Exploiting Tyrosinase Expression and Activity in Melanocytic Tumors

Abstract

Melanoma is an aggressive tumor that expresses the pigmentation enzyme tyrosinase. Tyrosinase expression increases during tumorigenesis, which could allow for selective treatment of this tumor type by strategies that use tyrosinase activity. Approaches targeting tyrosinase would involve gene transcription or signal transduction pathways mediated by p53 in a direct or indirect manner. Two pathways are proposed for exploiting tyrosinase expression: (a) a p53-dependent pathway leading to apoptosis or arrest and (b) a reactive oxygen species-mediated induction of endoplasmic reticulum stress in p53 mutant tumors. Both strategies could use tyrosinase-mediated activation of quercetin, a dietary polyphenol that induces the expression of p53 and modulates reactive oxygen species. In addition to antitumor signaling properties, activation of quercetin could complement conventional cancer therapy by the induction of phase II detoxification enzymes resulting in p53 stabilization and transduction of its downstream targets. In conclusion, recent advances in tyrosinase enzymology, prodrug chemistry, and modern chemotherapeutics present an intriguing and selective multitherapy targeting system where dietary bioflavonoids could be used to complement conventional cancer treatments.

Induction of Apoptosis and Inhibition of Angiogenesis by PEGylated Liposomal Quercetin in Both Cisplatin-Sensitive and Cisplatin-Resistant Ovarian Cancers

“…17 Que can also down-regulate the expression of oncogenes, e.g., c-myc and ki-ras 17 and induce wild-type p53. 18 All these data suggest that Que has the potential to be developed as an anticancer agent. The extreme water insolubility of Que hampers its delivery to the tumor at an effective concentration.…”

Quercetin in Cancer Prevention and Therapy

“…40 The way by which quercetin induces apoptosis in cancer cells is therefore more complex than the inhibition of PI3K/Akt/IKK/NF-κB axis and may occur regardless of p53 involvement. 21,39 Nevertheless, other ways are not less complicated. Without considering the role of quercetin in the oxidative pathway, the flavonol is a direct inhibitor of GSK-3β, a component of GSK-3β/β-catenin signaling pathway, whose inhibition leads to the suppression of cell cycle and induction of apoptosis.…”

“…However, the role of the quercetin molecule in NF-κB-p53 cross-talk still remains obscure. A relationship between quercetin and p53 has been reviewed recently, 20,21 but quercetin appears to be able to induce apoptosis regardless of the p53 signaling pathway. 21 Furthermore, this flavonoid is able to curb the PI3K/Akt/IKKα/NF-κB pathway in human salivary adenoid cystic carcinoma leading to the induction of cell apoptosis through a mitochondria-dependent mechanism.…”

“…A relationship between quercetin and p53 has been reviewed recently, 20,21 but quercetin appears to be able to induce apoptosis regardless of the p53 signaling pathway. 21 Furthermore, this flavonoid is able to curb the PI3K/Akt/IKKα/NF-κB pathway in human salivary adenoid cystic carcinoma leading to the induction of cell apoptosis through a mitochondria-dependent mechanism. 22 In these cells, PI3K/Akt/IKKα/NF-κB signaling pathway (Figure 2) plays a role in evading cell apoptosis; quercetin promotes cancer cell apoptosis by blocking PI3K/Akt upstream of the NF-κB signaling.…”

Quercetin in Cancer Treatment, Alone or in Combination with Conventional Therapeutics?

“…As mentioned above, it is known that flavonoids and isoflavonoids inhibit glucose influx [9,10]. In this context, it has been studied the action of these substances as competitive inhibitors of glucose transporter 1 (GLUT-1) [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. This glucose transporter has three ATP binding domains that are essential for its conformation and affinity.…”