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.
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