Antineoplastic properties of polyphenols in TPC-1 human papillary thyroid carcinoma cell line: a systematic review

Makiyama, Marielle Lang; Esposti, Maria Júlia Pigatti Degli; Siqueira, Maria Luíza Raitz; Bagatini, Margarete Dulce; Maciel, Sarah Franco Vieira de Oliveira; Moreno, Marcelo

doi:10.20945/2359-3997000000645

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Review • Arch. Endocrinol. Metab. 67 (6) • 2023 • https://doi.org/10.20945/2359-3997000000645 copy

Antineoplastic properties of polyphenols in TPC-1 human papillary thyroid carcinoma cell line: a systematic review

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Thyroid cancer usually responds to surgical and ablative therapy, but when it's refractory the alternative lies in tyrosine kinase inhibitors that, in addition to harmful side effects, acts only in a palliative way. The concern for other therapeutic possibilities brought evidence on flavonoids, hypothesizing a possible strategy. This review aimed to organize a compilation of in vitro studies using polyphenol substances in TPC-1 (human papillary thyroid carcinoma cell line) summarizing it's results and describing the metabolic pathways involved. Articles were selected on PubMed, Google Scholar, LILACS, BVS and SciELO, using keywords “thyroid cancer”, “flavonoids” and “TPC-1”, until June 2022. 185 studies were selected. After identification and exclusion of duplicates and exclusion criteria applied, 11 original articles were evaluated. Of these, the findings of flavonoids added to TPC-1 were: inhibition of cell growth and viability, promotion of cell cycle arrest and induction of apoptosis. Polyphenolic compounds have antineoplastic properties by different mechanisms as shown in vitro, but the concentrations needed are above usual dietary consumption and the findings are limited to experimental cellular studies. Despite that, these results should be useful to guide further analysis aiming to reveal the real safety and efficacy of polyphenols in this scenario.

Keywords
TPC-1; polyphenols; thyroid cancer; papillary thyroid cancer

References	Flavonoid molecule(s) and concentrations	Analysis methods	Main results
Kang and cols., 2011	Genistein – 72 h exposition with 10-50-100 μM/mL	MTT assay	Inhibition of cell growth in a dose dependent mode
	Resveratrol – up to 120 h exposition with 50 μM/mL	MTT assay	Inhibition of cell growth
	Quercetin – 72 h exposition with 10-50-100 μM/mL	MTT assay	Inhibition of cell growth in a dose dependent mode
Bian and cols., 2020	Resveratrol – 48 h exposition with up to 50 μM/mL	MTT assay	Decrease of cell viability in a dose dependent mode
		Flow cytometry	Cell cycle arrest and increase of apoptotic cells
		Colony formation	Colony formation decrease
		Western blotting	Increase of caspase-3,-8 and bax expression, and decrease of bcl-xl and mcl-1 expression
Perna and cols., 2018	Curcumin – 48 h exposition with 25 μM/mL	Immunoblotting	Degradated nrf2 and reduced VEGF expression
		Immunoblotting	Up regulation of TNFα in 2 of the 3 complexes tested
		MTT assay	Reduced cell viability
		Western blotting	Down regulation of cell cycle regulators (cyclin D1, β-catenin, p21, p53) and activators or inhibitors of apoptosis (pro-caspase3, bcl-2)
Esposito and cols., 2019	Curcumin – 48 h exposition with 25 μM/mL	MTT assay	Cell viability reduction
		Immunofluorescence	Damage of the cell nucleus
		Western blotting	Down regulation of cell cycle regulators (cyclin D1, β-catenin, P21, P53) and activators or inhibitors of apoptosis (pro-caspase3, bcl-2)
Zhou and cols., 2019	Naringin – 6, 12 or 25 μM/mL, dose- and time-dependently	MTT assay	Cell proliferation inhibition
		Flow cytometry	Cell apoptosis induction
		Western blotting	Enhancement of Caspase3 and bax expression, and reduction of cyclin D1, c-Myc, survivin, and bcl-2 expression; suppression of PI3K/AKT pathway activation
Orlandella and cols., 2022	Extract from Annurca Flesh Apple (AFPE) – 24 h exposition with up to 250 μM/mL	Flow cytometry	Reduction of cell viability and promotion of cell cycle arrest
	Extract from AFPE – 20 h exposition with 500 μM/mL	DCFDA/H2DCFDA- cellular ROS assay kit	Reduction of cell death induced by oxidative stress
Wu and cols., 2019	Epigallocatechin-3-gallate (EGCG) – 24 h exposition with doses from 10-200 μM/mL	EdU and MTS assays	Inhibition of cell proliferation and cell viability in a dose dependent mode
		Flow cytometry	Cell cycle arrest
	Up to 25 μM/mL of EGCG	TUNEL staining and western blotting	Increase of the apoptotic index in a dose dependent mode
	Up to 50-200 μM/mL EGCG	Western blotting	Increase of the bax/bcl-2 ratio and the expression levels of cleaved caspase-3 and cleaved PARP
	50-200 μM/mL EGCG	Western blotting	Gradually decrease of p-EGFR, RAS, p-RAF, p-MEK1/2, and p-ERK1/2
Yin and cols., 2017	Prunella vulgaris (PV) – Rutin, hyperoside and other flavonoids isolated and identified from PV: luteolin, homoorinetin, cinaroside, quercetin and kaempferol. Concentrations of 0, 5, 10, 20 and 30 % for 12, 24 and 36 h	CCK-8 assay	Cell proliferation inhibition
	IC50 PV for 24 h	Hoechst 33342 staining	Alteration of cellular morphology and cell nuclei
		DNA extraction and fragmentation assay	Induction of cell apoptosis
		RT-qPCR	Decrease bcl-2 expression and increase bax and caspases-3 expression
Liang and cols., 2020	Fisetin from 1 μM/mL to 30 μM/mL for 24 h	MTT assay	Promotion of a cytotoxic effect in a dose dependent mode
	15 μM/mL for 24 h	Morphological examination in fluorescence microscope	Induction of cell apoptosis without compromising cellular membrane
	20 μM/mL for 24 h	Morphological examination in fluorescence microscope	Elevated quantity of late apoptotic cells - strong effect on the nucleus morphology related to apoptosis
		DCFH-DA dye	ROS enhancement
		Spectrofluorimetry	Reduction of the mitochondrial membrane potential
	15-20 μM/mL for 24 h	Flow cytometry	Alteration of cell cycle progression in a dose dependent mode
		Western blotting	Down regulation of the cyclin D1 expression; up regulation of STAT3 and decreased expression of JAK-1
		ELISA	Elevated protein expression of cleaved caspase-3, and −9 in a dose dependent mode
Oh and cols., 2013	Silibinin – 100 μM/mL for 24 h	Quick cell proliferation assay kit II	Decrease in cell viability
Carvalho and cols., 2018	Xanthohumol – 10-100 μM/mL for 48 h	Sulforhodamine B assay	Decrease in cell viability in a dose dependent mode
	100 μM/mL for 48 h	TUNEL assay	High cell death rate and high percentage of fragmented DNA
	Concentrations up to 10 μM/mL for 48 h	Western blotting	Increase in caspase-3 and caspase-7 expression
	10 μM/mL for 72 h	Flow cytometry	Cell cycle arrest
	0.05-0.1-100 μM/mL for 72 h	Fenton reaction initiated deoxyribose degradation cell-free assay	Radical levels increase at higher concentrations (pro-oxidant effect)

Subclass	Substances	Source
Flavanols	Epigallocatechin, catechin, epicatechin	Food (astringency, bitterness, sourness, viscosity, aroma and color features)
Flavonols	Quercetin, kaempferol, myricetin, rutin	Cherries, grapes, apricots, red wine, chocolate and tea
Anthocyanidins	Pelargonidin, cyanidin, malvidin	Vegetables (colors blue, purple and red)
Flavones	Luteolin, apigenin, chrysin	Fruit and vegetables
Isoflavones	Genistein, daidzein	Leguminous plants
Flavonones	Naringenin, hesperidin, eriodictyol	Citrus

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[1] Correspondence to: Marielle Lang Makiyama, Avenida Fernando Machado, 615D 89803-003 – Chapecó, SC, Brasil, endocrinologistamarielle@yahoo.com