β-Ionone Induces Cell Cycle Arrest and Apoptosis in Human Prostate Tumor Cells

Abstract

3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase is the rate-limiting activity in the mevalonate pathway that provides essential intermediates for posttranslational modification of growth-associated proteins. Assorted dietary isoprenoids found in plant foods suppress HMG CoA reductase and have cancer chemopreventive activity. β-Ionone, a cyclic sesquiterpene and an end-ring analog of β-carotene, induced concentration-dependent inhibition of the proliferation of human DU145 (IC50 = 210 μmol/L) and LNCaP (IC50 = 130 μmol/L) prostate carcinoma cells and PC-3 prostate adenocarcinoma cells (IC50 = 130 μmol/L). Concomitantly, β-ionone-induced apoptosis and cell cycle arrest at the G1 phase in DU145 and PC-3 cells were shown by fluorescence microscopy, flow cytometry, and TUNEL reaction, and downregulation of cyclin-dependent kinase 4 (Cdk4) and cyclin D1 proteins. Growth suppression was accompanied by β-ionone-induced downregulation of reductase protein. A blend of β-ionone (150 μmol/L) and trans, trans-farnesol (25 μmol/L), an acyclic sesquiterpene that putatively initiates the degradation of reductase, suppressed the net growth of DU145 cells by 73%, an impact exceeding the sum of those of β-ionone (36%) and farnesol (22%), suggesting a synergistic effect. β-ionone, individually or in combination with other HMG CoA reductase suppressors, may have potential in prostate cancer chemoprevention and/or therapy.

Anti-Proliferative and Apoptotic Effects of Beta-Ionone in Human Leukemia Cell Line K562

“…We found that the beta-ionone significantly in- showed β-ionone has an inhibitory effect on human gastric adenocarcinoma cells growth [21]. It would be compatible with the research by Zhu et al who have studied the effect of β-ionone on in human osteosarcoma (U2os) cells and has showed that this plant-derived compound is able to inhibit cell proliferation [22], also compatible with the research by Jones et al that examined the effect of β-ionone in human prostate tumor cells, and showed that β-ionone inhibited cell proliferation and activates apoptosis via the mitochondrial pathway [23]. In this case, similar observations have been reported in the previous studies with other natural plant products such as lycopene [24,25], silymarin [26], curcumin [27], epigallocatechin-3-gallate [28], celastrol [29], tea polyphenol [30], berberine [31], gossypol [32], wogonin [33], Korean red ginseng extract [34] and Curcuma longa extract [35] in various cancer cell lines.…”

Farnesol Has an Anti-obesity Effect in High-Fat Diet-Induced Obese Mice and Induces the Development of Beige Adipocytes in Human Adipose Tissue Derived-Mesenchymal Stem Cells

“…Farnesol, a typical isoprenol, has been reported to exhibit protective effects against many human cancers, such as lung, prostate, and colon cancer ( Au-Yeung et al, 2008 ; Jones et al, 2013 ; Gliszczyńska et al, 2016 ). Farnesol also has a critical role in the amelioration of inflammatory reactions by regulating major inflammation-related factors including proinflammatory cytokines, cyclooxygenase-2, and nitric oxide synthase ( Inoue et al, 2000 ; Ku and Lin, 2015 ; Santhanasabapathy et al, 2015 ).…”

Efeito quimiopreventivo da β-ionona na hepatocarcinogênese associada ao desenvolvimento de esteatose hepática não alcoólica em ratos Wistar

“…Além disso, embora a BI apresente a capacidade de modular tanto a proliferação celular quanto a apoptose (Liu et al, 2004, Janakiram et al, 2010, Jones et al, 2013) "in vitro", em nosso estudo "in vivo" não houve diferença no índice apoptótico do grupo AS+BI em relação ao grupo AS nas pLPN e rLPN, estes resltados corroboram com estudo prévio do grupo no qual a BI não modulou a apoptose em pLPN (Cardozo et al, 2010). Entretanto, a proliferação celular em pLPN foi reduzida no grupo AS+BI, demonstrando seu potencial quimiopreventivo nestas lesões que comumente evoluem para o HCC (Schulte-Hermann, 1990;De Miglio et al, 2003).…”

“…Entretanto, a proliferação celular em pLPN foi reduzida no grupo AS+BI, demonstrando seu potencial quimiopreventivo nestas lesões que comumente evoluem para o HCC (Schulte-Hermann, 1990;De Miglio et al, 2003). Relata-se que a BI suprime a proliferação por induzir a parada do ciclo celular na fase G1 de células neoplásicas de melanoma murino B16, leucemia promielocítica aguda humana HL-60, de adenocarcinoma do cólon humano Caco-2 e HCT116 (Jones et al, 2013). O ciclo celular é dirigido pela família de proteínas conhecidas como ciclinas dependentes de quinase (CDKs), a associação das CDKs com as ciclinas (A, B, D e E) forma complexos denominados Ciclina/CDK, que são ativados e promovem fosforilação de sítios específicos em CDKs, resultando no funcionamento normal do ciclo celular (Schwartz, 2002;Lopez-Mejia & Fajas, 2015).…”