Vanillin Analogues o-Vanillin and 2,4,6-Trihydroxybenzaldehyde Inhibit NFĸB Activation and Suppress Growth of A375 Human Melanoma

Abstract

Abstract. Background Nuclear factor kappa-B (NFĸB) is a transcription factor playing a crucial role in malignant diseases (1-4). Upregulation of NFĸB activity is detected in various human tumours (5-7), including pancreatic adenocarcinoma (8), breast cancer (9), and melanoma (10), where it may contribute to malignant behaviour. In particular, NFĸB activation has been associated with cancer development and progression (5, 11), and may inhibit apoptosis and favour cancer cell proliferation, invasion, angiogenesis, and metastasis (12, 13). Importantly, increased NFĸB activation may induce tumour immune escape and chemotherapy resistance (14-16). Chemotherapy-induced cellular stress, in turn, might further increase NFĸB activity of tumour cells, protecting them from chemotherapy-induced apoptosis (17)(18)(19). Therefore, NFĸB signaling pathways could serve as potential targets for cancer therapy.Vanillin (4-hydroxy-3-methoxybenzaldehyde; compound 10, Table I) is a major component of the bean and pod of some plant species of the Vanilla genus, and is also synthesized on a large scale for use as a flavouring agent in food, fragrance and pharmaceutical industries. Multiple biological effects have been documented for vanillin. It exhibits antioxidant (20, 21), antimicrobial (22), analgesic (23, 24) and anti-sickling (25) properties. It was also proven to be an anticarcinogen in rats (26) and an antimutagen in a variety of in vitro models (27)(28)(29). Vanillin is relatively noncytotoxic towards cultured mammalian cells, but does potentiate the cytotoxicity of some DNA-damaging agents, including cisplatin (30) and mitomycin C (31), a property which correlates with its ability to impair DNA double-strand break repair via inhibition of DNA protein kinase (30). Although unable to suppress primary tumour growth itself, vanillin was found to exert anti-metastatic activity in the 4T1 mouse mammary carcinoma spontaneous metastasis model, and to inhibit tumour cell invasion and migration in vitro 5743

Vanillin Suppresses Cell Motility by Inhibiting STAT3-Mediated HIF-1α mRNA Expression in Malignant Melanoma Cells

“…Vanillin, a widely used flavoring agent from vanilla, has been shown to exhibit multiple biological effects, including anti-cancer, anti-mutagenic, and anti-bacterial activity in mammalian cells [9,14,23]. In this study, we demonstrate that vanillin effectively decreases HIF-1α protein levels and the expression of its target genes related to cell motility, angiogenesis, and glycolytic metabolism in A2058 and A375 malignant melanoma cells.…”

“…Vanillin derivatives can be developed to improve delivery efficacy at low concentrations, which are more effective for preventing malignant melanoma metastasis. Indeed, a recent report showed that 60 mg/kg/day of o -vanillin, a vanillin isomer, strongly suppressed tumor growth in mice bearing A375 human malignant melanoma xenografts [14]. For clinical application, it should be further evaluated whether o -vanillin has anti-metastatic effects via the inhibition of HIF-1α accumulation.…”

“…Vanillin inhibited mutagen induced-DNA damage or spontaneous mutation in bacteria and human cells by eliciting DNA repair [9,10,11]. Recent reports have shown that vanillin has anti-cancer effects through increased apoptosis and cell cycle arrest in melanoma, colon, and cervical cancer cells [12,13,14]. In addition, vanillin has also been reported to exhibit anti-invasive and anti-metastatic activities by suppressing the phosphoinositide 3-kinase (PI3K) and NF-κB signaling pathways in lung, breast, and liver cancer cells [15,16,17].…”

Diallyl trisulfide suppresses doxorubicin‐induced cardiomyocyte apoptosis by inhibiting MAPK/NF‐κB signaling through attenuation of ROS generation

“…Evidence indicates that NADPH oxidase‐derived, ROS‐induced apoptosis in cardiomyocytes exposed to high glucose is mediated via the JNK‐dependent activation of NF‐κB . Interesting, Marton's study demonstrated that NFkB activation was increased in Dox‐treated cell, and inhibition of NFkB activation can suppress cell growth . Another study by Li's group indicated that suppression of p65 by siRNA resulted in the inhibition of Dox‐induced cardiac apoptosis, indicating NFkB activation is involved in the Dox‐induced cardiac cell death .…”

Standardization of A375 human melanoma models on chicken embryo chorioallantoic membrane and Balb/c nude mice

“…This has contributed to the molecular elucidation of this aggressive type of tumor behavior, in terms of invasiveness (16), brain metastasis (42), angiogenesis and lymphangiogenesis (41,42), or the evaluation of compounds with promising effects by modulating different targets (43). …”