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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
Author(s) -
Braun Julia A.,
Herrmann Anja L.,
Blase Johanna I.,
Frensemeier Kristin,
Bulkescher Julia,
Scheffner Martin,
Galy Bruno,
HoppeSeyler Karin,
HoppeSeyler Felix
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32709
Subject(s) - senescence , oncogene , apoptosis , cancer research , cancer , biology , cancer cell , pi3k/akt/mtor pathway , cell cycle , microbiology and biotechnology , genetics
The malignant growth of human papillomavirus (HPV)‐positive cancer cells is dependent on the continuous expression of the viral E6/E7 oncogenes. Here, we examined the effects of iron deprivation on the phenotype of HPV‐positive cervical cancer cells. We found that iron chelators, such as the topical antifungal agent ciclopirox (CPX), strongly repress HPV E6/E7 oncogene expression, both at the transcript and protein level. CPX efficiently blocks the proliferation of HPV‐positive cancer cells by inducing cellular senescence. Although active mTOR signaling is considered to be critical for the cellular senescence response towards a variety of prosenescent agents, CPX‐induced senescence occurs under conditions of severely impaired mTOR signaling. Prolonged CPX treatment leads to p53‐independent Caspase‐3/7 activation and induction of apoptosis. CPX also eliminates HPV‐positive cancer cells under hypoxic conditions through induction of apoptosis. Taken together, these results show that iron deprivation exerts profound antiviral and antiproliferative effects in HPV‐positive cancer cells and suggest that iron chelators, such as CPX, possess therapeutic potential as HPV‐inhibitory, prosenescent and proapoptotic agents in both normoxic and hypoxic environments.