Taxifolin and Lucidin as Potential E6 Protein Inhibitors: p53 Function Re-Establishment and Apoptosis Induction in Cervical Cancer Cells

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.

Taxifolin Inhibits Breast Cancer Growth by Facilitating CD8+ T Cell Infiltration and Inducing a Novel Set of Genes including Potential Tumor Suppressor Genes in 1q21.3

“…As a nutritional supplement, taxifolin displays multiple health-promoting effects [ 11 , 12 , 13 ]. Its anticancer activities were observed in a range of cancer cells both in vitro and in vivo (xenografts), including lung cancer [ 14 ], colorectal cancer [ 15 , 16 , 17 ], liver cancer [ 18 ], skin cancer [ 19 ], osteosarcoma [ 20 ], gastric cancer [ 21 ], glioma [ 22 ], prostate cancer [ 23 ], cervical cancer [ 24 , 25 ], and breast cancer [ 26 ]. Activation of the Nrf-mediated anti-ROS cytoprotective pathway, Wnt/β-catenin signaling, and p53 contributed to the taxifolin-derived anticancer activities in colon cancer, breast cancer (BC), Ewing’s sarcoma, and cervical cancer [ 24 , 27 , 28 ].…”

Taxifolin Inhibits the Growth of Non-Small-Cell Lung Cancer via Downregulating Genes Displaying Novel and Robust Associations with Immune Evasion Factors

“…Taxifolin (dihydroquercetin), a flavonoid with established antioxidant and anti-inflammatory properties [15], might be beneficial in NSCLC therapy. Taxifolin displayed anticancer activities both in vitro and in vivo (xenografts) towards colorectal cancer [16][17][18], liver cancer [19], skin cancer [20], osteosarcoma [21], gastric cancer [22], glioma [23], prostate cancer [24], cervical cancer [25,26], breast cancer [27,28], and lung cancer [29]. The anti-cancer impact of taxifolin was attributable to activation of the Nrfmediated anti-ROS (reactive oxygen species) cytoprotective pathway, Wnt/β-catenin signaling, and p53 in colon cancer, breast cancer, Ewing's sarcoma, and cervical cancer [25,30,31].…”

“…Taxifolin displayed anticancer activities both in vitro and in vivo (xenografts) towards colorectal cancer [16][17][18], liver cancer [19], skin cancer [20], osteosarcoma [21], gastric cancer [22], glioma [23], prostate cancer [24], cervical cancer [25,26], breast cancer [27,28], and lung cancer [29]. The anti-cancer impact of taxifolin was attributable to activation of the Nrfmediated anti-ROS (reactive oxygen species) cytoprotective pathway, Wnt/β-catenin signaling, and p53 in colon cancer, breast cancer, Ewing's sarcoma, and cervical cancer [25,30,31]. Given the somatic mutations in TP53 occurring in 90% of LUSC and approximately 50% of LUAD [6], it is appealing to thoroughly investigate taxifolin-derived anti-oncogenic activities towards LUAD and LUSC.…”