Cell Cycle Control by Natural Phenols in Cisplatin-Resistant Cell Lines

Abstract

Fifteen plant polyphenols, including flavonoids, cinnamic acids, coumarins and capsaicin, were investigated for their capacity to suppress cell growth and regulate the cell cycle of in vitro human ovarian carcinoma (2008 cell line) and cervix squamous carcinoma cells (A431), and their cisplatin (CDDP)-resistant subclones (C13 and A431Pt, respectively). Evaluation of the cytotoxic effects of the polyphenols (0.01-100 µM) indicated that especially rhein and quercetin were almost equiactive in wild type and CDDP-resistant cells, indicating lack of cross-resistance with cisplatin. Capsaicin was more potent in CDDP-resistant subclones than in wild type cells. The order of their potencies is flavonoids > anthraquinones > vanilloids > coumarins > phenols, cinnamic acids. The natural phenols which were most cytotoxic (rhein, quercetin and capsaicin) were able to cause the arrest of the cancer cell cycle, suggesting that specific cell cycle regulatory proteins are possibly involved in their intracellular mechanism of action. In particular, the natural compounds were revealed to be more active in CDDP-resistant cells than in wild types, especially inducing apoptotic death.

Effect of Quercetin on Cell Cycle and Cyclin Expression in Ovarian Carcinoma and Osteosarcoma Cell Lines

“…The safety of the flavonoid has been demonstrated both in vitro (see for instance data in McCoy mouse fibroblast cells [23]) and in vivo studies [24]. These results indicate that this flavonoid, exceeding the resistance to CDDP (as shown by the concentration-response curves in this work, in agreement with our previous results [5]), might become an interesting tool to evaluate any chemosensitizing activity. From a pharmacokinetic point of view, following intravenous administration quercetin presents an elimination half-life of about 2 hours and a wide volume of distribution [25], compatible with a systemic treatment; however, the drug is extensively metabolized by the liver into conjugates, and, therefore, the possible cytostatic activity of the metabolites still remains to be elucidated in order to assess any therapeutic role.…”

Chlorogenic Acid Interaction with Cisplatin and Oxaliplatin: Studies in Cervical Carcinoma Cells

“…Cells: The A431 cell line was derived from human cervix squamous carcinoma; its CDDP-resistant variant (A431Pt) was selected by exposure to increasing CDDP concentrations for a period of 9 months [9,10]. The cells were routinely grown in humidified conditions of 5% CO 2 at 37°C, incubated with RPMI 1640 medium, 10% FBS, 2% glutamine and 1% pen-strep.…”

“…MTT assay: Cell viability was determined using the 3-(4,5dimethyl-thizol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay, as previously described [9,20]. Cells were plated in 96-well μL plates at a density of 2500/well.…”

“…Polyphenols, plantderived compounds, are beneficial to human health and present antiinflammatory, anticancer, and immunomodulatory activities [4][5][6][7][8]. It has been reported that polyphenols modulate the pathways involved in carcinogenesis [9,10] through either direct interaction or modulation of gene expression [6,11]. Several in vitro and in vivo studies have shown that treatment with polyphenols in combination is more effective in inhibiting cancer growth than treatment with a single antitumor drug [9,12,13].…”

“…Various studies report that in vitro and in vivo combinations of polyphenols and chemotherapeutic agents open up new perspectives in the identification of promising combinations for cancer therapy [9,12,13].…”