Taxifolin and Lucidin as Potential E6 Protein Inhibitors: p53 Function Re-Establishment and Apoptosis Induction in Cervical Cancer Cells
by
, , , , and
Diana Gomes
1,2,3, 
Shivani Yaduvanshi
4,
Samuel Silvestre
1,5,6,7
,
Ana Paula Duarte
1,5,7
,
Adriana O. Santos
1,
Christiane P. Soares
8,
Veerendra Kumar
4,*,
Luís Passarinha
1,2,3,5
and
Ângela Sousa
1,*
1
CICS-UBI—Health Sciences Research Centre, University of Beira Interior, Avenida Infante D. Henrique, 6200-506 Covilhã, Portugal
2
Associate Laboratory i4HB—Institute for Health and Bioeconomy, Faculdade de Ciências e Tecnologia, Universidade NOVA, 2819-516 Caparica, Portugal
3
UCIBIO—Applied Molecular Biosciences Unit, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal
4
Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University, Noida Uttar Pradesh 201303, India
5
Laboratório de Fármaco-Toxicologia-UBIMedical, Universidade da Beira Interior, 6200-284 Covilhã, Portugal
6
CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal
7
C4—Cloud Computing Competence Centre, UBIMedical, University of Beira Interior, Estrada Municipal 506, 6200-284 Covilhã, Portugal
8
Department of Clinical Analysis, School of Pharmaceutical Sciences, São Paulo State University (UNESP), Campus Ville, Araraquara, São Paulo 14800-903, Brazil
*
Authors to whom correspondence should be addressed.
Cancers 2022, 14(12), 2834; https://doi.org/10.3390/cancers14122834
Submission received: 1 May 2022
/
Revised: 29 May 2022
/
Accepted: 6 June 2022
/
Published: 8 June 2022
(This article belongs to the Collection Innovative Concepts in the Diagnosis and Treatment of Gynecologic Malignancies)
Simple Summary
Human papillomavirus (HPV)-related cancers continue to be a major medical concern, and there exists an urgent need to improve the current therapeutic approaches by combining strategies or proposing new compounds to offer more specific and less invasive treatments. The aim of this work was to discover potential inhibitors of the E6/E6AP/p53 complex formation. We started this work with an initial in silico approach including molecular docking and molecular dynamics simulations, and these tools allowed us to select potential inhibitors, using E6 protein as a target. In addition, we found that lucidin and taxifolin were able to selectively decrease the viability of HPV-positive cells to re-establish p53 protein levels and to induce apoptosis. These findings represent a promising starting point for the development of anti-HPV drugs.
Abstract
Cervical cancer is the fourth leading cause of death in women worldwide, with 99% of cases associated with a human papillomavirus (HPV) infection. Given that HPV prophylactic vaccines do not exert a therapeutic effect in individuals previously infected, have low coverage of all HPV types, and have poor accessibility in developing countries, it is unlikely that HPV-associated cancers will be eradicated in the coming years. Therefore, there is an emerging need for the development of anti-HPV drugs. Considering HPV E6’s oncogenic role, this protein has been proposed as a relevant target for cancer treatment. In the present work, we employed in silico tools to discover potential E6 inhibitors, as well as biochemical and cellular assays to understand the action of selected compounds in HPV-positive cells (Caski and HeLa) vs. HPV-negative (C33A) and non-carcinogenic (NHEK) cell lines. In fact, by molecular docking and molecular dynamics simulations, we found three phenolic compounds able to dock in the E6AP binding pocket of the E6 protein. In particular, lucidin and taxifolin were able to inhibit E6-mediated p53 degradation, selectively reduce the viability, and induce apoptosis in HPV-positive cells. Altogether, our data can be relevant for discovering promising leads for the development of specific anti-HPV drugs.
