic Effects of Enoxacin Mediated by Other Mechanisms
3.1. Effect on Cancer Cells
Effect | Conc. [μM] | Cell Line/Tissue | Ref. |
---|---|---|---|
No cytotoxicity | 31 | A673 | [74] |
124 | Wi-38, MRC-5 | [36] | |
20 | HEK 293 | [91] | |
5–100 | Primary BMMs | [82] | |
5–100 | Raw 264.7 | [77] | |
No genotoxicity | 0–3121 | WTK-1 | [90] |
Apoptosis | 62 | NCI-H460 | [70] |
150 | H460, A549 | [69] | |
Apoptosis, cell cycle arrest | 31–156 | MCF-7 | [71] |
20–80 | HeLa, C33A | [73] | |
124 | DU145, LNCaP, VCaP, PC-3, 22Rv1, Co115 | [38] | |
124 | HCT-116, RKO | [36] | |
Cytotoxicity (PI) | 78–312 | A375 | [48] |
Cytotoxicity (MTS) | 31 | TC 252, Patient derived ESFT spheres | [74] |
Cytotoxicity (MTT) | 124 | HCT-116, RKO, HepG2, SNU-1, SNU-638, MDA-MB 231, MCF-7, H23, H1299, A549, MDA-MB-231, HepG2, KG1a, RAJI | [36] |
124 | A673, TC252, STA-ET-8.2 | [37] | |
156 | A375, Mel-Juso, Mel-Ho | [48] | |
12.5–100 | A549 | [45] | |
Decreased invasiveness | 124 | DU145 | [38] |
Cytochrome P450 inhibition | 10–1000 | freshly isolated rat hepatocytes | [75] |
Inhibition of osteoclastogenesis | 10; 100 | Primary MMO | [76] |
10–100 | Primary MMO, Raw 264.7 | [77] | |
5; 10; 50 | Primary BMMs | [82] | |
Inhibition of bone resorption | 10; 25; 100 | Primary MMO | [76] |
5; 10; 50 | Primary BMMs | [82] | |
Inhibition of the interaction between V-ATPase B-subunit and F-actin | 10; 25; 100 | rabbit muscle actin and the Vma2p-MBP microfilaments | [76] |
Inhibition of the interaction between microfilaments and V-ATPase (a) B2-subunit (b) a3-subunit | 50 | Primary MMO | [77] |
Impairment of JNK signaling | 25 | Raw 264.7 | [82] |
3.2. Effects on Normal Cells
4. Phototoxicity
4.1. Mechanism and Effect on Cancer Cells
Effect | UVA Irradiation Dose [J/cm2] | Conc. [μM] | Cell Line | Ref. |
---|---|---|---|---|
Photosynthetization | 3; 6 | 62 | The THP-1 cells from tumoral monocytes | [92] |
Phototoxicity | 4.3 | 4.5 | HeLa | [93] |
Photohemolysis | 20 | 3.1; 31; 312 | Sheep red blood cells | [93] |
DNA strand breaking | 1.6 | 3.1; 31; 312 | pUC18 plasmid was | [93] |
apoptosis | 4 | 100 | HaCaT | [97] |
Increased protoporphyrin accumulation and photosensitivity | 0.54 0.54 | 156–312 (with 1 mM ALA) 312 (with 1 mM ALA) | HeLa A431 | [94] |
Apoptosis | Approx. 0.84 ^ | 100 | AsPC1 | [95] |
Apoptosis | 0.84 | 200 | HL-60 | [96] |
4.2. Mechanism and Effect on Normal Cells
5. Enoxacin Derivatives and Their Anticancer Activity
6. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
8-oxodGuo | 8-Oxo-7,8-dihydro-2′-deoxyguanosine |
ALA | δ-aminolevulinic acid |
amiRNAs | artificial miRNAs |
ATF6 | activating transcription factor 6 |
Bax | Bcl-2-associated X protein |
Bcl-2 | B-cell lymphoma 2 |
BE | bis-enoxacin |
CHOP | C/EBP homologous protein also knows as DNA damage-inducible transcript 3 |
CSC | cancer stem–like cells |
DDR | DNA damage response |
DICER | endoribonuclease DICER |
dnTGFβRII | dominant negative TGF-β receptor |
Drosha | type III RNase Drosha |
EC50 | effective concentration |
EMT | epithelial–mesenchymal transition |
ENX | enoxacin |
ESFT | Ewing’s sarcoma family tumor |
EVs | extracellular vesicles |
FACS | fluorescence-activated cell sorting |
GW/P-bodies | GW-Processing bodies |
IRE1 | inositol-requiring enzyme 1 |
MCL-1 | induced myeloid leukemia cell differentiation protein |
METTL3 | methyltransferase-like 3 |
miRNA | microRNA |
MMP2 | matrix metalloproteinase-2 |
mRNA | messengerRNA |
NAC | N-acetyl-cysteine |
NOXA | phorbol-12-myristate-13-acetate-induced protein 1 also known as Noxa |
NSCLC | non-small-celllungcancer |
piRNA | Piwi-interacting RNA |
PIWIL3 | Piwi-like protein 3 |
PolII | polymerase II |
pri-miRNA | primary transcript |
Ran | GTP-binding nuclear protein Ran |
RISC | RNA-induced silencing complex |
ROS | reactive oxygen species |
sgRNA | single-guide RNA |
SMER | small-molecule enhancer of microRNA |
SN-38 | 7-ethyl-10-hydroxy-camptothecin |
TLR | Toll-like receptor |
TRBP | TAR RNA-binding protein 2 |
V-ATPase | vacuolar H+-ATPase |
Cell Lines List | |
Human Cancer Cells | |
breast cancer | MCF7 |
cervical cancer | HeLa, C33A |
colorectal cancer | Co115, RKO and HCT-116 |
epidermoid carcinoma | A431 |
Ewing’s sarcoma family tumor (ESFT) | A673, TC252, STA-ET-8.2 |
leukemia | HL-60 |
liver cancer | Hep-3B |
lymphoma | WTK-1 |
melanoma | A375, Mel-Juso, Mel-Ho |
non-small cell lung | H460, A549, PC9 |
ovarian cancer | A2780 |
pancreatic cancer | AsPC1, PANC-1 |
prostate cancer | DU145, LNCaP, VCaP, PC-3, 22Rv1, Co115 |
thyroid cancer | Cal62, TPC1, SW1736 |
human non-cancer cells | |
embryonic kidney | HEK 293 |
keratinocyte | HaCaT |
primary pediatric mesenchymal stem cells | hpMSCs |
animal cells | |
murine macrophage | Raw 264.7 |
murine breast cancer cells | 4T1 |
African green monkey’s normal kidney cells | Vero |
References
- Idowu, T.; Schweizer, F. Ubiquitous Nature of Fluoroquinolones: The Oscillation between Antibacterial and Anticancer Activities. Antibiotics 2017, 6, 26. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mitscher, L.A. Bacterial Topoisomerase Inhibitors: Quinolone and Pyridone Antibacterial Agents. Chem. Rev. 2005, 105, 559–592. [Google Scholar] [CrossRef] [PubMed]
- Wood, M.J. Tissue Penetration and Clinical Efficacy of Enoxacin in Respiratory Tract Infections. Clin. Pharmacokinet. 1989, 16, 38–45. [Google Scholar] [CrossRef] [PubMed]
- Chin, N.X.; Neu, H.C. In vitro activity of enoxacin, a quinolone carboxylic acid, compared with those of norfloxacin, new β-lactams, aminoglycosides, and trimethoprim. Antimicrob. Agents Chemother. 1983, 24, 754–763. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Paton, J.H.; Reeves, D.S. Fluoroquinolone Antibiotics. Drugs 1988, 36, 193–228. [Google Scholar] [CrossRef] [PubMed]
- Penetrex: Description. Available online: https://www.rxlist.com/penetrex-drug.htm (accessed on 14 June 2022).
- Hooper, D.C.; Jacoby, G.A. Topoisomerase Inhibitors: Fluoroquinolone Mechanisms of Action and Resistance. Cold Spring Harb. Perspect. Med. 2016, 6, a025320. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dalhoff, A. Selective toxicity of antibacterial agents—still a valid concept or do we miss chances and ignore risks? Infection 2021, 49, 29–56. [Google Scholar] [CrossRef]
- Felicetti, T.; Cecchetti, V.; Manfroni, G. Modulating microRNA Processing: Enoxacin, the Progenitor of a New Class of Drugs. J. Med. Chem. 2020, 63, 12275–12289. [Google Scholar] [CrossRef]
- Jadhav, A.K.; Karuppayil, S.M. Molecular docking studies on thirteen fluoroquinolines with human topoisomerase II a and b. Silico Pharmacol. 2017, 5. [Google Scholar] [CrossRef] [Green Version]
- Gao, F.; Zhang, X.; Wang, T.; Xiao, J. Quinolone hybrids and their anti-cancer activities: An overview. Eur. J. Med. Chem. 2019, 165, 59–79. [Google Scholar] [CrossRef]
- Suaifan, G.A.R.Y.; Mohammed, A.A.M. Fluoroquinolones structural and medicinal developments (2013–2018): Where are we now? Bioorganic Med. Chem. 2019, 27, 3005–3060. [Google Scholar] [CrossRef] [PubMed]
- Yadav, V.; Talwar, P. Repositioning of fluoroquinolones from antibiotic to anti-cancer agents: An underestimated truth. Biomed. Pharmacother. 2019, 111, 934–946. [Google Scholar] [CrossRef] [PubMed]
- Abdel-Aal, M.A.A.; Abdel-Aziz, S.A.; Shaykoon, M.S.A.; Abuo-Rahma, G.E.A. Towards anticancer fluoroquinolones: A review article. Arch. Pharm. 2019, 352, 1800376. [Google Scholar] [CrossRef]
- Lee, Y.; Kim, M.; Han, J.; Yeom, K.H.; Lee, S.; Baek, S.H.; Kim, V.N. MicroRNA genes are transcribed by RNA polymerase II. EMBO J. 2004, 23, 4051–4060. [Google Scholar] [CrossRef] [PubMed]
- Peng, Y.; Croce, C.M. The role of microRNAs in human cancer. Signal Transduct. Target. Ther. 2016, 1, 15004. [Google Scholar] [CrossRef] [Green Version]
- MacFarlane, L.-A.; Murphy, P.R. MicroRNA: Biogenesis, Function and Role in Cancer. Curr. Genom. 2010, 11, 537–561. [Google Scholar] [CrossRef] [Green Version]
- Iwakawa, H.; Tomari, Y. Life of RISC: Formation, action, and degradation of RNA-induced silencing complex. Mol. Cell 2022, 82, 30–43. [Google Scholar] [CrossRef]
- Zhang, R.; Jing, Y.; Zhang, H.; Niu, Y.; Liu, C.; Wang, J.; Zen, K.; Zhang, C.-Y.; Li, D. Comprehensive Evolutionary Analysis of the Major RNA-Induced Silencing Complex Members. Sci. Rep. 2018, 8, 14189. [Google Scholar] [CrossRef]
- Liu, J.; Rivas, F.V.; Wohlschlegel, J.; Yates, J.R.; Parker, R.; Hannon, G.J. A role for the P-body component GW182 in microRNA function. Nat. Cell Biol. 2005, 7, 1161–1166. [Google Scholar] [CrossRef]
- Jakymiw, A.; Pauley, K.M.; Li, S.; Ikeda, K.; Lian, S.; Eystathioy, T.; Satoh, M.; Fritzler, M.J.; Chan, E.K.L. The role of GW/P-bodies in RNA processing and silencing. J. Cell Sci. 2007, 120, 1317–1323. [Google Scholar] [CrossRef] [Green Version]
- Fabbri, M.; Paone, A.; Calore, F.; Galli, R.; Gaudio, E.; Santhanam, R.; Lovat, F.; Fadda, P.; Mao, C.; Nuovo, G.J.; et al. MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc. Natl. Acad. Sci. USA 2012, 109, E2110–E2116. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Calin, G.A.; Dumitru, C.D.; Shimizu, M.; Bichi, R.; Zupo, S.; Noch, E.; Aldler, H.; Rattan, S.; Keating, M.; Rai, K.; et al. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc. Natl. Acad. Sci. USA 2002, 99, 15524–15529. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Calin, G.A.; Croce, C.M. MicroRNAs and chromosomal abnormalities in cancer cells. Oncogene 2006, 25, 6202–6210. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hayashita, Y.; Osada, H.; Tatematsu, Y.; Yamada, H.; Yanagisawa, K.; Tomida, S.; Yatabe, Y.; Kawahara, K.; Sekido, Y.; Takahashi, T. A polycistronic MicroRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation. Cancer Res. 2005, 65, 9628–9632. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mavrakis, K.J.; Wolfe, A.L.; Oricchio, E.; Palomero, T.; De Keersmaecker, K.; McJunkin, K.; Zuber, J.; James, T.; Chang, K.; Khan, A.A.; et al. Genome-wide RNA-mediated interference screen identifies miR-19 targets in Notch-induced T-cell acute lymphoblastic leukaemia. Nat. Cell Biol. 2010, 12, 372–379. [Google Scholar] [CrossRef] [Green Version]
- Zhang, L.; Huang, J.; Yang, N.; Greshock, J.; Megraw, M.S.; Giannakakis, A.; Liang, S.; Naylor, T.L.; Barchetti, A.; Ward, M.R.; et al. microRNAs exhibit high frequency genomic alterations in human cancer. Proc. Natl. Acad. Sci. USA 2006, 103, 9136–9141. [Google Scholar] [CrossRef] [Green Version]
- Calin, G.A.; Sevignani, C.; Dumitru, C.D.; Hyslop, T.; Noch, E.; Yendamuri, S.; Shimizu, M.; Rattan, S.; Bullrich, F.; Negrini, M.; et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc. Natl. Acad. Sci. USA 2004, 101, 2999–3004. [Google Scholar] [CrossRef] [Green Version]
- O’Donnell, K.A.; Wentzel, E.A.; Zeller, K.I.; Dang, C.V.; Mendell, J.T. c-Myc-regulated microRNAs modulate E2F1 expression. Nature 2005, 435, 839–843. [Google Scholar] [CrossRef]
- Chang, T.C.; Yu, D.; Lee, Y.S.; Wentzel, E.A.; Arking, D.E.; West, K.M.; Dang, C.V.; Thomas-Tikhonenko, A.; Mendell, J.T. Widespread microRNA repression by Myc contributes to tumorigenesis. Nat. Genet. 2008, 40, 43–50. [Google Scholar] [CrossRef] [Green Version]
- del C. Monroig, P.; Calin, G.A. MicroRNA and Epigenetics: Diagnostic and Therapeutic Opportunities. Curr. Pathobiol. Rep. 2013, 1, 43–52. [Google Scholar] [CrossRef]
- Thomson, J.M.; Newman, M.; Parker, J.S.; Morin-Kensicki, E.M.; Wright, T.; Hammond, S.M. Extensive post-transcriptional regulation of microRNAs and its implications for cancer. Genes Dev. 2006, 20, 2202–2207. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Karube, Y.; Tanaka, H.; Osada, H.; Tomida, S.; Tatematsu, Y.; Yanagisawa, K.; Yatabe, Y.; Takamizawa, J.; Miyoshi, S.; Mitsudomi, T.; et al. Reduced expression of Dicer associated with poor prognosis in lung cancer patients. Cancer Sci. 2005, 96, 111–115. [Google Scholar] [CrossRef] [PubMed]
- Dome, J.S.; Coppes, M.J. Recent advances in Wilms tumor genetics. Curr. Opin. Pediatr. 2002, 14, 5–11. [Google Scholar] [CrossRef]
- Shan, G.; Li, Y.; Zhang, J.; Li, W.; Szulwach, K.E.; Duan, R.; Faghihi, M.A.; Khalil, A.M.; Lu, L.; Paroo, Z.; et al. A small molecule enhances RNA interference and promotes microRNA processing. Nat. Biotechnol. 2008, 26, 933–940. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Melo, S.; Villanueva, A.; Moutinho, C.; Davalos, V.; Spizzo, R.; Ivan, C.; Rossi, S.; Setien, F.; Casanovas, O.; Simo-Riudalbas, L.; et al. Small molecule enoxacin is a cancer-specific growth inhibitor that acts by enhancing TAR RNA-binding protein 2-mediated microRNA processing. Proc. Natl. Acad. Sci. USA 2011, 108, 4394–4399. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- De Vito, C.; Riggi, N.; Cornaz, S.; Suvà, M.L.; Baumer, K.; Provero, P.; Stamenkovic, I. A TARBP2-Dependent miRNA Expression Profile Underlies Cancer Stem Cell Properties and Provides Candidate Therapeutic Reagents in Ewing Sarcoma. Cancer Cell 2012, 21, 807–821. [Google Scholar] [CrossRef] [Green Version]
- Sousa, E.J.; Graça, I.; Baptista, T.; Vieira, F.Q.; Palmeira, C.; Henrique, R.; Jerónimo, C. Enoxacin inhibits growth of prostate cancer cells and effectively restores microRNA processing. Epigenetics 2013, 8, 548–558. [Google Scholar] [CrossRef] [Green Version]
- Ramírez-Moya, J.; Wert-Lamas, L.; Riesco-Eizaguirre, G.; Santisteban, P. Impaired microRNA processing by DICER1 downregulation endows thyroid cancer with increased aggressiveness. Oncogene 2019, 38, 5486–5499. [Google Scholar] [CrossRef]
- Gioia, U.; Francia, S.; Cabrini, M.; Brambillasca, S.; Michelini, F.; Jones-Weinert, C.W.; d’Adda di Fagagna, F. Pharmacological boost of DNA damage response and repair by enhanced biogenesis of DNA damage response RNAs. Sci. Rep. 2019, 9, 6460. [Google Scholar] [CrossRef] [Green Version]
- Abell, N.S.; Mercado, M.; Cañeque, T.; Rodriguez, R.; Xhemalce, B. Click quantitative mass spectrometry identifies PIWIL3 as a mechanistic target of RNA interference activator enoxacin in cancer cells. J. Am. Chem. Soc. 2017, 139, 1400–1403. [Google Scholar] [CrossRef]
- Yamashiro, H.; Siomi, M.C. PIWI-Interacting RNA in Drosophila: Biogenesis, Transposon Regulation, and beyond. Chem. Rev. 2018, 118, 4404–4421. [Google Scholar] [CrossRef] [PubMed]
- Jiang, L.; Wang, W.J.; Li, Z.W.; Wang, X.Z. Downregulation of Piwil3 suppresses cell proliferation, migration and invasion in gastric cancer. Cancer Biomark. 2017, 20, 499–509. [Google Scholar] [CrossRef]
- Li, L.; Yu, C.; Gao, H.; Li, Y. Argonaute proteins: Potential biomarkers for human colon cancer. BMC Cancer 2010, 10, 38. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cao, S.; Sun, R.; Wang, W.; Meng, X.; Zhang, Y.; Zhang, N.; Yang, S. RNA helicase DHX9 may be a therapeutic target in lung cancer and inhibited by enoxacin. Am. J. Transl. Res. 2017, 9, 674–682. [Google Scholar]
- Chou, C.-H.; Chang, N.-W.; Shrestha, S.; Hsu, S.-D.; Lin, Y.-L.; Lee, W.-H.; Yang, C.-D.; Hong, H.-C.; Wei, T.-Y.; Tu, S.-J.; et al. miRTarBase 2016: Updates to the experimentally validated miRNA-target interactions database. Nucleic Acids Res. 2016, 44, D239–D247. [Google Scholar] [CrossRef]
- Hoffman, Y.; Pilpel, Y.; Oren, M. microRNAs and Alu elements in the p53-Mdm2-Mdm4 regulatory network. J. Mol. Cell Biol. 2014, 6, 192–197. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Valianatos, G.; Valcikova, B.; Growkova, K.; Verlande, A.; Mlcochova, J.; Radova, L.; Stetkova, M.; Vyhnakova, M.; Slaby, O.; Uldrijan, S. A small molecule drug promoting miRNA processing induces alternative splicing of MdmX transcript and rescues p53 activity in human cancer cells overexpressing MdmX protein. PLoS ONE 2017, 12, e0185801. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Vracar, T.C.; Zuo, J.; Park, J.S.; Azer, D.; Mikhael, C.; Holliday, S.A.; Holsey, D.; Han, G.; VonMoss, L.; Neubert, J.K.; et al. Enoxacin and bis-enoxacin stimulate 4T1 murine breast cancer cells to release extracellular vesicles that inhibit osteoclastogenesis. Sci. Rep. 2018, 8, 16182. [Google Scholar] [CrossRef]
- Chrzanowska, A.; Struga, M.; Roszkowski, P.; Koliński, M.; Kmiecik, S.; Jałbrzykowska, K.; Zabost, A.; Stefańska, J.; Augustynowicz-Kopeć, E.; Wrzosek, M.; et al. The Effect of Conjugation of Ciprofloxacin and Moxifloxacin with Fatty Acids on Their Antibacterial and Anticancer Activity. Int. J. Mol. Sci. 2022, 23, 6261. [Google Scholar] [CrossRef]
- Chrzanowska, A.; Roszkowski, P.; Bielenica, A.; Olejarz, W.; Stępień, K.; Struga, M. Anticancer and antimicrobial effects of novel ciprofloxacin fatty acids conjugates. Eur. J. Med. Chem. 2020, 185, 111810. [Google Scholar] [CrossRef]
- Dvorak, H.F. Leaky tumor vessels: Consequences for tumor stroma generation and for solid tumor therapy. Prog. Clin. Biol. Res. 1990, 354A, 317–330. [Google Scholar] [PubMed]
- Yang, J.-S.; Lai, E.C. Alternative miRNA Biogenesis Pathways and the Interpretation of Core miRNA Pathway Mutants. Mol. Cell 2011, 43, 892–903. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Maurin, T.; Cazalla, D.; Yang, J.-S.; Bortolamiol-Becet, D.; Lai, E.C. RNase III-independent microRNA biogenesis in mammalian cells. RNA 2012, 18, 2166–2173. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yang, J.-S.; Lai, E.C. Dicer-independent, Ago2-mediated microRNA biogenesis in vertebrates. Cell Cycle 2010, 9, 4455–4460. [Google Scholar] [CrossRef] [Green Version]
- Xu, Y.; Fang, F.; Zhang, J.; Josson, S.; St. Clair, W.H.; St. Clair, D.K. miR-17* Suppresses Tumorigenicity of Prostate Cancer by Inhibiting Mitochondrial Antioxidant Enzymes. PLoS ONE 2010, 5, e14356. [Google Scholar] [CrossRef]
- Yamakuchi, M.; Ferlito, M.; Lowenstein, C.J. miR-34a repression of SIRT1 regulates apoptosis. Proc. Natl. Acad. Sci. USA 2008, 105, 13421–13426. [Google Scholar] [CrossRef] [Green Version]
- Wei, W.; Yang, Y.; Cai, J.; Cui, K.; Li, R.; Wang, H.; Shang, X.; Wei, D. MiR-30a-5p Suppresses Tumor Metastasis of Human Colorectal Cancer by Targeting ITGB3. Cell. Physiol. Biochem. 2016, 39, 1165–1176. [Google Scholar] [CrossRef]
- Zhang, J.; Zhang, Y.; Li, X.; Wang, H.; Li, Q.; Liao, X. MicroRNA-212 inhibits colorectal cancer cell viability and invasion by directly targeting PIK3R3. Mol. Med. Rep. 2017, 16, 7864–7872. [Google Scholar] [CrossRef] [Green Version]
- Gambari, R.; Brognara, E.; Spandidos, D.A.; Fabbri, E. Targeting oncomiRNAs and mimicking tumor suppressor miRNAs: New trends in the development of miRNA therapeutic strategies in oncology (Review). Int. J. Oncol. 2016, 49, 5–32. [Google Scholar] [CrossRef] [Green Version]
- Nurzadeh, M.; Naemi, M.; Sheikh Hasani, S. A comprehensive review on oncogenic miRNAs in breast cancer. J. Genet. 2021, 100, 15. [Google Scholar] [CrossRef]
- Penna, E.; Orso, F.; Taverna, D. miR-214 as a Key Hub that Controls Cancer Networks: Small Player, Multiple Functions. J. Investig. Dermatol. 2015, 135, 960–969. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cao, M.; Seike, M.; Soeno, C.; Mizutani, H.; Kitamura, K.; Minegishi, Y.; Noro, R.; Yoshimura, A.; Cai, L.; Gemma, A. MiR-23a regulates TGF-β-induced epithelial-mesenchymal transition by targeting E-cadherin in lung cancer cells. Int. J. Oncol. 2012, 41, 869–875. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Khordadmehr, M.; Shahbazi, R.; Sadreddini, S.; Baradaran, B. miR-193: A new weapon against cancer. J. Cell. Physiol. 2019, 234, 16861–16872. [Google Scholar] [CrossRef] [PubMed]
- Itoh, A.; Adams, D.; Huang, W.; Wu, Y.; Kachapati, K.; Bednar, K.J.; Leung, P.S.C.; Zhang, W.; Flavell, R.A.; Gershwin, M.E.; et al. Enoxacin Up-Regulates MicroRNA Biogenesis and Down-Regulates Cytotoxic CD8 T-Cell Function in Autoimmune Cholangitis. Hepatology 2021, 74, 835–846. [Google Scholar] [CrossRef]
- Smalheiser, N.R.; Zhang, H.; Dwivedi, Y. Enoxacin elevates microRNA levels in rat frontal cortex and prevents learned helplessness. Front. Psychiatry 2014, 5, 6. [Google Scholar] [CrossRef] [Green Version]
- Huang, X.; Chen, Z.; Liu, Y. RNAi-mediated control of CRISPR functions. Theranostics 2020, 10, 6661–6673. [Google Scholar] [CrossRef]
- miRBase miRNA’s Nomenclature. Available online: https://www.mirbase.org/help/nomenclature.shtml (accessed on 14 June 2022).
- Yang, L.; Yuan, Y.; Fu, C.; Xu, X.; Zhou, J.; Wang, S.; Kong, L.; Li, Z.; Guo, Q.; Wei, L. LZ-106, a novel analog of enoxacin, inducing apoptosis via activation of ROS-dependent DNA damage response in NSCLCs. Free Radic. Biol. Med. 2016, 95, 155–168. [Google Scholar] [CrossRef]
- Mondal, E.R.; Das, S.K.; Mukherjee, P. Comparative evaluation of antiproliferative activity and induction of apoptosis by some fluoroquinolones with a human non-small cell lung cancer cell line in culture. Asian Pac. J. Cancer Prev. 2004, 5, 196–204. [Google Scholar]
- Mukherjee, P.; Mandal, E.R.; Das, S.K. Evaluation of Antiproliferative Activity of Enoxacin on a Human Breast Cancer Cell Line. Int. J. Hum. Genet. 2005, 5, 57–63. [Google Scholar] [CrossRef]
- Xu, H.; Mao, M.; Zhao, R.; Zhao, Q. Enoxacin Exerts Anti-Tumor Effects Against Prostate Cancer through Inducing Apoptosis. Technol. Cancer Res. Treat. 2021, 20, 153303382199528. [Google Scholar] [CrossRef]
- McDonnell, A.M.; Pyles, H.M.; Diaz-Cruz, E.S.; Barton, C.E. Enoxacin and epigallocatechin gallate (EGCG) act synergistically to inhibit the growth of cervical cancer cells in culture. Molecules 2019, 24, 1580. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cornaz-Buros, S.; Riggi, N.; Devito, C.; Sarre, A.; Letovanec, I.; Provero, P.; Stamenkovic, I. Targeting cancer stem-like cells as an approach to defeating cellular heterogeneity in Ewing sarcoma. Cancer Res. 2014, 74, 6610–6622. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Brown, H.S.; Wilby, A.J.; Alder, J.; Houston, J.B. Comparative use of isolated hepatocytes and hepatic microsomes for cytochrome P450 inhibition studies: Transporter-enzyme interplay. Drug Metab. Dispos. 2010, 38, 2139–2146. [Google Scholar] [CrossRef] [PubMed]
- Ostrov, D.A.; Magis, A.T.; Wronski, T.J.; Chan, E.K.L.; Toro, E.J.; Donatelli, R.E.; Sajek, K.; Haroun, I.N.; Nagib, M.I.; Piedrahita, A.; et al. Identification of enoxacin as an inhibitor of osteoclast formation and bone resorption by structure-based virtual screening. J. Med. Chem. 2009, 52, 5144–5151. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Toro, E.J.; Zuo, J.; Ostrov, D.A.; Catalfamo, D.; Bradaschia-Correa, V.; Arana-Chavez, V.; Caridad, A.R.; Neubert, J.K.; Wronski, T.J.; Wallet, S.M.; et al. Enoxacin directly inhibits osteoclastogenesis without inducing apoptosis. J. Biol. Chem. 2012, 287, 17894–17904. [Google Scholar] [CrossRef] [Green Version]
- Toro, E.J.; Ostrov, D.A.; Wronski, T.J.; Shannon Holliday, L. Rational Identification of Enoxacin as a Novel V-ATPase-Directed Osteoclast Inhibitor. Curr. Protein Pept. Sci. 2012, 13, 180–191. [Google Scholar] [CrossRef] [Green Version]
- Baron, R.; Neff, L.; Louvard, D.; Courtoy, P.J. Cell-mediated extracellular acidification and bone resorption: Evidence for a low pH in resorbing lacunae and localization of a 100-kD lysosomal membrane protein at the osteoclast ruffled border. J. Cell Biol. 1985, 101, 2210–2222. [Google Scholar] [CrossRef] [Green Version]
- Stransky, L.; Cotter, K.; Forgac, M. The function of v-atpases in cancer. Physiol. Rev. 2016, 96, 1071–1091. [Google Scholar] [CrossRef] [Green Version]
- Katara, G.K.; Kulshrestha, A.; Mao, L.; Wang, X.; Sahoo, M.; Ibrahim, S.; Pamarthy, S.; Suzue, K.; Shekhawat, G.S.; Gilman-Sachs, A.; et al. Mammary epithelium-specific inactivation of V-ATPase reduces stiffness of extracellular matrix and enhances metastasis of breast cancer. Mol. Oncol. 2018, 12, 208–223. [Google Scholar] [CrossRef] [Green Version]
- Liu, X.; Qu, X.; Wu, C.; Zhai, Z.; Tian, B.; Li, H.; Ouyang, Z.; Xu, X.; Wang, W.; Fan, Q.; et al. The effect of enoxacin on osteoclastogenesis and reduction of titanium particle-induced osteolysis via suppression of JNK signaling pathway. Biomaterials 2014, 35, 5721–5730. [Google Scholar] [CrossRef]
- Wu, Q.; Wu, W.; Jacevic, V.; Franca, T.C.C.; Wang, X.; Kuca, K. Selective inhibitors for JNK signalling: A potential targeted therapy in cancer. J. Enzyme Inhib. Med. Chem. 2020, 35, 574–583. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Davies, B.I.; Maesen, F.P.V.; Teengs, J.P. Serum and sputum concentrations of enoxacin after single oral dosing in a clinical and bacteriological study. J. Antimicrob. Chemother. 1984, 14, 83–89. [Google Scholar] [CrossRef] [PubMed]
- WHO’s International Clinical Trials Registry Platform. Available online: https://trialsearch.who.int/ (accessed on 9 June 2022).
- EU Clinical Trials Register. Available online: https://www.clinicaltrialsregister.eu/ctr-search/search?query=enoxacin (accessed on 9 June 2022).
- Clinical Trials. Available online: https://clinicaltrials.gov/ct2/results?cond=&term=enoxacin&cntry=&state=&city=&dist= (accessed on 9 June 2022).
- Foroumadi, A.; Emami, S.; Rajabalian, S.; Badinloo, M.; Mohammadhosseini, N.; Shafiee, A. N-Substituted piperazinyl quinolones as potential cytotoxic agents: Structure-activity relationships study. Biomed. Pharmacother. 2009, 63, 216–220. [Google Scholar] [CrossRef] [PubMed]
- Kodawara, T.; Higashi, T.; Negoro, Y.; Kamitani, Y.; Igarashi, T.; Watanabe, K.; Tsukamoto, H.; Yano, R.; Masada, M.; Iwasaki, H.; et al. The Inhibitory Effect of Ciprofloxacin on the β-Glucuronidase-mediated Deconjugation of the Irinotecan Metabolite SN-38-G. Basic Clin. Pharmacol. Toxicol. 2016, 118, 333–337. [Google Scholar] [CrossRef]
- Itoh, T.; Mitsumori, K.; Kawaguchi, S.; Sasaki, Y.F. Genotoxic potential of quinolone antimicrobials in the in vitro comet assay and micronucleus test. Mutat. Res.—Genet. Toxicol. Environ. Mutagen. 2006, 603, 135–144. [Google Scholar] [CrossRef]
- Fedorowicz, J.; Sączewski, J.; Konopacka, A.; Waleron, K.; Lejnowski, D.; Ciura, K.; Tomašič, T.; Skok, Ž.; Savijoki, K.; Morawska, M.; et al. Synthesis and biological evaluation of hybrid quinolone-based quaternary ammonium antibacterial agents. Eur. J. Med. Chem. 2019, 179, 576–590. [Google Scholar] [CrossRef]
- Sauvaigo, S.; Douki, T.; Odin, F.; Caillat, S.; Ravanat, J.-L.; Cadet, J. Analysis of Fluoroquinolone-mediated Photosensitization of 2′-Deoxyguanosine, Calf Thymus and Cellular DNA: Determination of Type-I, Type-II and Triplet–Triplet Energy Transfer Mechanism Contribution. Photochem. Photobiol. 2001, 73, 230. [Google Scholar] [CrossRef]
- Yamamoto, T.; Tsurumaki, Y.; Takei, M.; Hosaka, M.; Oomori, Y. In vitro method for prediction of the phototoxic potentials of fluoroquinolones. Toxicol. Vitr. 2001, 15, 721–727. [Google Scholar] [CrossRef]
- Ohgari, Y.; Miyata, Y.; Chau, T.T.; Kitajima, S.; Adachi, Y.; Taketani, S. Quinolone compounds enhance δ-aminolevulinic acid-induced accumulation of protoporphyrin IX and photosensitivity of tumour cells. J. Biochem. 2011, 149, 153–160. [Google Scholar] [CrossRef]
- Nishi, K.; Kato, M.; Sakurai, S.; Matsumoto, A.; Iwase, Y.; Yumita, N. Enoxacin with UVA irradiation induces apoptosis in the AsPC1 human pancreatic cancer cell line through ROS generation. Anticancer Res. 2017, 37, 6211–6214. [Google Scholar] [CrossRef]
- Shinada, H.; Watanabe, T.; Okudaira, K.; Iwase, Y.; Nishi, K.; Yumita, N. Apoptosis induced by ultraviolet a exposure in the presence of enoxacin in HL-60 Cells. Anticancer Res. 2019, 39, 687–693. [Google Scholar] [CrossRef] [PubMed]
- Kurita, M.; Shimauchi, T.; Kobayashi, M.; Atarashi, K.; Mori, K.; Tokura, Y. Induction of keratinocyte apoptosis by photosensitizing chemicals plus UVA. J. Dermatol. Sci. 2007, 45, 105–112. [Google Scholar] [CrossRef] [PubMed]
- Ezelarab, H.A.A.; Abbas, S.H.; Hassan, H.A.; Abuo-Rahma, G.E.-D.A. Recent updates of fluoroquinolones as antibacterial agents. Arch. Pharm. 2018, 351, 1800141. [Google Scholar] [CrossRef] [PubMed]
- Andersson, M.I.; MacGowan, A.P. Development of the quinolones. J. Antimicrob. Chemother. 2003, 51, S1–S11. [Google Scholar] [CrossRef]
- Domagala, J.M. Structure-activity and structure-side-effect relationships for the quinolone antibacterials. J. Antimicrob. Chemother. 1994, 33, 685–706. [Google Scholar] [CrossRef]
- Yang, L.; Zhou, J.; Meng, F.; Fu, C.; Zou, X.; Liu, J.; Zhang, C.; Tan, R.; Li, Z.; Guo, Q.; et al. G1 phase cell cycle arrest in NSCLC in response to LZ-106, an analog of enoxacin, is orchestrated through ROS overproduction in a P53-dependent manner. Carcinogenesis 2019, 40, 131–144. [Google Scholar] [CrossRef]
- Toro, E.J.; Zuo, J.; Guiterrez, A.; La Rosa, R.L.; Gawron, A.J.; Bradaschia-Correa, V.; Arana-Chavez, V.; Dolce, C.; Rivera, M.F.; Kesavalu, L.; et al. Bis-enoxacin Inhibits Bone Resorption and Orthodontic Tooth Movement. J. Dent. Res. 2013, 92, 925–931. [Google Scholar] [CrossRef] [Green Version]
- Xu, Q.; Zhan, P.; Li, X.; Mo, F.; Xu, H.; Liu, Y.; Lai, Q.; Zhang, B.; Dai, M.; Liu, X. Bisphosphonate-enoxacin inhibit osteoclast formation and function by abrogating RANKL-induced JNK signalling pathways during osteoporosis treatment. J. Cell. Mol. Med. 2021, 25, 10126–10139. [Google Scholar] [CrossRef]
- Guoqiang, H.; Rui, W.; Xuemeng, W.; Tong, Y.; Na, W.; Ruizhi, S. N-Methyl Enoxacin Aldothiosemicarbazone Derivatives and Methods of Making and Applications Thereof. CN106632324A, 7 September 2018. [Google Scholar]
- Yaling, J.; Yangjie, L.; Shuping, L.; Guoqiang, H.; Huili, Z. N-Methyl Enoxacin Aldehyde-4-aryl Thiosemicarbazide Derivative, and Preparation Method and Application Thereof. CN106674220A, 9 October 2018. [Google Scholar]
- Yansong, W.; Guoqiang, H.; Rui, W.; Qiang, Y.; Shumin, W.; Ni, L. N-Methyl Enoxacin (Rhodanine Unsaturated Ketone) Amide Derivative, Preparation Method and Applications Thereof. CN106317051A, 31 August 2018. [Google Scholar]
- Yongqiang, L.; Zhenyu, S.; Zhi, Z.; Na, W.; Jiaojiao, S.; Bin, L.; Guoqiang, H. 1-(N-Enoxacin Amide)-6-fluoro-7-piperazine-nalidixic Acid Compound as well as Preparation Method and Application Thereof. CN108191890A, 28 June 2019. [Google Scholar]
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Jałbrzykowska, K.; Chrzanowska, A.; Roszkowski, P.; Struga, M. The New Face of a Well-Known Antibiotic: A Review of the Anticancer Activity of Enoxacin and Its Derivatives. Cancers 2022, 14, 3056. https://doi.org/10.3390/cancers14133056
Jałbrzykowska K, Chrzanowska A, Roszkowski P, Struga M. The New Face of a Well-Known Antibiotic: A Review of the Anticancer Activity of Enoxacin and Its Derivatives. Cancers. 2022; 14(13):3056. https://doi.org/10.3390/cancers14133056
Chicago/Turabian StyleJałbrzykowska, Karolina, Alicja Chrzanowska, Piotr Roszkowski, and Marta Struga. 2022. "The New Face of a Well-Known Antibiotic: A Review of the Anticancer Activity of Enoxacin and Its Derivatives" Cancers 14, no. 13: 3056. https://doi.org/10.3390/cancers14133056