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A Combination of Flavonoids Suppresses Cell Proliferation and the E6 Oncogenic Pathway in Human
Federico De Marco1, Fabio Altieri2, Stefano Giuliani1
1IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy.
Abstract:
Despite the availability of excellent HPV-specific vaccines, HPV-related conditions and, notably, their related neoplastic diseases are expected to impact human health for many years to come. Polyphenols and flavonoids are a large class of natural products, credited with a wide range of pharmacological properties including antineoplastic activity. However, the currently available data depict a rather heterogeneous and sometimes contradictory landscape, and no univocal conclusions can be drawn. To shed light on such a controversial issue, a restricted list of promising polyphenols were evaluated for their antineoplastic activity on HPV-transformed cells. Among them, Kaempferol, Galangin, and Luteolin proved to have distinct anti-clonal activity with ID50 values, respectively, of 1.25, 6.25, and 3.0 microMolar, and three other compounds, namely, Chrysin, Quercetin, and Apigenin, showed fair although less intense activity with ID values, respectively, of 25.0, 40, and 25 microMolar. Interestingly, a distinct anti-proliferative effect could also be suggested for Kaempferol, Luteolin, and Apigenine. Cooperative anti-clonal effects could be suggested for binary and ternary compositions made of Kaepferol, Galangin, and Luteolin once combined at concentrations ranging from 2 to 8 microMolar. At these concentrations, the single components and the triple combination induced distinct cell cycle modulation associated with marked restoration of the p53 and p21Cip1/Waf1 levels, consistent with the disruption of the E6/E6AP interaction whose continuous activity is necessary for both the induction and maintenance of the viral-induced neoplastic phenotype.
Insights
Certain polyphenols, including Kaempferol, Galangin, and Luteolin, show significant anti-cancer activity against human papillomavirus (HPV)-transformed cells. These natural compounds may disrupt HPV
Area of Science:
- Natural Product Chemistry
- Oncology
- Virology
Background:
- Human papillomavirus (HPV)-related neoplastic diseases remain a significant health concern despite available vaccines.
- Polyphenols and flavonoids possess diverse pharmacological properties, including potential antineoplastic activity.
- Existing research on polyphenols' anti-cancer effects is heterogeneous, necessitating further investigation.
Purpose of the Study:
- To evaluate the antineoplastic activity of selected promising polyphenols against HPV-transformed cells.
- To identify specific polyphenols and their combinations demonstrating significant anti-clonal and anti-proliferative effects.
Main Methods:
- Screening of various polyphenols for anti-clonal activity on HPV-transformed cell lines.
- Determination of half-maximal inhibitory concentrations (ID50) for active compounds.
- Assessment of anti-proliferative effects and analysis of cell cycle modulation and protein levels (p53, p21Cip1/Waf1).
Main Results:
- Kaempferol, Galangin, and Luteolin exhibited distinct anti-clonal activity with low ID50 values (1.25, 6.25, and 3.0 μM, respectively).
- Chrysin, Quercetin, and Apigenin showed moderate anti-clonal activity (ID50 values of 25.0, 40, and 25 μM).
- Combinations of Kaempferol, Galangin, and Luteolin demonstrated cooperative anti-clonal effects, modulating cell cycle and restoring p53/p21Cip1/Waf1 levels, suggesting disruption of HPV E6/E6AP interaction.
Conclusions:
- Kaempferol, Galangin, and Luteolin are promising natural compounds with significant antineoplastic activity against HPV-transformed cells.
- Synergistic effects were observed in combinations of these polyphenols, enhancing their anti-cancer potential.
- The observed effects are linked to cell cycle regulation and restoration of tumor suppressor proteins, indicating a mechanism against HPV-induced oncogenesis.
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