NVN1000, a novel nitric oxide-releasing compound, inhibits HPV-18 virus production by interfering with E6 and E7 oncoprotein functions

Banerjee, N. Sanjib; Moore, Dwight; Wang, Hsu-Kun; Broker, Thomas R.; Chow, Louise T.

doi:10.1016/j.antiviral.2019.104559

Cited by 16 publications

(21 citation statements)

References 36 publications

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“…These results are at variance with the induction of γ-H2AX and cleaved caspase-7 in raft cultures of HPV-31 infected human foreskin keratinocytes (HFK) upon extensive passage [24]. In our raft cultures of early passage HPV-18 infected PHK raft cultures, we did not detect cleaved caspase-3, nor elevated levels of γ-H2AX relative to untreated, uninfected or HPV-18 infected raft cultures using IF or prolonged exposure of immunoblots ([12,13,39,44,45] and our unpublished observation).…”

Section: Resultsmentioning

confidence: 98%

Targeting DNA Damage Response as a Strategy to Treat HPV Infections

Banerjee

Moore

Parker

et al. 2019

IJMS

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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 90–99% 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.

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Section: Resultsmentioning

confidence: 98%

Targeting DNA Damage Response as a Strategy to Treat HPV Infections

Banerjee

Moore

Parker

et al. 2019

IJMS

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“…Berdazimer sodium has been topically applied in a three-dimensional epithelial tissue culture model to mechanistically study the impact on the HPV infection cycle. 42 In this study, Banerjee et al applied a 2 mg/mL dose of berdazimer sodium to primary human keratinocyte (PHK) raft cultures that had been previously infected with HPV-18. The treatment period with the NO-releasing compound consisted of 1-hour daily exposure for six consecutive days of treatment.…”

Section: Nitric Oxidementioning

confidence: 99%

Nitric oxide as a topical treatment for cervical intraepithelial neoplasia caused by high-risk human papillomavirus infection

Riccio

Maeda-Chubachi

Messersmith

et al. 2020

MRAJ

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Persistent human papillomavirus (HPV) infection, especially of the high-risk (HR) HPV-16 and HPV-18 types, is linked to anogenital and oropharyngeal cancer. In women, HR-HPV infections of the cervix lead to growth of precancerous cervical intraepithelial neoplasias (CIN) before onset of invasive cervical cancer. Low incidence of widespread, preventive HPV vaccination and the disadvantages of surgical CIN excision (e.g., recurrence rates, pain, and risk of complications in future pregnancies) highlight the need for novel treatments to target HPV infection. Nitric oxide (NO) is a small molecule gaseous species with potent antiviral activity. This review of the preclinical and clinical development of nitric oxide-based topical treatments by Novan, Inc and others supports that NO delivery to the site of infection has the therapeutic potential to manage HPV infection and CIN.

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“…NO inhibits DNA replication in several viruses including, human herpesviridae family, human papillomavirus (HPV), and MC. 1,3 The results of a 12-week phase 2 dose-finding study of SB206 compared to vehicle in children with MC were recently published. 1 A total of 256 nonimmunocompromised children, ≥2 years of age, were randomized to receive vehicle (n = 66), SB206 4% (n = 47), 8% (n = 48), 12% (n = 47) twice daily (BID), or 12% daily (QD) (n = 48) for 12 weeks.…”

mentioning

confidence: 99%

“…It has recently been demonstrated that NO inhibits HPV DNA replication by reducing the activity of E6 and E7 oncoproteins, impairing the S-phase progression and causing DNA damage. 3 This particular effect is of utmost interest as E6 and E7 oncoproteins play a key role in HPV-induced carcinomas. 3…”

mentioning

confidence: 99%