scholarly journals In Silico Approaches: A Way to Unveil Novel Therapeutic Drugs for Cervical Cancer Management

2021 ◽  
Vol 14 (8) ◽  
pp. 741
Author(s):  
Diana Gomes ◽  
Samuel Silvestre ◽  
Ana Paula Duarte ◽  
Aldo Venuti ◽  
Christiane P. Soares ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Small Molecules ◽  
In Silico ◽  
Access To Health Services ◽  
Cancer Management ◽  
Hpv E6 ◽  
Therapeutic Drugs ◽  
E6 Oncoprotein ◽  
Access To Health ◽  
E6 And E7

Cervical cancer (CC) is the fourth most common pathology in women worldwide and presents a high impact in developing countries due to limited financial resources as well as difficulties in monitoring and access to health services. Human papillomavirus (HPV) is the leading cause of CC, and despite the approval of prophylactic vaccines, there is no effective treatment for patients with pre-existing infections or HPV-induced carcinomas. High-risk (HR) HPV E6 and E7 oncoproteins are considered biomarkers in CC progression. Since the E6 structure was resolved, it has been one of the most studied targets to develop novel and specific therapeutics to treat/manage CC. Therefore, several small molecules (plant-derived or synthetic compounds) have been reported as blockers/inhibitors of E6 oncoprotein action, and computational-aided methods have been of high relevance in their discovery and development. In silico approaches have become a powerful tool for reducing the time and cost of the drug development process. Thus, this review will depict small molecules that are already being explored as HR HPV E6 protein blockers and in silico approaches to the design of novel therapeutics for managing CC. Besides, future perspectives in CC therapy will be briefly discussed.

scholarly journals Elucidation of Rutin role in inducing caspase dependent apoptosis via HPV-E6 and E7 downregulation in cervical cancer HeLa cells

2021 ◽  
Author(s):  
Pratibha Pandey ◽  
Fahad Khan ◽  
Mohd Farhan ◽  
Asif Jafri
Keyword(s):  
Cervical Cancer ◽  
Hela Cells ◽  
Human Cancer ◽  
Drug Candidate ◽  
Cancer Management ◽  
Hpv E6 ◽  
Cancer Pathogenesis ◽  
Hela Cell Lines ◽  
In Silico Studies ◽  
E6 And E7

Over the recent few years rutin has gained wider attention in exhibiting inhibitory potential against several oncotargets for inducing apoptotic and antiproliferative activity in several human cancer cells. Several deregulated signaling pathways are implicated in cancer pathogenesis. Therefore we have inclined our research towards exploring the anticancerous efficacy of a very potent phytocompound for modulating the incontinent expression of these two crucial E6 and E7 oncogenes. Further, inhibitory efficacy of rutin against HPV-E6 AND E7 oncoproteins in cervical cancer has not been elucidated yet. This research addresses the growth inhibitory efficacy of rutin against E6 and E7 oncoprotein in HeLa cells, which is known to inactivate several tumor suppressor protein such as p53 and pRB. Rutin treatment exhibited reduced cell viability with increased cell accumulation in G0/G1 phase of cell cycle in Hela cell lines. Additionally rutin treatment has also led to downregulation of E6 and E7 expression associated with an increased expression of p53 and pRB levels. This has further resulted in enhanced Bax expression and decreased Bcl-2 expression releasing cytochrome c into cytosol followed by caspase cascade activation with cleavage of caspase-3 caspase-8 and caspase-9. Further, in silico studies have also supported our in vitro findings by exhibiting significant binding energy against selected target oncoproteins. Therefore, our research findings might recommend rutin as one of the potent drug candidate in cervical cancer management via targeting two crucial oncoproteins associated with viral progression.

An In Silico Appraisal of Azoic and Disulphide Derivatives for Anticancer Activity Against HPV E6 Oncoprotein to Medicate Cervical Cancer

2014 ◽  
Vol 17 (1) ◽  
pp. 38-46 ◽  
Author(s):  
Arpita Choudhury ◽  
Manabendra Choudhury ◽  
Pankaj Chetia ◽  
Abhishek Chowdhury ◽  
Anupam Talukdar
Keyword(s):  
Cervical Cancer ◽  
Anticancer Activity ◽  
In Silico ◽  
Hpv E6 ◽  
E6 Oncoprotein

scholarly journals Complementary Targeting of Rb Phosphorylation and Growth in Cervical Cancer Cell Cultures and a Xenograft Mouse Model by SHetA2 and Palbociclib

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1269 ◽  
Author(s):  
Amy L. Kennedy ◽  
Rajani Rai ◽  
Zitha Redempta Isingizwe ◽  
Yan Daniel Zhao ◽  
Stanley A. Lightfoot ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cyclin D1 ◽  
Cell Lines ◽  
Cancer Cell ◽  
Xenograft Model ◽  
Cervical Cancer Cell ◽  
Chi Square ◽  
Western Blots ◽  
Hpv E6 ◽  
E6 And E7

Cervical cancer is caused by high-risk human papillomavirus (HPV) types and treated with conventional chemotherapy with surgery and/or radiation. HPV E6 and E7 proteins increase phosphorylation of retinoblastoma (Rb) by cyclin D1/cyclin dependent kinase (CDK)4/6 complexes. We hypothesized that cyclin D1 degradation by the SHetA2 drug in combination with palbociclib inhibition of CDK4/6 activity synergistically reduces phosphorylated Rb (phospho-Rb) and inhibits cervical cancer growth. The effects of these drugs, alone, and in combination, were evaluated in SiHa and CaSki HPV-positive and C33A HPV-negative cervical cancer cell lines using cell culture, western blots and ELISA, and in a SiHa xenograft model. Endpoints were compared by isobolograms, ANOVA, and Chi-Square. In all cell lines, combination indexes documented synergistic interaction of SHetA2 and palbociclib in association SHetA2 reduction of cyclin D1 and phospho-Rb, palbociclib reduction of phospho-Rb, and enhanced phospho-Rb reduction upon drug combination. Both drugs significantly reduced phospho-Rb and growth of SiHa xenograft tumors as single agents and acted additively when combined, with no evidence of toxicity. Dilated CD31-negative blood vessels adjacent to, or within, areas of necrosis and apoptosis were observed in all drug-treated tumors. These results justify development of the SHetA2 and palbociclib combination for targeting phospho-Rb in cervical cancer treatment.

scholarly journals Survivin Clinical Features in Cervical Cancer

2017 ◽  
Vol 1 (1) ◽  
pp. 6
Author(s):  
Miftakh Nur Rahman ◽  
Chyntia Resti Wijaya ◽  
Maria Novalentina
Keyword(s):  
Cell Cycle ◽  
Cervical Cancer ◽  
Critical Role ◽  
Survivin Expression ◽  
Hpv Infection ◽  
Cytotoxic T Cell ◽  
Hpv E6 ◽  
E6 Oncoprotein ◽  
Cycle Dependent ◽  
Oncogenic Protein

Cervical cancer is the primary lethal malignancy for women worldwide, but because it develops over time, it would be one of the most preventable types of cancer. Dysregulation of apoptosis in cells plays a critical role in the malignancy development. Survivin is the smallest inhibitor apoptotic protein (IAP) which has an important part in regulating cell division and inhibitor of apoptosis. This review focused on survivin features in cervical cancer from mechanisms of malignancy relationship to human papillomavirus (HPV) infection through E6 oncogenic protein, role as a biomarker in diagnosis, prognosis, staging and prediction of metastasis, and also as a target for therapy. Regulation of survivin divided into two main groups; cell cycle dependent and cell cycle independent pathway to maintain life and death balance. Survivin expression is upregulated by E6 protein simultaneously repressing p53. Thus cancerous cervical tissue developed. Survivin is also upregulated in hypoxia, a common condition in many tumors and increased angiogenesis. Survivin plays a major role in chemotherapy and radiation resistance in many cases of cervical cancer. As a target of therapy, survivin has a promising performance, suggested very specific and no issue of resistance and also reducing resistance to chemo and radiation therapy. The goal of treatment is to lower survivin expression through transcription inhibition, immunotherapy based on cytotoxic T cell (CTL) activity and gene therapy.  Keywords: cervical cancer, survivin, HPV E6 oncoprotein, therapy

scholarly journals E6-mediated activation of JNK drives EGFR signalling to promote proliferation and viral oncoprotein expression in cervical cancer

2020 ◽  
Author(s):  
Ethan L. Morgan ◽  
James A. Scarth ◽  
Molly R. Patterson ◽  
Christopher W. Wasson ◽  
Georgia C. Hemingway ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Human Papillomaviruses ◽  
Signalling Pathway ◽  
Viral Oncoprotein ◽  
Hpv E6 ◽  
Cervical Cancer Cells ◽  
E6 And E7 ◽  
Novel Therapeutic

AbstractHuman papillomaviruses (HPV) are a major cause of malignancy worldwide, contributing to ~5% of all human cancers including almost all cases of cervical cancer and a growing number of ano-genital and oral cancers. HPV-induced malignancy is primarily driven by the viral oncogenes, E6 and E7, which manipulate host cellular pathways to increase cell proliferation and enhance cell survival, ultimately predisposing infected cells to malignant transformation. Consequently, a more detailed understanding of viral-host interactions in HPV-associated disease offers the potential to identify novel therapeutic targets. Here, we identify that the c-Jun N-terminal kinase (JNK) signalling pathway is activated in cervical disease and in cervical cancer. The HPV E6 oncogene induces JNK1/2 phosphorylation in a manner that requires the E6 PDZ binding motif. We show that blockade of JNK1/2 signalling using small molecule inhibitors, or knockdown of the canonical JNK substrate c-Jun, reduces cell proliferation and induces apoptosis in cervical cancer cells. We further demonstrate that this phenotype is at least partially driven by JNK-dependent activation of EGFR signalling via increased expression of EGFR and the EGFR ligands EGF and HB-EGF. JNK/c-Jun signalling promoted the invasive potential of cervical cancer cells and was required for the expression of the epithelial to mesenchymal transition (EMT)-associated transcription factor Slug and the mesenchymal marker Vimentin. Furthermore, JNK/c-Jun signalling is required for the constitutive expression of HPV E6 and E7, which are essential for cervical cancer cell growth and survival. Together, these data demonstrate a positive feedback loop between the EGFR signalling pathway and HPV E6/E7 expression, identifying a regulatory mechanism in which HPV drives EGFR signalling to promote proliferation, survival and EMT. Thus, our study has identified a novel therapeutic target that may be beneficial for the treatment of cervical cancer.

Role of molecular biomarker human papilloma virus (HPV) E6 oncoprotein in cervical cancer screening

2020 ◽  
Vol 158 (3) ◽  
pp. 590-596
Author(s):  
Rifat Ara ◽  
Sabera Khatun ◽  
Shahana Pervin ◽  
Munira Jahan ◽  
Umme Shahera ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Screening ◽  
Human Papilloma Virus ◽  
Cervical Cancer Screening ◽  
Molecular Biomarker ◽  
Papilloma Virus ◽  
Hpv E6 ◽  
E6 Oncoprotein

HPV-targeted tumor-infiltrating lymphocytes for cervical cancer.

2014 ◽  
Vol 32 (18_suppl) ◽  
pp. LBA3008-LBA3008 ◽  
Author(s):  
Christian S. Hinrichs ◽  
Sanja Stevanovic ◽  
Lindsey Draper ◽  
Robert Somerville ◽  
John Wunderlich ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Cervical Cancer ◽  
T Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
The Other ◽  
High Dose ◽  
Complete Regression ◽  
Hpv E6 ◽  
E6 And E7 ◽  
Infiltrating Lymphocytes

LBA3008 Background: Adoptive T-cell therapy (ACT) is a promising cancer treatment modality with potentially broad application. It is not known if ACT can mediate regression of carcinomas, the most common solid tumors in humans. We studied carcinoma of the uterine cervix, a virally induced malignancy that constitutively expresses the HPV E6 and E7 oncoproteins, as a model cancer to test if ACT can mediate regression of an epithelial malignancy. Methods: We initiated a clinical trial to treat metastatic HPV+ cancers with tumor-infiltrating lymphocytes (TIL) selected for HPV E6- and E7-reactivity (HPV-TIL). Patients from the cervical cancer cohort are reported here. HPV-TIL infusion was preceded b y non-myeloablative conditioning and followed by high-dose bolus aldesleukin. HPV-reactivity was assessed by ELISPOT, IFN-gamma production, and CD137 expression assays. Results: Nine patients were treated on the study. They received a median of 81 x 109 T cells (range 33 to 159 x 109) as a single infusion. The infused cells possessed reactivity against high-risk HPV E6 and/or E7 in 6/8 patients. The two patients with no HPV reactivity did not respond to treatment. 3/6 patients with HPV reactivity demonstrated objective tumor responses by RECIST (1 PR and 2 CR). One patient had a 39% best response. Two patients with widespread metastases had complete tumor responses that are ongoing 18 and 11 months after treatment. One patient with a complete response had a chemotherapy-refractory HPV-16+ squamous cell carcinoma and the other a chemoradiation-refractory HPV-18+ adenocarcinoma. Both patients demonstrated prolonged repopulation with HPV-reactive T cells following treatment. Increased frequencies of HPV-specific T cells were detectable after 13 months in one patient and 6 months in the other. Two patients with HPV-reactive TIL that did not respond to treatment did not display repopulation with HPV-reactive T cells. Conclusions: HPV-TIL can mediate durable, complete regression of metastatic cervical cancer. Continued investigation of HPV-TIL for cervical cancer, and possibly other HPV+ malignancies, is warranted. Cellular therapy can mediate complete regression of an epithelial malignancy. Clinical trial information: NCT01585428.

scholarly journals The Human Papillomavirus (HPV) E6 Oncoprotein Regulates CD40 Expression via the AT-Hook Transcription Factor AKNA

Cancers ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 521 ◽  
Author(s):  
Joaquin Manzo-Merino ◽  
Alfredo Lagunas-Martínez ◽  
Carla Contreras-Ochoa ◽  
Marcela Lizano ◽  
Leonardo Castro-Muñoz ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Human Papillomavirus ◽  
High Risk ◽  
Immune Surveillance ◽  
Dependent Manner ◽  
Hpv E6 ◽  
E6 Oncoprotein ◽  
Inflammatory State ◽  
Cervical Cancer Development ◽  
Carcinogenic Process

Persistent infection with high-risk Human Papillomavirus (HR-HPV) is the main requisite for cervical cancer development. Normally, HPV is limited to the site of infection and regulates a plethora of cellular elements to avoid the immune surveillance by inducing an anti-inflammatory state, allowing the progress through the viral cycle and the carcinogenic process. Recent findings suggest that the AT-hook transcriptional factor AKNA could play a role in the development of cervical cancer. AKNA is strongly related to the expression of co-stimulatory molecules such CD40/CD40L to achieve an anti-tumoral immune response. To date, there is no evidence demonstrating the effect of the HPV E6 oncoprotein on the AT-hook factor AKNA. In this work, minimal expression of AKNA in cervical carcinoma compared to normal tissue was found. We show the ability of E6 from high-risk HPVs 16 and 18 to interact with and down-regulate AKNA as well as its co-stimulatory molecule CD40 in a proteasome dependent manner. We also found that p53 interacts with AKNA and promotes AKNA expression. Our results indicate that the de-regulation of CD40 and AKNA is induced by the HPV E6 oncoprotein, and this event involves the action of p53 suggesting that the axis E6/p53A/AKNA might play an important role in the de-regulation of the immune system during the carcinogenic process induced by HR-HPV.

scholarly journals Correction: PAMAM/5-fluorouracil drug conjugate for targeting E6 and E7 oncoproteins in cervical cancer: a combined experimental/in silico approach

RSC Advances ◽  
2017 ◽  
Vol 7 (19) ◽  
pp. 11281-11281 ◽  
Author(s):  
Arunkumar Rengaraj ◽  
Balaji Subbiah ◽  
Yuvaraj Haldorai ◽  
Dhanusha Yesudhas ◽  
Hyung Joong Yun ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
In Silico ◽  
Drug Conjugate ◽  
E6 And E7 Oncoproteins ◽  
E6 And E7

Correction for ‘PAMAM/5-fluorouracil drug conjugate for targeting E6 and E7 oncoproteins in cervical cancer: a combined experimental/in silico approach’ by Arunkumar Rengaraj et al., RSC Adv., 2017, 7, 5046–5054.

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