Nitroxoline: repurposing its antimicrobial to antitumor application

Abstract

Cancer is a disease receiving an outstanding input of funds for basic and clinical research but is, nevertheless, still the second leading cause of death in the developed world and a great burden for health systems. New drugs are therefore needed to improve therapy, prolong survival of cancer patients and improve their quality of life. The high cost of development and clinical evaluation of new drugs limits the number that actually enter clinical use. To overcome this problem, repurposing of established drugs for new indications has gained a lot of interest, especially in the field of oncology. The well-established antimicrobial agent nitroxoline has been identified as a promising candidate to be repurposed for cancer treatment in several independent studies. Here we have reviewed a wide range of molecular mechanisms and tumor models involving nitroxoline in impairment of tumor progression. Furthermore, nitroxoline was used as a lead compound for structure-based chemical synthesis of new derivatives in order to improve its potency as well as selectivity for various targets. The potent antitumor activity of nitroxoline points strongly in the direction of its repurposing for cancer treatment and to the benefits of this strategy for patients and healthcare system.

In Vitro Selective Growth-Inhibitory Activities of Phytochemicals, Synthetic Phytochemical Analogs, and Antibiotics against Diarrheagenic/Probiotic Bacteria and Cancer/Normal Intestinal Cells

“…Amongst them, the anticancer effect has generally been reported for quinoline alkaloids [ 18 ]. In addition to those earlier mentioned, benzylisoquinoline alkaloid sanguinarine ( Sanguinaria canadensis ) [ 7 , 19 ], and 8-hydroxyquinoline derivatives ferron [ 20 ] and nitroxoline [ 21 ] are examples of antimicrobial drugs with potent anticancer activity. Another type of synthetic phytochemical analog with reported antimicrobial and anticancer properties is metal-pyridine derivative complex zinc pyrithione (pyrithione found in Polyalthia nemoralis ) [ 7 , 22 ].…”

Evaluation of novel cathepsin-X inhibitors in vitro and in vivo and their ability to improve cathepsin-B-directed antitumor therapy

“…For CatB inhibition, we used nitroxoline, a well-established antimicrobial agent, which we have identified as a potent, selective, reversible inhibitor of CatB endopeptidase activity with strong antitumor activity in vitro and in vivo [36,44]. Antitumor activity of nitroxoline was independently demonstrated by multiple other studies, where especially its antiangiogenic properties by inhibiting type 2 methionine aminopeptidase and sirtuin-1 [45] were highlighted, together with its ability to induce apoptosis and cell-cycle arrest (reviewed in [46]). Similarly to the action of the single inhibitors nitroxoline and Z9, the combined use of nitroxoline and Z9 significantly affected tumor cell migration, invasion, and adhesion in all the assays tested.…”

Chelation in Antibacterial Drugs: From Nitroxoline to Cefiderocol and Beyond

“…Its use dates back to the beginning of the 20th century [ 82 , 83 ], but is currently becoming an option for the treatment of infections caused by multidrug-resistant uropathogens, primarily due to an increase of the bacterial resistance to more commonly used antibacterials and its unique MOA [ 10 , 13 , 20 ]. Out of all classes of antibacterials, 8-HQ derivatives are the only ones currently in use whose antibacterial actions, and bioactivity in general, rest almost exclusively on their chelation properties [ 31 , 35 , 79 , 82 , 84 ]. Chelation is also responsible for NIT’s unique ability to inhibit the formation of bacterial biofilm (i.e., biofilm activity) [ 12 , 18 ], as explained in the following paragraph.…”