Washington: Scientists — including one of Indian origin — have identified cancer drugs that may be repurposed to treat infections caused by human papillomaviruses (HPV). HPV infections caused an estimated 266,000 deaths from cervical cancer worldwide in 2012, according to the World Health Organization (WHO). Highly efficacious vaccines against HPV infection exist, including the recently approved Gardasil 9, which immunises against nine genotypes of HPV known to cause cervical, vulvar, vaginal and anal cancers, and genital warts.
However, the vaccine needs to be given before a person becomes sexually active, since it has no therapeutic efficacy against existing HPV infections. "Safe, effective and inexpensive therapeutic agents are urgently needed," said Sanjib Banerjee, assistant professor at University of Alabama at Birmingham in the US. Epithelium of anogenital sites — the cervix, penis and anus — or epithelium of the mouth and throat are sites of HPV infection.
However, HPVs cannot be propagated in conventional cell culture, hampering the investigation into their pathogenic effects. Researchers discovered that the productive programme of HPV depends on differentiation of the epithelium into a full-thickness, squamous epithelium. Furthermore, HPV reactivates host DNA replication in these differentiated cells, such that the replication proteins and substrates become available to support viral DNA amplification.
Researchers re-produced a fully differentiated human squamous epithelium by culturing primary human keratinocytes at an air-media interphase for two to three weeks, a growth they call raft culture. In 2009, their lab developed a breakthrough model for a raft culture of HPV-18-infected primary human keratinocytes, allowing a robust amplification of HPV-18 DNA and production of infective viral progeny.
This productive raft culture is an ideal model for preclinical investigation of potential anti-HPV agents. Researchers hypothesised that inhibitors of histone deacetylases, or HDACs, would inhibit HPV DNA amplification because of their known mechanism of disrupting chromosomal DNA replication. Chromosomal replication requires HDAC alterations of histone proteins, the proteins that act like spools that wind DNA to help package and condense chromosomes and the viral genome.
Vorinostat inhibits many HDACs, so it might interrupt not only chromosomal replication but also viral DNA replication. Using the HPV-18 model raft cultures, the researchers found that vorinostat effectively inhibited HPV-18 DNA amplification and virus production. Importantly, vorinostat also induced the programmed cell death called apoptosis in a fraction of the differentiated cells.
Cell death could be attributable to DNA breakage when chromosomal DNA replication was interrupted. Similar results were obtained with two additional HDAC inhibitors, belinostat and panobinostat. In contrast, the differentiated cells of uninfected raft cultures, which do not replicate their DNA, were thus largely spared in the presence of the inhibitors. The team also examined how vorinostat affected levels and functions of viral oncoproteins, and they described the mechanisms that led to programmed cell death in HPV-18-infected cultures.
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Updated Date: Dec 02, 2018 21:44:30 IST