An overview of early investigational drugs for the treatment of human papilloma virus infection and associated dysplasia

Hampson, Lynne; Martin-Hirsch, P; Hampson, Ian N.

doi:10.1517/13543784.2015.1099628

Cited by 26 publications

(19 citation statements)

References 70 publications

(61 reference statements)

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“…Currently, there is no cure to this disease, especially to high-risk patients infected by high-risk human be considered ideal, simply due to the adverse reproductive consequences and the presence papillomaviruses (HPVs) such as HPV16 and HPV18. Standard treatments such as ablation and cervical conization are the common strategies for early cervical cancer therapy, but are not recommended for high-risk HPV-infected patients [32]. In addition, most of the cervical cancer patients also receive radiotherapy and chemotherapy either solely or in combination.…”

Section: Discussionmentioning

confidence: 99%

Interferon α Induces the Apoptosis of Cervical Cancer HeLa Cells by Activating both the Intrinsic Mitochondrial Pathway and Endoplasmic Reticulum Stress-Induced Pathway

Shi

Cao

Liu

2016

IJMS

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The interferon α (IFN-α) has been often used as a sensitizing agent for the treatment of various malignancies such as hepatocellular carcinoma, malignant melanoma, and renal cell cancer by promoting the apoptosis of thesetumor cell types. However, the effect of IFN-α on cervical cancer remains unknown. In this study, HeLa cells were used as a testing model for the treatment of IFN-α on cervical cancer. The results indicate that IFN-α markedly inhibits the proliferation and induces the apoptosis of HeLa cells. The activation of caspase 3, the up-regulation of both Bim and cleaved poly (ADP-ribose) polymerase (PARP) 1, the down-regulation of Bcl-xL, as well as the release of cytochrome c from mitochondria were significantly induced upon IFN-α treatment, indicating that the intrinsic apoptotic pathway could be activated by IFN-α treatment. In addition, caspase 4—which is involved in the endoplasmic reticulum (ER) stress-induced apoptosis—was activated in response to IFN-α treatment. Knocking down caspase 4 by small interfering RNA (siRNA) markedly reduced the IFN-α-mediated cell apoptosis. However, no significant changes in the expressions of caspases 8 and 10 were observed upon IFN-α treatment, indicating that the apoptosis caused by IFN-α might be independent of the extrinsic apoptotic pathway. These findings suggest that IFN-α may possess anti-cervical cancer capacity by activating cell apoptosis via the intrinsic mitochondrial pathway and caspase-4-related ER stress-induced pathway.

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Section: Discussionmentioning

confidence: 99%

Interferon α Induces the Apoptosis of Cervical Cancer HeLa Cells by Activating both the Intrinsic Mitochondrial Pathway and Endoplasmic Reticulum Stress-Induced Pathway

Shi

Cao

Liu

2016

IJMS

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“…Nowadays prophylactic vaccines, Cervarix [3] and Gardasil [4], have been approved and effectively applied for the prevention of HPV infection. However, for people already infected, current therapies consist of the use of chemotherapeutic agents or the application of surgical and ablative techniques to eliminate developed tumors [5]. These treatments are invasive, non-specific, and tend to be expensive, difficulting their availability to millions of patients, particularly in developing countries.…”

Section: Introductionmentioning

confidence: 99%

Molecular modeling simulation studies reveal new potential inhibitors against HPV E6 protein

Ricci-Lopez¹,

Vidal-Limón²,

Zunñiga

et al. 2019

PLoS ONE

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High-risk strains of human papillomavirus (HPV) have been identified as the etiologic agent of some anogenital tract, head, and neck cancers. Although prophylactic HPV vaccines have been approved; it is still necessary a drug-based treatment against the infection and its oncogenic effects. The E6 oncoprotein is one of the most studied therapeutic targets of HPV, it has been identified as a key factor in cell immortalization and tumor progression in HPV-positive cells. E6 can promote the degradation of p53, a tumor suppressor protein, through the interaction with the cellular ubiquitin ligase E6AP. Therefore, preventing the formation of the E6-E6AP complex is one of the main strategies to inhibit the viability and proliferation of infected cells. Herein, we propose an in silico pipeline to identify small-molecule inhibitors of the E6-E6AP interaction. Virtual screening was carried out by predicting the ADME properties of the molecules and performing ensemble-based docking simulations to E6 protein followed by binding free energy estimation through MM/PB(GB)SA methods. Finally, the top-three compounds were selected, and their stability in the E6 docked complex and their effect in the inhibition of the E6-E6AP interaction was corroborated by molecular dynamics simulation. Therefore, this pipeline and the identified molecules represent a new starting point in the development of anti-HPV drugs.

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“…Although CDV has proven efficacious in the therapy of HPV-associated diseases, it has some limitations, the nephrotoxicity being the most encountered side-effect. Recent publications revealed some promising compounds such as the HIV-protease inhibitors lopinavir and nelfinavir, but further characterizations of their anti-HPV activity are needed [ 46 ]. Also, inhibition of cellular pathways frequently altered in HPV-induced neoplasia, such as phosphatidylinositol-3-kinase signaling represent a suitable target for therapeutic intervention [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Resistance to the nucleotide analogue cidofovir in HPV(+) cells: a multifactorial process involving UMP/CMP kinase 1

et al. 2016

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Human papillomavirus (HPV) is responsible for cervical cancer, and its role in head and neck carcinoma has been reported. No drug is approved for the treatment of HPV-related diseases but cidofovir (CDV) exhibits selective antiproliferative activity.In this study, we analyzed the effects of CDV-resistance (CDVR) in two HPV(+) (SiHaCDV and HeLaCDV) and one HPV(−) (HaCaTCDV) tumor cell lines. Quantification of CDV metabolites and analysis of the sensitivity profile to chemotherapeutics was performed. Transporters expression related to multidrug-resistance (MRP2, P-gp, BCRP) was also investigated.Alterations of CDV metabolism in SiHaCDV and HeLaCDV, but not in HaCaTCDV, emerged via impairment of UMP/CMPK1 activity. Mutations (P64T and R134M) as well as down-regulation of UMP/CMPK1 expression were observed in SiHaCDV and HeLaCDV, respectively. Altered transporters expression in SiHaCDV and/or HeLaCDV, but not in HaCaTCDV, was also noted.Taken together, these results indicate that CDVR in HPV(+) tumor cells is a multifactorial process.

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An overview of early investigational drugs for the treatment of human papilloma virus infection and associated dysplasia

Cited by 26 publications

References 70 publications

Interferon α Induces the Apoptosis of Cervical Cancer HeLa Cells by Activating both the Intrinsic Mitochondrial Pathway and Endoplasmic Reticulum Stress-Induced Pathway

Interferon α Induces the Apoptosis of Cervical Cancer HeLa Cells by Activating both the Intrinsic Mitochondrial Pathway and Endoplasmic Reticulum Stress-Induced Pathway

Molecular modeling simulation studies reveal new potential inhibitors against HPV E6 protein

Resistance to the nucleotide analogue cidofovir in HPV(+) cells: a multifactorial process involving UMP/CMP kinase 1

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