Dental News - Cancer drug may help treat human papillomavirus infections, study finds

Dental Tribune International

Mon. 10. December 2018

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BIRMINGHAM, Ala, U.S.: Known to cause several cancers, human papillomaviruses (HPV) are contracted by around 12,000 people—aged between 15 and 24—each day, according to The Oral Cancer Foundation. In a new study based on preclinical experiments at the University of Alabama at Birmingham (UAB), researchers suggest that cancer drugs vorinostat, belinostat and panobinostat could be repurposed to treat infections caused by HPV.

“Safe, effective and inexpensive therapeutic agents are urgently needed,” said Prof. Sanjib Banerjee, assistant professor of Biochemistry and Molecular Genetics at UAB and lead author of the study.

Since HPVs cannot be propagated in conventional cell culture, the investigation into their pathogenic effects has been hampered. Prof. Louise Chow and Prof. Thomas Broker from the Department of Biochemistry and Molecular Genetics have investigated HPV-host interactions for decades. They have discovered that the productive program of HPVs depends on the differentiation of the epithelium into a full thickness, squamous epithelium. Additionally, HPV reactivates host DNA replication in these differentiated cells in such a way that the replication proteins and substrates become available to support viral DNA amplification.

Reproducing a fully differentiated human squamous epithelium by culturing primary human keratinocytes at an air-media interphase for two to three weeks, Chow and Broker named the growth a raft culture. In 2009, their lab developed a breakthrough model for a raft culture of HPV-18-infected primary human keratinocytes, allowing the robust amplification of HPV-18 DNA and the production of infective viral progeny. According to the researchers, this productive raft culture established an ideal model for preclinical investigations of potential anti-HPV agents.

With this in mind, Banerjee and his colleagues hypothesized that inhibitors of histone deacetylases (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, therefore it might not only interrupt chromosomal replication, but also viral DNA replication.

Using the HPV-18 model raft cultures, researchers found that vorinostat effectively inhibited HPV-18 DNA amplification and virus production. Importantly, vorinostat also induced programmed cell death—called apoptosis—in a fraction of the differentiated cells. The death could be attributable to the 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 UAB team also reported that vorinostat caused extensive cell death in raft cultures of dysplastic and cancer cell lines harboring HPV-16.

“On the basis of these detailed studies, we suggest that HDAC inhibitors are promising compounds for treating benign HPV infections, abrogating progeny production and hence interrupting infectious transmission,” said Banerjee. However, Banerjee also went on to say that further investigation would be required to verify that these agents could also be useful in treating HPV-associated dysplasia and cancers.

The study, titled “Vorinostat, a pan-HDAC inhibitor, abrogates productive HPV-18 DNA amplification” was published on 1 November in the Proceedings of the National Academy of Sciences of the United States of America.

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