Targeting DNA Damage Response as a Strategy to Treat HPV Infections

Autor: N. Sanjib Banerjee, Dianne W. Moore, Louise T. Chow, Thomas R. Broker, Cameron J. Parker
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Keratinocytes
Male
cervical cancer
Cellular differentiation
Papillomavirus E7 Proteins
Uterine Cervical Neoplasms
Virus Replication
lcsh:Chemistry
0302 clinical medicine
lcsh:QH301-705.5
Spectroscopy
Cells
Cultured
Cervical cancer
Cell Death
Human papillomavirus 18
MK-8776
HPV infection
General Medicine
3. Good health
Computer Science Applications
030220 oncology & carcinogenesis
Chk1 inhibitor
Female
medicine.drug
Programmed cell death
Combination therapy
DNA damage
Antineoplastic Agents
raft culture
DDR
Catalysis
Article
Inorganic Chemistry
03 medical and health sciences
Cell Line
Tumor
medicine
Humans
Physical and Theoretical Chemistry
Molecular Biology
Protein Kinase Inhibitors
Cisplatin
business.industry
Organic Chemistry
Papillomavirus Infections
medicine.disease
HPV productive infection
030104 developmental biology
Pyrimidines
lcsh:Biology (General)
lcsh:QD1-999
Apoptosis
DNA
Viral
Cancer research
Pyrazoles
business
HeLa Cells
Zdroj: International Journal of Molecular Sciences
Volume 20
Issue 21
International Journal of Molecular Sciences, Vol 20, Iss 21, p 5455 (2019)
ISSN: 1422-0067
Popis: Mucosotropic human papillomaviruses (HPVs) cause prevalent anogenital infections, some of which can progress to cancers. It is imperative to identify efficacious drug candidates, as there are few therapeutic options. We have recapitulated a robust productive program of HPV-18 in organotypic raft cultures of primary human keratinocytes. The HPV E7 protein induces S phase reentry, along with DNA damage response (DDR) in differentiated cells to support viral DNA amplification. A number of small molecule inhibitors of DDR regulators are in clinical use or clinical trials to treat cancers. Here, we used our raft culture system to examine effects of inhibitors of ATR/Chk1 and ATM/Chk2 on HPV infection. The inhibitors impaired S-phase reentry and progression as well as HPV DNA amplification. The Chk1 inhibitor MK-8776 was most effective, reducing viral DNA amplification by 90&ndash
99% and caused DNA damage and apoptosis, preferentially in HPV infected cells. We found that this sensitivity was imparted by the E7 protein and report that MK-8776 also caused extensive cell death of cervical cancer cell lines. Furthermore, it sensitized the cells to cisplatin, commonly used to treat advanced cervical cancer. Based on these observations, the Chk1 inhibitors could be potential effective agents to be re-purposed to treat the spectrum of HPV infections in single or combination therapy.
Databáze: OpenAIRE
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