beta-ionone and Neoplasm-Metastasis

β-Ionone is an end-ring analog of β-carotenoids which widely distributed in fruit and vegetables. Recent studies have demonstrated anti-proliferative, anti-metastatic and apoptosis induction properties of β-ionone in vitro and in vivo. Also, the studies have focused on investigating the β-ionone action on different types of malignant cells and the possible mechanisms of action. Moreover, the quest of new synthetic β-ionone-based compounds possessing anti-proliferative, anti-metastatic and apoptosis induction activities may enable the discovery of compounds which can be used in combination regimes thus overcoming tumor resistance to conventional anticancer agents. These new agents will also be useful for targeting distinct signaling pathways, to activate selectively mechanisms for apoptosis in cancer cells but devoid of undesirable side effects. In this paper, we reviewed the potentialities of β-ionone and related compounds in cancer prevention and chemotherapy.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Humans; Neoplasm Metastasis; Norisoprenoids; Signal Transduction

We previously reported that the olfactory receptor OR51E2, overexpressed in LNCaP prostate cancer cells, promotes cell invasiveness upon stimulation of its agonist β-ionone, and this phenomenon increases metastatic spread. Furthermore, we showed that the induced cell invasiveness involves a PI3 kinase dependent signalling pathway. We report here the results of a new investigation to address whether gallein, a small inhibitor of G protein βγ subunit interaction with PI3 kinase, can inhibit β-ionone effects both in vitro and in vivo.. We demonstrate that gallein can inhibit the β-ionone-induced cell invasiveness in vitro, as well as the spread of metastases in vivo. LNCaP cell invasiveness, assessed using spheroid cultures in collagen gels in vitro, was increased by β-ionone and the effect was reversed by co-administration of gallein. LNCaP tumour cells, subcutaneously inoculated to immunodeficient mice, generated more metastases in vivo when β-ionone was applied through the skin. Furthermore, the intraperitoneal injection of gallein inhibited this increased metastasis spread. Our results thus support the role of OR51E2 in the β-ionone observed effects, and suggest that gallein could be a potential new agent in personalized medicine of the tumours expressing OR51E2.

Topics: Animals; Cell Line, Tumor; GTP-Binding Protein beta Subunits; GTP-Binding Protein gamma Subunits; Humans; Male; Mice; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Norisoprenoids; Prostatic Neoplasms; Receptors, Odorant; Signal Transduction; Tumor Cells, Cultured; Xanthenes

Olfactory receptors are G protein-coupled receptors. Some of them are expressed in tumor cells, such as the OR51E2 receptor overexpressed in LNCaP prostate cancer cells. It is considered a prostate tumor marker. We previously demonstrated that this receptor is able to promote LNCaP cell invasiveness in vitro upon stimulation with its odorant agonist β-ionone, leading to increased generation of metastases in vivo. In the present study, we show that even a relatively short exposure to β-ionone is sufficient to promote metastasis emergence. Moreover, α-ionone, considered an OR51E2 antagonist, in fact promotes prostate tumor growth in vivo. The combination of α-ionone with β-ionone triggers a higher increase in the total tumor burden than each molecule alone. To support the in vivo results, we demonstrate in vitro that α-ionone is a real agonist of OR51E2, mainly sustaining LNCaP cell growth, while β-ionone mainly promotes cell invasiveness. So, while structurally close, α-ionone and β-ionone appear to induce different cellular effects, both leading to increased tumor aggressiveness. This behaviour could be explained by a different coupling to downstream effectors, as it has been reported for the so-called biased ligands of other G protein-coupled receptors.

Topics: Animals; Cell Line, Tumor; Cell Movement; Disease Progression; Humans; Male; Mice; Neoplasm Metastasis; Neoplasm Proteins; Neoplasm Transplantation; Norisoprenoids; Prostatic Neoplasms; Receptors, Odorant; Up-Regulation

We identified the olfactory receptor 51E2 in human melanoma and have measured both OR51E2 mRNA and protein expression in melanoma tissue sections. qPCR analysis revealed that the receptor is upregulated in melanoma cells compared to normal melanocytes, indicating that OR51E2 may play a role in early melanoma development and progression. Activation of endogenous OR51E2 in cultured cells derived from metastatic and vertical-growth phase (VGP) by its ligand β-ionone results in an increase in the intracellular Ca

Topics: Calcium; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Gene Expression Regulation, Neoplastic; Humans; Ligands; Melanocytes; Melanoma; Neoplasm Metastasis; Neoplasm Proteins; Norisoprenoids; Polymerase Chain Reaction; Real-Time Polymerase Chain Reaction; Receptors, Odorant; RNA Interference; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Skin Neoplasms; Treatment Outcome

The combination of anti-cancer drugs with nutritional factors is a potential strategy for improving the efficacy of chemotherapy, particularly for hepatocellular carcinoma because its conventional therapies are mostly ineffective. Using a highly invasive hepatoma SK-Hep-1 cell line, we investigated the possible synergistic anti-metastatic efficacy of a combination of sorafenib (SF), a multi-kinase inhibitor, and β-ionone (BI), a precursor of carotenoids. We found that SF (1 μM) in combination with BI (1 μM) synergistically inhibited cell invasion and additively inhibited cell migration, especially at 48 h of incubation. Mechanistically, the combination of SF and BI was found to decrease the protein expression of focal adhesion kinase (FAK) and Rho, and to enhance the protein expression of tissue inhibitor matrix metalloproteinase (TIMP)-1 and TIMP-2. In addition, the combination of SF and BI inhibited the activity of matrix metalloproteinase (MMP)-2 and MMP-9 and decreased the phosphorylation of FAK and of Rac1 proteins. Importantly, SF enhanced the suppressing effect of BI (1-50 μM) on the viability of SK-Hep-1 cells, but not on murine hepatic BNL CL.2 cells, indicating the selective cytotoxicity of this combination on tumor cells. The combination of SF and BI could be a potential therapeutic strategy against human hepatoma cells.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Carcinoma, Hepatocellular; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cell Survival; Drug Synergism; Focal Adhesion Protein-Tyrosine Kinases; Humans; Liver Neoplasms; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neoplasm Invasiveness; Neoplasm Metastasis; Niacinamide; Norisoprenoids; Phenylurea Compounds; Phosphorylation; Pyridines; rac1 GTP-Binding Protein; rho GTP-Binding Proteins; Sorafenib; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2

To determine the effect of beta-ionone on the potential metastasis of human gastric adenocarcinoma cell line SGC-7901 and the underlying mechanism.. Using curve of cellular growth, Zymograms, and RT-PCR assays, we analyzed the growth rate, the activities of two types IV collagenase of Matrix met alloproteinase 9 (MMP-9) and MMP-2 and the expression of nm23-H1 gene, tissue inhibitor of met alloproteinase 1 (TIMP-1) and TIMP-2 in SGC-7901 cells which were treated with progressively increasing concentrations (25, 50, 100 and 200 micromol/L) of beta-ionone for 24 h and 48 h.. The growth of SGC-7901 cells was inhibited by beta-ionone. Eight days after treatment with different concentrations of beta-ionone, as mentioned above, the inhibition rates were 25.93%, 28.21%, 74.36% and 90.11%, respectively compared to the negative control. The estimated IC50 value of beta-ionone for SGC-7901 cells was estimated to be 89 micromol/L; beta-ionone did not show any effect on the activities of MMP-9 and MMP-2 in SGC-7901 cells. However, the expression of nm23-H1, TIMP-1 and TIMP-2 mRNA transcripts gradually increased in response to beta-ionone in a dose-dependent manner.. beta-ionone can inhibit the growth and proliferation of SGC-7901 cells. It may show some effects on the potential metastasis of SGC-7901 cells indicates by its upregulation of nm23-H1, TIMP-1 and TIMP-2 expression. However, beta-ionone may have no effect on the activities of type IV collagenase in SGC-7901 cells. The mechanism by which beta-ionone inhibits the potential metastasis of SGC-7901 cells needs to be studied further.

Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Proliferation; Humans; Neoplasm Metastasis; NM23 Nucleoside Diphosphate Kinases; Norisoprenoids; RNA, Messenger; Stomach Neoplasms; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2