Effects of the antifungal agent ciclopirox in HPV‐positive cancer cells: Repression of viral <i>E6/E7</i> oncogene expression and induction of senescence and apoptosis

Braun, Julia A.; Herrmann, Anja L.; Blase, Johanna I; Frensemeier, Kristin; Bulkescher, Julia; Scheffner, Martin; Galy, Bruno; Hoppe‐Seyler, Karin; Hoppe‐Seyler, Felix

doi:10.1002/ijc.32709

Cited by 24 publications

(32 citation statements)

References 53 publications

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“…In both cases, ADPKD cells were more responsive to CPX-O than NHK cells. This is in contrast to a range from 0.5 μM to 10 μM used in various cancer cell lines, such as HPV-positive cancer cells, pancreatic cancer cell lines, and neuroblastoma cell lines ( 21 , 50 , 51 ). Moreover, we used CPX-O at a concentration of 10 mg/kg body weight for 27 days, whereas others have used the range of 20–60 mg/kg to observe therapeutic effects in mouse models of pancreatic cancer and diabetes ( 50 , 52 ).…”

Section: Discussionmentioning

confidence: 77%

Ciclopirox olamine induces ferritinophagy and reduces cyst burden in polycystic kidney disease

Radadiya¹,

Thornton²,

Puri³

et al. 2021

JCI Insight

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Despite the recent launch of Tolvaptan, the search for safer polycystic kidney disease (PKD) drugs continues. Ciclopirox (CPX) or its olamine salt (CPX-O) are contained in number of commercially available antifungal agents. CPX is also reported to possess anticancer activity. Several mechanisms of action have been proposed including chelation of iron and inhibition of iron dependent enzymes. Here, we show that CPX-O inhibited in vitro cystogenesis of primary human PKD cyst-lining epithelial cells cultured in a 3D collagen matrix. To assess in vivo role of CPX-O, we treated PKD mice with CPX-O. CPX-O reduced the kidney-to-body weight ratios of PKD mice. This was also associated with decreased cell proliferation, decreased cystic area and improved renal function. Ferritin levels were significantly elevated in cystic kidneys of PKD mice, and CPX-O treatment reduced renal ferritin levels. The reduction in ferritin was associated with increased ferritinophagy marker, NCOA4 which reversed upon CPX-O treatment in PKD mice. Interestingly, these effects on ferritin appeared independent of iron. These data suggest that CPX-O can induce ferritin degradation via ferritinophagy which is associated with decreased cyst growth progression in PKD mice. Most importantly these data indicate that CPX-O has the potential to treat autosomal dominant PKD.

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Section: Discussionmentioning

confidence: 77%

Ciclopirox olamine induces ferritinophagy and reduces cyst burden in polycystic kidney disease

Radadiya¹,

Thornton²,

Puri³

et al. 2021

JCI Insight

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“…We recently found that the iron chelator ciclopirox olamine (CPX) efficiently blocks HPV E6/E7 oncogene expression, and acts anti-proliferative in cervical cancer cells [ 8 ]. CPX has been used clinically for decades as a topical antifungal agent for the treatment of mycoses of the skin, mucosa and nails, exhibiting an excellent pharmacological safety profile [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

“…CPX has been used clinically for decades as a topical antifungal agent for the treatment of mycoses of the skin, mucosa and nails, exhibiting an excellent pharmacological safety profile [ 9 , 10 ]. Notably, there has been an increasing interest in CPX to be possibly repurposed for cancer therapy [ 11 ], as it exerts anti-tumorigenic activities in a broad range of preclinical tumor models, including colorectal cancer [ 12 , 13 ], pancreatic cancer [ 14 ], breast cancer [ 15 ], cervical cancer [ 8 ], neuroblastoma [ 16 ], and hematologic malignancies [ 17 ]. Recently, clinical trials have been initiated employing a parenterally administrable CPX prodrug in bladder cancer patients [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

“…Mechanistically, CPX targets multiple molecular pathways, which can mostly be attributed to the chelation of intracellular iron. Among others, CPX inhibits the enzymes ribonucleotide reductase [ 17 ] and deoxyhypusine hydroxylase [ 19 ], downregulates the cell cycle regulators cyclin D1 and E [ 15 ], and inhibits mTORC1 signaling [ 8 , 20 ]. Furthermore, potentially adding to their anti-tumorigenic effects, CPX and other iron chelators can inhibit mitochondrial oxidative phosphorylation (OXPHOS), probably due to decreased activity and expression of the iron-containing enzymes comprising the mitochondrial respiratory complexes [ 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

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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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“…A short inhibitory RNA sequence that complementarily binds to the mRNA of HPV onco- and transcription activator-like effector nucleases (TALENs) [ 245 ], micro-RNAs like miR-214 [ 246 ], and iron-chelating drugs [ 247 ] showed a high efficiency in depleting the expression of HPV oncoproteins, thus reverting tumour phenotypes. These molecules require a coupling and delivery system into host cells in order to exert their functions.…”

Section: Treatment Regimensmentioning

confidence: 99%

Current Updates on Cancer-Causing Types of Human Papillomaviruses (HPVs) in East, Southeast, and South Asia

Xia

Long

et al. 2021

Cancers

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Human papillomavirus (HPV) infection remains one of the most prominent cancer-causing DNA viruses, contributing to approximately 5% of human cancers. While association between HPV and cervical cancers has been well-established, evidence on the attribution of head and neck cancers (HNC) to HPV have been increasing in recent years. Among the cancer-causing HPV genotypes, HPV16 and 18 remain the major contributors to cancers across the globe. Nonetheless, the distribution of HPV genotypes in ethnically, geographically, and socio-economically diverse East, Southeast, and South Asia may differ from other parts of the world. In this review, we garner and provide updated insight into various aspects of HPV reported in recent years (2015–2021) in these regions. We included: (i) the HPV genotypes detected in normal cancers of the uterine cervix and head and neck, as well as the distribution of the HPV genotypes by geography and age groups; (ii) the laboratory diagnostic methods and treatment regimens used within these regions; and (iii) the oncogenic properties of HPV prototypes and their variants contributing to carcinogenesis. More importantly, we also unveil the similarities and discrepancies between these aspects, the areas lacking study, and the challenges faced in HPV studies.

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Effects of the antifungal agent ciclopirox in HPV‐positive cancer cells: Repression of viral E6/E7 oncogene expression and induction of senescence and apoptosis

Cited by 24 publications

References 53 publications

Ciclopirox olamine induces ferritinophagy and reduces cyst burden in polycystic kidney disease

Ciclopirox olamine induces ferritinophagy and reduces cyst burden in polycystic kidney disease

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

Current Updates on Cancer-Causing Types of Human Papillomaviruses (HPVs) in East, Southeast, and South Asia

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