Repurposing of nitroxoline as a potential anticancer agent against human prostate cancer - a crucial role on AMPK/mTOR signaling pathway and the interplay with Chk2 activation

Abstract

Nitroxoline is an antibiotic by chelating Zn2+ and Fe2+ from biofilm matrix. In this study, nitroxoline induced G1 arrest of cell cycle and subsequent apoptosis in prostate cancer cells through ion chelating-independent pathway. It decreased protein levels of cyclin D1, Cdc25A and phosphorylated Rb, but activated AMP-activated protein kinase (AMPK), a cellular energy sensor and signal transducer, leading to inhibition of downstream mTOR-p70S6K signaling. Knockdown of AMPKα significantly rescued nitroxoline-induced inhibition of cyclin D1-Rb-Cdc25A axis indicating AMPK-dependent mechanism. However, cytoprotective autophagy was simultaneously evoked by nitroxoline. Comet assay and Western blot analysis demonstrated DNA damaging effect and activation of Chk2 other than Chk1 to nitroxoline action. Instead of serving as a DNA repair transducer, nitroxoline-mediated Chk2 activation was identified to function as a pro-apoptotic inducer. In conclusion, the data suggest that nitroxoline induces anticancer activity through AMPK-dependent inhibition of mTOR-p70S6K signaling pathway and cyclin D1-Rb-Cdc25A axis, leading to G1 arrest of cell cycle and apoptosis. AMPK-dependent activation of Chk2, at least partly, contributes to apoptosis. The data suggest the potential role of nitroxoline for therapeutic development against prostate cancers.

Retracted: Bilobalide alleviates tumor necrosis factor‐alpha‐induced pancreatic beta‐cell MIN6 apoptosis and dysfunction through upregulation of miR‐153

“…AMPK/mTOR pathway is known as a common signaling pathway associated with tumors (An et al, ; C. Cao et al, ). It mainly takes part in the progression of proliferation and autophagy (An et al, ; Chang, Hsu, Leu, Chen, & Guh, ; H. Tang et al, ). AMPK/mTOR pathway had been reported to suppress progression in breast cancer (Ren, Ren, Cheng, & Xu, ) and participated in promoting autophagy in B251 cells (Wang, Zhang, Luo, Ning, & Fang, ).…”

Integrative proteomic and functional analyses provide novel insights into the action of the repurposed drug candidate nitroxoline in AsPC-1 cells

“…In that study, nitroxoline was found to affect viability, to drastically reduce clonogenic activity, to hamper cell cycle and to promote apoptosis in pancreatic cancer cell lines, both as a single agent and in combinations with other drugs 7 . In addition to pancreatic cancer, this drug affects viability and growth of cell lines representative of other tumors, including neuroblastoma, glioma, myeloma, prostate, lung, kidney and bladder cancers [8][9][10][11][12][13][14][15][16][17][18][19] . Remarkably, this antibiotic is also effective in several cancer xenograft and genetically engineered mice models [8][9][10]12,14,15,18 .…”

“…Nitroxoline is an antibiotic widely used in several countries from 1960s and is able to chelate divalent metal ions such as Mg 2+ and Mn 2+ , an activity which is considered as a possible mechanism for its antibacterial action 3 . To analyze mechanisms by which this antibacterial exerts its anticancer activity, several studies screened for specific candidate targets and molecular pathways known to play an important role in cancer biology [7][8][9][10][11][12][13][14][15][16][17][18][19] . Using this approach, disparate targets have been proposed to be responsible for nitroxoline anticancer effects.…”

Nitroxoline: repurposing its antimicrobial to antitumor application

“…The effect of nitroxoline on cell-cycle arrest and apoptosis was also confirmed in prostate cancer cells (Chang et al, 2015). Nitroxoline induced G1 cell-cycle arrest on both hormone-sensitive and hormone-refractory prostate cancers.…”

“…It is crucial for cell proliferation, growth, survival and metabolism, and effects G1 cell-cycle arrest via the cyclin D1-Rb-Cdc25A axis. Moreover, nitroxoline contributes to cell apoptosis by inducing AMPK dependent activation of Chk2 that encodes a serine/threonine kinase that coordinates cell responses to DNA damage (Chang et al, 2015). On the other hand, through the AMPK pathway, nitroxoline also induces autophagy, resulting in a decreased effect on apoptosis (Chang et al, 2015).…”