Nutr Cancer. 2013;65(4):600-10. doi: 10.1080/01635581.2013.776091.

β-ionone induces cell cycle arrest and apoptosis in human prostate tumor cells.

Jones S, Fernandes NV, Yeganehjoo H, Katuru R, Qu H, Yu Z, Mo H.

Department of Nutrition and Food Sciences, Texas Woman’s University, Denton, Texas 76204, USA.

 

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 endring 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.

PMID: 23659452

 

Supplement:

Fruits, vegetables, and grains are sources of anticarcinogenic agents such as phytochemicals, often called “phytonutrients” in the media.  β-ionone (Figure 1) is a type of phytochemical categorized as an isoprenoid and exhibits the five-carbon isoprene unit common among isoprenoids.  It is an end ring analog of β-carotene and is a component of many foods that contain β-carotene. Foods in which β-ionone can be found include apricots, beans, bell peppers, blackberries, blueberries, broccoli, carrots, cherries, citrus fruit, corn, grapes and wine, mangos, parsley, peaches, plums, raspberries, strawberries, sweet potatoes, and tomatoes.  It is a passive constituent of milk.  It is also used in fragrance and perfumery.

Many nonsterol isoprenoids, including β-ionone, are synthesized by the mevalonate pathway (Figure 2) in cells.  Mevalonate is formed by the action of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase) and is an important intermediate in the biosynthesis of cholesterol.  HMG CoA reductase is the rate-limiting enzyme of the mevalonate pathway.  Two intermediates of the pathway, farnesyl pyrophosphate and geranylgeranyl pyrophosphate, are essential substrates for post-translational processing or prenylation of proteins (nuclear lamins and small G proteins such as p21 ras) integral to cell proliferation.

The activity of HMG CoA reductase is partly controlled by cholesterol levels through a feedback mechanism at the transcriptional level and post-transcriptional control.  Total suppression of the reductase activity requires at least two mevalonate products, a sterol (usually cholesterol from LDL) and a nonsterol metabolite.  Isoprenoids have been determined to be involved in feedback regulation of HMG CoA reductase and to suppress the enzyme.  The reductase in tumor cells is resistant to sterol feedback regulation, but it is highly sensitive to post-transcriptional regulation mediated by isoprenoids that can promote the degradation of the enzyme.  This makes the dysregulated HMG CoA reductase the “Achilles’ heel” of tumors and vulnerable to phytochemicals such as β-ionone. When reductase is degraded and activity is suppressed, intermediates in the mevalonate pathway are depleted and become limiting factors for the posttranslational processing and prenylation of growth-related proteins necessary for the accelerated growth of tumor cells (3).  The main effect is that tumor cell growth is inhibited.

β-Ionone is known to downregulate HMG CoA reductase (4), and consequently to suppress tumor cell proliferation by inducing cell cycle arrest at the G1 phase in numerous cancer cell lines.  As expected, this study demonstrated that β-ionone suppressed the proliferation of prostate cancer cell lines PC-3, LNCaP, and DU145 cells in a concentration-dependent fashion.  Cell cycle arrest at the G1 phase, initiation of apoptosis, and downregulation of HMG CoA reductase were exhibited.  Lovastatin and trans, trans-farnesol were synergistic with β-ionone in inhibiting tumor cell growth.  We have also previously shown that certain chemical derivatives based on the structure of β-ionone may have higher anti-tumor potential.

Unlike β-carotene, β-ionone does not possess much antioxidant activity. A recent JAMA study showed that antioxidant intake had no impact on overall mortality. Another paper recently appeared in the journal Science demonstrated that antioxidants accelerated lung cancer progression in mice. The tumor-suppressive activity of β-ionone and isoprenoids is likely independent of antioxidant functions.

 

Important Points:                                                                            

1.  Isoprenoids, including β-ionone, suppress HMG CoA reductase activity.  Consequently, β-ionone inhibits growth of tumor cells.  The growth of 3 types of prostate cancer cells were inhibited in this study.

2. The activity of β-ionone and other isoprenoids on HMG CoA reductase may offer a mechanism for prostate cancer chemoprevention and chemotherapy (4) and for other cancers, as well.

3.  The synergistic impact of β-ionone and other isprenoids from fruits, vegetables, and grains may be chemoprotective, so following the dietary guidelines that emphasize intake of plant foods may decrease the incidence of certain cancers, including prostate cancer.

4.  Normal cells are somewhat resistant to β-ionone-mediated growth suppression, so the growth of normal cells are not affected as much as tumor cells.

Huanbiao Mo-fig1

Figure 1.  Structure of β-ionone.



Huanbiao Mo-fig2

Figure 2.  A simplified mevalonate pathway highlighting some of the important intermediates and the regulation of the pathway.

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