Ciclopirox activates ATR-Chk1 signaling pathway leading to Cdc25A protein degradation

Shen, Tao; Zhou, Hongyu; Shang, Chaowei; Luo, Yan; Wu, Yang; Huang, Shile

doi:10.18632/genesandcancer.166

Cited by 13 publications

(5 citation statements)

References 67 publications

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“…Total p53 levels are reduced by CPX under 1 g/L, but not under 4.5 g/L glucose. In contrast, phosphorylated p53 (Ser15) and RPA32 (Ser33), two markers indicating DNA damage [ 39 , 40 ], are upregulated under both 1 g/L and 4.5 g/L glucose, in line with findings that CPX possesses genotoxic potential [ 41 ]. Interestingly, p21, which is regarded as a key factor for senescence induction [ 7 ], is repressed after 48 h treatment under 1 g/L glucose, while increased glucose levels (4.5 g/L) counteract this downregulation ( Figure 3 C).…”

Section: Resultsmentioning

confidence: 55%

Delineating the Switch between Senescence and Apoptosis in Cervical Cancer Cells under Ciclopirox Treatment

Herrmann

Kuhn

Holzer

et al. 2021

Cancers

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The iron-chelating drug ciclopirox (CPX) may possess therapeutic potential for cancer treatment, including cervical cancer. As is observed for other chemotherapeutic drugs, CPX can induce senescence or apoptosis in cervical cancer cells which could differently affect their therapy response. The present study aims to gain insights into the determinants which govern the switch between senescence and apoptosis in cervical cancer cells. We performed proteome analyses, proliferation studies by live-cell imaging and colony formation assays, senescence and apoptosis assays, and combination treatments of CPX with inhibitors of oxidative phosphorylation (OXPHOS) or glycolysis. We found that CPX downregulates OXPHOS factors and facilitates the induction of apoptosis under limited glucose availability, an effect which is shared by classical OXPHOS inhibitors. Under increased glucose availability, however, CPX-induced apoptosis is prevented and senescence is induced, an activity which is not exerted by classical OXPHOS inhibitors, but by other iron chelators. Moreover, we show that the combination of CPX with glycolysis inhibitors blocks cervical cancer proliferation in a synergistic manner. Collectively, our results reveal that the phenotypic response of cervical cancer cells towards CPX is strongly dependent on glucose availability, link the pro-apoptotic and pro-senescent activities of CPX to its bifunctionality as an OXPHOS inhibitor and iron chelator, respectively, and provide a rationale for combining CPX with glycolysis inhibitors.

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Section: Resultsmentioning

confidence: 55%

Delineating the Switch between Senescence and Apoptosis in Cervical Cancer Cells under Ciclopirox Treatment

Herrmann

Kuhn

Holzer

et al. 2021

Cancers

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“…For example, CPX anticancer activities are dependent, in part, on its iron-chelating activity. Furthermore, CPX caused DNA damage which is related to iron chelation (30). Indeed, CPX reportedly inhibited ribonucleotide reductase which is essential for DNA synthesis, via iron chelation mechanisms (11).…”

Section: Discussionmentioning

confidence: 99%

“…CPX also showed antitumor activities against several cancers, including inhibition of breast cancer by mediating apoptosis through a caspase-dependent pathway (22,23), driving colorectal cancer cell death by activating PERK-dependent endoplasmic reticulum stress and targeting DJ-1 (24)(25)(26), having a therapeutic role in head and neck squamous cell carcinoma as an iron chelator (27), targeting histone demethylases in MYC-driven neuroblastomas (28), inhibiting mTORC1 signaling by activation of AMPK and activating ATR-Chk1 signaling pathway leading to Cdc25A protein degradation in rhabdomyosarcoma (29,30). Recently, a study comparing tumor-related signaling pathways with known compounds reported that CPX had potential roles in LUAD treatment (31).…”

Section: Introductionmentioning

confidence: 99%

Ciclopirox Olamine Exerts Tumor-Suppressor Effects via Topoisomerase II Alpha in Lung Adenocarcinoma

et al. 2022

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BackgroundGlobally, lung cancer is one of the most malignant tumors, of which lung adenocarcinoma (LUAD) is the most common subtype, with a particularly poor prognosis. Ciclopirox olamine (CPX) is an antifungal drug and was recently identified as a potential antitumor agent. However, how CPX and its mechanism of action function during LUAD remain unclear.MethodsThe effects of CPX on cell proliferation, cell cycle, reactive oxygen species (ROS) levels, and apoptosis were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, colony formation, western blotting, flow cytometry assays, and immunohistochemistry. Global gene expression levels were compared between control and CPX-treated LUAD cells. A LUAD xenograft mouse model was used to evaluate the potential in vivo effects of CPX.ResultsWe observed that CPX displayed strong antitumorigenic properties in LUAD cells, inhibited LUAD proliferation, induced ROS production, caused DNA damage, and activated the ATR-CHK1-P53 pathway. Topoisomerase II alpha (TOP2A) is overexpressed in LUAD and associated with a poor prognosis. By analyzing differentially expressed genes (DEGs), TOP2A was significantly down-regulated in CPX-treated LUAD cells. Furthermore, CPX treatment substantially inhibited in vivo LUAD xenograft growth without toxicity or side effects to the hematological system and internal organs.ConclusionsCollectively, for the first time, we showed that CPX exerted tumor-suppressor effects in LUAD via TOP2A, suggesting CPX could potentially function as a promising chemotherapeutic for LUAD treatment.

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“…In solid tumor cells, CHK1 has been reported to be involved in controlling cell cycle progression by inducing CDC25 degradation. 35 , 36 Furthermore, inhibition of CHK1 activity in Ewing sarcoma cells has been reported to result in DNA damage and apoptosis by promoting CDK2-mediated degradation of RRM2. 37 The activation of CHK1 also is also a step in the development of resistance in several solid tumors against irradiation and chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

GDC-0575, a CHK1 Inhibitor, Impairs the Development of Colitis and Colitis-Associated Cancer by Inhibiting CCR2+ Macrophage Infiltration in Mice

Li¹,

Huang²,

Li³

et al. 2021

OTT

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Background Checkpoint kinase 1 (CHK1) plays an important role in DNA damage response and cell cycle progression. Thus, targeting CHK1 is an efficient strategy for cancer therapy. Purpose The present study aimed to investigate the potential therapeutic effects of GDC-0575, a CHK1-specific inhibitor, in colitis-associated cancer (CAC) and colitis. Methods We established a DSS-induced acute colitis model and an azoxymethane/dextran sodium sulfate (DSS)-induced CAC model using mice and tested the effect of GDC-0575 on them. Flow cytometry and immunofluorescence were employed to investigate the infiltration of immune cells, and inflammatory cytokine expression in the colon of mice with CAC or colitis was investigated using ELISA and qPCR. We also investigated the correlation between CHK1 and CCL2/CCR2 in human colorectal cancer (CRC) tissues. Results Administration of GDC-0575 significantly inhibited CHK1 expression in the colon and dramatically impaired the development of CAC and colitis in mice. Moreover, the inhibition of CHK1 expression resulted in efficient inhibition of infiltration by iNOS-positive macrophages, but had no significant effect on CD4 T cells, CD8 T cells, and myeloid-derived suppressor cells (MDSCs). Significant downregulation of TNF-α, IL-6, and IL-1β and dramatic upregulation of IL-10 were observed in the colons of both mice with CAC and colitis treated with GDC-0575. CCL2 expression was also downregulated by GDC-0575 in both mice with CAC and colitis; this was followed by the inhibition of CCR2 + macrophage infiltration in the colon. Furthermore, we report a positive correlation between CHK1 expression and CCL2/CCR2 expression in the malignant tissues of patients with CRC. Conclusion Taken together, we infer that GDC-0575 impairs the development of CAC and colitis by regulating cytokine expression and inhibiting CCR2 + macrophage infiltration in mice colon.

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Ciclopirox activates ATR-Chk1 signaling pathway leading to Cdc25A protein degradation

Cited by 13 publications

References 67 publications

Delineating the Switch between Senescence and Apoptosis in Cervical Cancer Cells under Ciclopirox Treatment

Delineating the Switch between Senescence and Apoptosis in Cervical Cancer Cells under Ciclopirox Treatment

Ciclopirox Olamine Exerts Tumor-Suppressor Effects via Topoisomerase II Alpha in Lung Adenocarcinoma

GDC-0575, a CHK1 Inhibitor, Impairs the Development of Colitis and Colitis-Associated Cancer by Inhibiting CCR2+ Macrophage Infiltration in Mice

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