scholarly journals Targeting Human Papillomavirus-Associated Cancer by Oncoprotein-Specific Recombinant Antibodies

2021 ◽  
Vol 22 (17) ◽  
pp. 9143
Author(s):  
Maria Gabriella Donà ◽  
Paola Di Bonito ◽  
Maria Vincenza Chiantore ◽  
Carla Amici ◽  
Luisa Accardi
Keyword(s):  
Biological Activities ◽  
Dominant Role ◽  
Critical Issue ◽  
Recombinant Antibodies ◽  
Human Papillomaviruses ◽  
Great Promise ◽  
Hpv16 E6 ◽  
Regulatory Pathways ◽  
Associated Lesions ◽  
Hpv Oncoproteins

In recent decades, recombinant antibodies against specific antigens have shown great promise for the therapy of infectious diseases and cancer. Human papillomaviruses (HPVs) are involved in the development of around 5% of all human cancers and HPV16 is the high-risk genotype with the highest prevalence worldwide, playing a dominant role in all HPV-associated cancers. Here, we describe the main biological activities of the HPV16 E6, E7, and E5 oncoproteins, which are involved in the subversion of important regulatory pathways directly associated with all known hallmarks of cancer. We then review the state of art of the recombinant antibodies targeted to HPV oncoproteins developed so far in different formats, and outline their mechanisms of action. We describe the advantages of a possible antibody-based therapy against the HPV-associated lesions and discuss the critical issue of delivery to tumour cells, which must be addressed in order to achieve the desired translation of the antibodies from the laboratory to the clinic.

scholarly journals Intrabodies targeting human papillomavirus 16 E6 and E7 oncoproteins for therapy of established HPV-associated tumors

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Francesca Paolini ◽  
Carla Amici ◽  
Mariantonia Carosi ◽  
Claudia Bonomo ◽  
Paola Di Bonito ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Antitumor Activity ◽  
Tumor Growth ◽  
Tumor Progression ◽  
Cellular Transformation ◽  
Neoplastic Progression ◽  
Single Chain ◽  
Hpv16 E6 ◽  
Associated Lesions ◽  
E6 And E7

Abstract Background The oncogenic activity of the high risk human papillomavirus type 16 (HPV16) is fully dependent on the E6 and E7 viral oncoproteins produced during viral infection. The oncoproteins interfere with cellular homeostasis by promoting proliferation, inhibiting apoptosis and blocking epithelial differentiation, driving the infected cells towards neoplastic progression. The causal relationship between expression of E6/E7 and cellular transformation allows inhibiting the oncogenic process by hindering the activity of the two oncoproteins. We previously developed and characterized some antibodies in single-chain format (scFvs) against the HPV16 E6 and E7 proteins, and demonstrated both in vitro and in vivo their antitumor activity consisting of protective efficacy against tumor progression of HPV16-positive cells. Methods Envisioning clinical application of the best characterized anti-HPV16 E6 and –HPV16 E7 scFvs, we verified their activity in the therapeutic setting, on already implanted tumors. Recombinant plasmids expressing the anti-HPV16 E6 scFvI7 with nuclear targeting sequence, or the anti-HPV16 E7 scFv43M2 with endoplasmic reticulum targeting sequence were delivered by injection followed by electroporation to three different preclinical models using C57/BL6 mice, and their effect on tumor growth was investigated. In the first model, the HPV16+ TC-1 Luc cells were used to implant tumors in mice, and tumor growth was measured by luciferase activity; in the second model, a fourfold number of TC-1 cells was used to obtain more aggressively growing tumors; in the third model, the HPV16+ C3 cells where used to rise tumors in mice. To highlight the scFv possible mechanism of action, H&E and caspase-3 staining of tumor section were performed. Results We showed that both the anti-HPV16 E6 and HPV16 E7 scFvs tested were efficacious in delaying tumor progression in the three experimental models and that their antitumor activity seems to rely on driving tumor cells towards the apoptotic pathway. Conclusion Based on our study, two scFvs have been identified that could represent a safe and effective treatment for the therapy of HPV16-associated lesions. The mechanism underlying the scFv effectiveness appears to be leading cells towards death by apoptosis. Furthermore, the validity of electroporation, a methodology allowed for human treatment, to deliver scFvs to tumors was confirmed.

scholarly journals Recent Approaches to Chiral 1,4-Dihydropyridines and their Fused Analogues

Catalysts ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1019
Author(s):  
Martins Rucins ◽  
Aiva Plotniece ◽  
Eiva Bernotiene ◽  
Wei-Bor Tsai ◽  
Arkadij Sobolev
Keyword(s):  
Kinetic Resolution ◽  
Stereoselective Synthesis ◽  
Biological Activities ◽  
Great Promise ◽  
Racemic Mixtures ◽  
Treatment Of Hypertension ◽  
Opposite Action ◽  
Recent Developments ◽  
Substantial Progress ◽  
Active Calcium

The purpose of this review is to highlight recent developments in the synthesis of chiral 1,4-dihydropyridines and their fused analogues. 1,4-Dihydropyridines are among the most active calcium antagonists that are used for the treatment of hypertension. Enantiomers of unsymmetrical 1,4-dihydropyridines often show different biological activities and may have even an opposite action profile. Hantzsch synthesis usually produces racemic mixtures of unsymmetrical 1,4-dihydropyridines. Therefore, the development of stereoselective synthesis of 1,4-dihydropyridines is one of the priorities of medicinal chemistry. Over the years, numerous methodologies have been developed for the production of enantiopure 1,4-dihydropyridines, such as stereoselective synthesis using chiral auxiliaries and chiral cyclocondensation partners, chromatographical methods, resolution of diastereomeric 1,4-dihydropyridine salts, enzyme catalysed kinetic resolution, or asymmetrisation of ester groups of 1,4-dihydropyridines. These approaches have been studied in detail and are relatively well established. The catalytic asymmetric approach holds the greatest promise in delivering the most practical and widely applicable methods. Substantial progress has been made toward the development of enantioselective organocatalytic methods for the construction of the chiral dihydropyridines. However, most of them do not provide a convenient way to pharmacologically important 1,4-dihydropyridine-3,5-dicarboxylates. Organocatalytic enantioselective desymmetrisation of prochiral 1,4-dihydropyridine-3,5-dicarbaldehydes also has great promise in the synthesis of pharmacologically important 1,4-dihydropyridine-3,5-dicarboxylates.

scholarly journals The E6 Oncoproteins of High-Risk Papillomaviruses Bind to a Novel Putative GAP Protein, E6TP1, and Target It for Degradation

1999 ◽  
Vol 19 (1) ◽  
pp. 733-744 ◽  
Author(s):  
Qingshen Gao ◽  
Seetha Srinivasan ◽  
Sarah N. Boyer ◽  
David E. Wazer ◽  
Vimla Band
Keyword(s):  
High Risk ◽  
P53 Protein ◽  
Single Gene ◽  
Human Papillomaviruses ◽  
Dominant Negative ◽  
Hpv16 E6 ◽  
Hpv E6 ◽  
E6 Oncoprotein ◽  
E6 Protein

ABSTRACT The high-risk human papillomaviruses (HPVs) are associated with carcinomas of the cervix and other genital tumors. Previous studies have identified two viral oncoproteins, E6 and E7, which are expressed in the majority of HPV-associated carcinomas. The ability of high-risk HPV E6 protein to immortalize human mammary epithelial cells (MECs) has provided a single-gene model to study the mechanisms of E6-induced oncogenic transformation. In this system, the E6 protein targets the p53 tumor suppressor protein for degradation, and mutational analyses have shown that E6-induced degradation of p53 protein is required for MEC immortalization. However, the inability of most dominant-negative p53 mutants to induce efficient immortalization of MECs suggests the existence of additional targets of the HPV E6 oncoprotein. Using the yeast two-hybrid system, we have isolated a novel E6-binding protein. This polypeptide, designated E6TP1 (E6-targeted protein 1), exhibits high homology to GTPase-activating proteins for Rap, including SPA-1, tuberin, and Rap1GAP. The mRNA for E6TP1 is widely expressed in tissues and in vitro-cultured cell lines. The gene for E6TP1 localizes to chromosome 14q23.2-14q24.3 within a locus that has been shown to undergo loss of heterozygosity in malignant meningiomas. Importantly, E6TP1 is targeted for degradation by the high-risk but not the low-risk HPV E6 proteins both in vitro and in vivo. Furthermore, the immortalization-competent but not the immortalization-incompetent HPV16 E6 mutants target the E6TP1 protein for degradation. Our results identify a novel target for the E6 oncoprotein and provide a potential link between HPV E6 oncogenesis and alteration of a small G protein signaling pathway.

scholarly journals NFX1 Plays a Role in Human Papillomavirus Type 16 E6 Activation of NFκB Activity

2010 ◽  
Vol 84 (21) ◽  
pp. 11461-11469 ◽  
Author(s):  
Mei Xu ◽  
Rachel A. Katzenellenbogen ◽  
Carla Grandori ◽  
Denise A. Galloway
Keyword(s):  
Human Papillomavirus ◽  
Human Telomerase Reverse Transcriptase ◽  
Hpv16 E6 ◽  
Regulatory Pathways ◽  
Cellular Processes ◽  
Hpv E6 ◽  
Host Cell Interactions ◽  
Nfκb Pathway ◽  
Human Telomerase ◽  
Dual Regulator

ABSTRACT High-risk human papillomavirus (HR HPV) requires differentiating epithelial cells to continue to divide in order to replicate the viral DNA. To achieve this, HPV perturbs several regulatory pathways, including cellular apoptosis and senescence signals. HPV E6 has been identified as a regulator of the NFκB signaling pathway, a pathway important in many cellular processes, as well as regulation of virus-host cell interactions. We report here that NFX1-91, an endogenously expressed transcriptional regulator of human telomerase reverse transcriptase (hTERT) that is targeted by HPV type 16 (HPV16) E6/E6-associated protein (E6AP) for degradation, is also critical for regulation of the NFκB pathway by HPV16 E6. Microarray analysis revealed induction of NFκB-responsive genes and reduction of NFκB inhibitors with knockdown of NFX1-91. Knockdown of NFX1-91 induced downregulation of p105, an NFκB inhibitor in both primary human foreskin keratinocytes (HFKs) and HCT116 cells. Chromatin immunoprecipitation assays further confirmed that NFX1-91 bound to the p105 promoter and upregulated its expression. Similarly, in HPV16 E6-positive cells, reduction of p105 expression was observed, paralleling knockdown of NFX1-91 expression. Overall, our data suggest a mechanism for HPV16 E6 activation of the NFκB pathway through NFX1-91. Also, it provides evidence that NFX1-91 can function as a dual regulator, not only a transcriptional repressor, but also a transcriptional activator, when bound to DNA.

Advances of biphenyl small-molecule inhibitors targeting PD-1/PD-L1 interaction in cancer immunotherapy

2021 ◽  
Author(s):  
Roufen Chen ◽  
Dandan Yuan ◽  
JunJie Ma
Keyword(s):  
Monoclonal Antibodies ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Biological Activities ◽  
Treatment Strategies ◽  
Structural Features ◽  
Great Promise ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
High Production Cost

Immunotherapy inhibiting the programmed death-1/programmed death ligand-1 (PD-1/PD-L1) interaction has emerged as one of the most attractive cancer treatment strategies. So far, the clinically used PD-1/PD-L1 inhibitors are monoclonal antibodies, but monoclonal antibodies have several limitations, such as poor pharmacokinetic properties, unchecked immune responses and high production cost. The development of small-molecule inhibitors targeting PD-1/PD-L1 interaction is showing great promise as a potential alternative or complementary therapeutic approach of monoclonal antibodies. In this article, the authors classify the reported biphenyl small-molecule inhibitors into symmetrical and asymmetrical types based on their structural features and further review their representative inhibitors and biological activities, as well as the binding models for providing insight into further exploration of more potent biphenyl small-molecule inhibitors targeting PD-1/PD-L1 interaction.

scholarly journals HPV16 E6 Promotes Breast Cancer Proliferation via Upregulation of COX-2 Expression

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Y. X. Wang ◽  
Y. Z. Li ◽  
Z. Y. Zhang ◽  
J. Q. Wang ◽  
J. Cui ◽  
...  
Keyword(s):  
Breast Cancer ◽  
North China ◽  
Human Papillomaviruses ◽  
Luciferase Reporter ◽  
Cancer Proliferation ◽  
Invasive Ductal Breast Carcinoma ◽  
Hpv16 E6 ◽  
Invasive Ductal Breast Cancer ◽  
Cox 2 ◽  
Related Mortality

Background.Breast cancer remains the leading cause of cancer-related mortality worldwide. It has been indicated that human papillomaviruses 16 (HPV16) might participate in the pathogenesis and development of breast cancer. However, the detected rate of HPV16 varies with region. We will investigate HPV16 E6 expression in North China and explore the effects and mechanism of HPV16 E6 on breast cancer proliferation in this study.Methods.The expressions of HPV16 E6 and COX-2 in paraffin-embedded tissues of the invasive ductal breast cancer were detected by qPCR and IHC. The effects of HPV16 E6 on breast cancer proliferation were determined by function studies. The mechanism of HPV16 E6 in promoting breast cancer proliferation was explored by Western blot and Dual-Luciferase Reporter Assay.Results.HPV16 E6 was positive in 28% invasive ductal breast carcinoma in North China; HPV16 E6 promoted breast cancer proliferation. Inhibition of COX-2 by siCOX-2 or Celecoxib attenuated the proliferation of breast cancer cells with HPV16 E6 expression; and the upregulation of COX-2 could be suppressed by the inhibition of NF-κB activity.Conclusion.HPV16 E6 promotes breast cancer proliferation by activation of NF-κB signaling pathway and increase of COX-2 expression. COX-2 will be a potential target for HPV16 E6-associated breast cancer.

scholarly journals Disruption of repressive p130–DREAM complexes by human papillomavirus 16 E6/E7 oncoproteins is required for cell-cycle progression in cervical cancer cells

2011 ◽  
Vol 92 (11) ◽  
pp. 2620-2627 ◽  
Author(s):  
Nurshamimi Nor Rashid ◽  
Rohana Yusof ◽  
Roger J. Watson
Keyword(s):  
Cell Cycle ◽  
Cervical Cancer ◽  
Cancer Cells ◽  
Cell Cycle Progression ◽  
Human Papillomaviruses ◽  
G1 Arrest ◽  
Cycle Progression ◽  
Hpv16 E6 ◽  
Cervical Cancer Cells ◽  
E6 And E7

Human papillomaviruses (HPVs) with tropism for mucosal epithelia are the major aetiological factors in cervical cancer. Most cancers are associated with so-called high-risk HPV types, in particular HPV16, and constitutive expression of the HPV16 E6 and E7 oncoproteins is critical for malignant transformation in infected keratinocytes. E6 and E7 bind to and inactivate the cellular tumour suppressors p53 and Rb, respectively, thus delaying differentiation and inducing proliferation in suprabasal keratinocytes to enable HPV replication. One member of the Rb family, p130, appears to be a particularly important target for E7 in promoting S-phase entry. Recent evidence indicates that p130 regulates cell-cycle progression as part of a large protein complex termed DREAM. The composition of DREAM is cell cycle-regulated, associating with E2F4 and p130 in G0/G1 and with the B-myb transcription factor in S/G2. In this study, we addressed whether p130–DREAM is disrupted in HPV16-transformed cervical cancer cells and whether this is a critical function for E6/E7. We found that p130–DREAM was greatly diminished in HPV16-transformed cervical carcinoma cells (CaSki and SiHa) compared with control cell lines; however, when E6/E7 expression was targeted by specific small hairpin RNAs, p130–DREAM was reformed and the cell cycle was arrested. We further demonstrated that the profound G1 arrest in E7-depleted CaSki cells was dependent on p130–DREAM reformation by also targeting the expression of the DREAM component Lin-54 and p130. The results show that continued HPV16 E6/E7 expression is necessary in cervical cancer cells to prevent cell-cycle arrest by a repressive p130–DREAM complex.

Defect Reduction and Its Mechanism of Selective Ge Epitaxy in Trenches on Si(001) Substrates Using Aspect Ratio Trapping

2007 ◽  
Vol 994 ◽  
Author(s):  
Ji-Soo Park ◽  
J. Bai ◽  
M. Curtin ◽  
B. Adekore ◽  
Z. Cheng ◽  
...  
Keyword(s):  
Aspect Ratio ◽  
Growth Process ◽  
Lattice Mismatch ◽  
Dominant Role ◽  
Great Promise ◽  
Silicon Substrates ◽  
Threading Dislocations ◽  
Defect Reduction ◽  
Device Applications ◽  
Conventional Photolithography

AbstractDefect-free germanium has been demonstrated in SiO2 trenches on silicon via aspect ratio trapping, whereby defects arising from lattice mismatch are trapped by laterally confining sidewalls. Results were achieved through a combination of conventional photolithography, reactive ion etching of SiO2, and selective growth of Ge as thin as 450 nm. It was revealed that facets, when formed early on in the growth process, play a dominant role in determining the configurations of threading dislocations in the films. This approach shows great promise for the integration of Ge and/or III-V materials, sufficiently large for key device applications, onto silicon substrates.

scholarly journals Topical Application of Temperature-Sensitive Gel Containing Caerin 1.1 and 1.9 Peptides on TC-1 Tumour-Bearing Mice Induced High-Level Immune Response in the Tumour Microenvironment

2021 ◽  
Vol 11 ◽  
Author(s):  
Guoying Ni ◽  
Xiaosong Liu ◽  
Hejie Li ◽  
Conor E. Fogarty ◽  
Shu Chen ◽  
...  
Keyword(s):  
T Cells ◽  
Single Cell ◽  
Topical Application ◽  
Immune Activation ◽  
Tumour Microenvironment ◽  
Temperature Sensitive ◽  
Hpv16 E6 ◽  
Tumour Bearing ◽  
Associated Lesions ◽  
High Level

The development of topical cream drugs that increase the immune activation of tumour-infiltrating lymphocytes against tumour and chronic viral infection-associated lesions is of great immunotherapeutic significance. This study demonstrates that the topical application of a temperature-sensitive gel containing caerin 1.1 and 1.9 peptides reduces nearly 50% of the tumour weight of HPV16 E6/E7-transformed TC-1 tumour-bearing mice via improving the tumour microenvironment. Confocal microscopy confirms the time-dependent penetration of caerin 1.9 through the epidermal layer of the ear skin structure of mice. Single-cell transcriptomic analysis shows that the caerin 1.1/1.9 gel expands the populations with high immune activation level and largely stimulates the pro-inflammatory activity of NK and dendritic cells. Closely associated with INFα response, Cebpb seems to play a key role in altering the function of all Arg1hi macrophages in the caerin group. In addition, the caerin gel treatment recruits almost two-fold more activated CD8+ T cells to the TME, relative to the untreated tumour, which shows a synergistic effect derived from the regulation of S1pr1, Ccr7, Ms4a4b and Gimap family expression. The TMT10plex-labelling proteomic quantification further demonstrates the activation of interferon-alpha/beta secretion and response to cytokine stimulus by the caerin gel, while the protein contents of several key regulators were elevated by more than 30%, such as Cd5l, Gzma, Ifit1, Irf9 and Stat1. Computational integration of the proteome with the single-cell transcriptome consistently suggested greater activation of NK and T cells with the topical application of caerin peptide gel.

scholarly journals The Human Papillomavirus Type 16 E6 Gene Alone Is Sufficient To Induce Carcinomas in Transgenic Animals

1999 ◽  
Vol 73 (7) ◽  
pp. 5887-5893 ◽  
Author(s):  
Shiyu Song ◽  
Henry C. Pitot ◽  
Paul F. Lambert
Keyword(s):  
Animal Experiments ◽  
Basal Layer ◽  
Transgenic Animals ◽  
Human Papillomaviruses ◽  
Skin Tumors ◽  
Benign Tumors ◽  
Hpv16 E6 ◽  
Adult Mice ◽  
E6 Gene ◽  
E6 And E7

ABSTRACT High-risk human papillomaviruses (HPVs) are the causative agents of certain human cancers. HPV type 16 (HPV16) is the papillomavirus most frequently associated with cervical cancer in women. The E6 and E7 genes of HPV are expressed in cells derived from these cancers and can transform cells in tissue culture. Animal experiments have demonstrated that E6 and E7 together cause tumors. We showed previously that E6 and E7 together or E7 alone could induce skin tumors in mice when these genes were expressed in the basal epithelia of the skin. In this study, we investigated the role that the E6 gene plays in carcinogenesis. We generated K14E6 transgenic mice, in which the HPV16 E6 gene was directed in its expression by the human keratin 14 promoter (hK14) to the basal layer of the epidermis. We found that E6 induced cellular hyperproliferation and epidermal hyperplasia and caused skin tumors in adult mice. Interestingly, the tumors derived from E6 were mostly malignant, as opposed to the tumors from E7 mice, which were mostly benign. This result leads us to hypothesize that E6 may contribute differently than E7 to HPV-associated carcinogenesis; whereas E7 primarily contributes to the early stages of carcinogenesis that lead to the formation of benign tumors, E6 primarily contributes to the late stages of carcinogenesis that lead to malignancy.

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