A simple phenolic antioxidant protocatechuic acid enhances tumor promotion and oxidative stress in female ICR mouse skin: dose- and timing-dependent enhancement and involvement of bioactivation by tyrosinase

Abstract

The modifying effects of topical application of the phenolic antioxidant protocatechuic acid (PA) on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse skin tumor promotion were investigated. Dimethylbenz[a]anthracene-initiated female ICR mice were treated with TPA (1.6 nmol) twice weekly for 20 weeks to promote papilloma formation. Pre-treatment with 16nmol PA 30 min prior to each TPA treatment significantly inhibited the number of papillomas per mouse by 52% (P < 0.05). On the other hand, PA pre-treatment at a high dose (1600 nmol) significantly enhanced tumor numbers by 38% (P < 0.05). Interestingly, in the group treated with a quite high dose (20000 nmol) of PA 5 min prior to each TPA application, the average number of tumors per mouse was reduced by 38%, whereas the same PA dose 3 h before TPA treatment significantly enhanced tumor numbers by 84% (P < 0.01). These results suggested that topically applied PA was converted to compound(s) lacking antioxidative properties and/or rather possessing the potential to enhance tumor development. A similar tendency was also observed in the short-term experiment of TPA-induced inflammation and oxidative stress; i.e. two groups pre-treated with PA at 20000 nmol, 30min and 3h before TPA treatment, did not show suppression or even significantly enhanced TPA-induced leukocyte infiltration, H(2)O(2) generation, thiobarbituric acid-reacting substances level and proliferating cell nuclear antigen index, while PA treatment together with TPA significantly suppressed these parameters. Treatment with a high dose (20000 nmol) of PA alone for 3h enhanced oxidative stress by reducing glutathione levels in mouse skin, which was counteracted by the tyrosinase inhibitor arbutin. Oxidative stress responses such as leukocyte infiltration and H(2)O(2) generation were also counteracted by arbutin. These results suggested that tyrosinase-dependent oxidative metabolism of PA was at least partially involved in the enhanced effects of PA on TPA-induced inflammatory responses and thus tumor promotion.

Preparation and controlled-release studies of a protocatechuic acid-magnesium/aluminum-layered double hydroxide nanocomposite

“…Protocatechuic acid terminates these attacks through its scavenging and chelating activities. 28 Further, protocatechuic acid demonstrates other remarkable pharmacological activities such as anticancer, 29 antitumor, 30 antimutagenic, 31 antibacterial, 32 anti-inflammatory, 33 antigenotoxic, 34 cardioprotective, and chemopreventive. 35 It has been shown to cause markedly apoptotic effects in the treatment of several types of cancer cells, including human leukemia (pa-2000-leukemia), cervix, breast, lung, liver, and prostate.…”

In vitrostudy on cytotoxic effect and anti-DENV2 activity ofCarica papayaL. leaf

“…The fresh leaf contains the richest source of minerals with antioxidant properties that may help to increase the hemoglobin, hematocrit, RBC and total protein contents (Halim et al 2011), and thrombocyte count (Kathiresan et al 2009). The leaf contains xanthine oxidase inhibitors (anti-gout) (Saiful et al 2012) and protocatechuic acids such as simple phenolic antioxidants (Hyogo et al 2010;Nakamura et al 2000) which could scavenge superoxide free radicals induced by DENV2. The plant leaf extract inhibited lipid peroxidation in rat liver and brain and has been shown to have in vitro 2,2-diphenylpicrylhydrazyl (DPPH) (Lee et al 2011), 2,2-Azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS), nitric oxide, superoxide radical, and hydroxide radical scavenging activity (Srikanth et al 2010).…”

Antioxidant Defense and UV-Induced Melanogenesis: Implications for Melanoma Prevention

“…Liu et al, 2011;Marrot et al, 2008;Schafer et al, 2010). It has been demonstrated that inhibition of tyrosinase involved in upregulation of GSH detoxification systems including GSH content and GPx and GST activities was able to suppress tumor promotion in mouse skin (Nakamura et al, 2000). Moreover, an influence of GST variations (e.g., GST deficiency) on melanoma risk has been previously discussed (Mossner et al, 2007).…”