Nobiletin from Citrus Fights Cancer, Heals Liver, Heart
Citrus peels are increasingly attracting research attention. This is no mistake, as we find studies proving that citrus peel can help prevent cancer and help the liver heal.
Peels can be healthier
The peels of many common fruits are healthier than the fruit inside. This is because the fruit tree will produce defensive mechanisms that will help protect its seeds.
After all, the seeds are the tree’s potential offspring. Fruits and their seeds contain the potential of the tree to reproduce. One might even suggest that the seeds are in fact the tree’s babies – but in fetal form. Each seed can germinate into a whole tree – an amazing feat of nature. But I digress.
The point is that these seeds are important to the fruit tree. For this reason, the tree produces a number of defense mechanisms to protect these important seeds. These include the obvious, such as a hard rind or shell over the seed(s). But these rinds or shells also include special biochemicals produced by the tree that act in numerous ways: Namely to serve as antioxidants, natural pesticides and antimicrobials.
Because of this, the rinds and peels of even the most delicious juicy and sweet fruits will provide our bodies with these same antioxidants and antimicrobials, which in turn help our bodies defend against diseases and invaders. Some of these compounds have also been found to communicate with our own defense mechanisms – stimulating our immune cells when invaders threaten our tissues and cells.
The amazing anti-cancer nobiletin
One of these special biochemicals is nobiletin. Nobiletin is what is called a polymethoxylated flavone. A flavone is a type of flavonoid – which are often found among citrus plants and a number of herbal medicines. Flavones have a number of medicinal effects upon the human body. They are antioxidants, but also tend to be antimicrobial and anticancer as well.
In particular, this nobiletin flavone is found most often among citrus peels. These include oranges, mandarins, tangerines and other citrus. Other polymethoxy flavones in citrus include tangeretin, hesperidin and hesperetin, and other important citrus flavonoids include naringenin, and naringin.
But nobiletin has gained significant traction in medical research due to its outstanding benefits to our health. As a result, over the past decade, nobiletin has been studied extensively by medical researchers from around the world. As we’ve reported in other articles, nobiletin and other components of citrus peel can reduce LDL-cholesterol, halt diabetes in its tracks and inhibit cancer growth.
Most of us have been oblivious to the fact there has been a flurry of research showing that not only does citrus oil provide aromatherapy – helping to calm the mind – but a flavonoid extract of the citrus peel called nobiletin halts cancer growth among liver cells and others.
Multiple cancers halted by nobiletin
Speaking of cancer, several studies in the past year or two have found that nobiletin inhibits several types of cancer growth.
Researchers from Japan’s NARO Western Region Agricultural Research Center found that nobiletin inhibits the growth of leukemia by modulating the natural killer cell function. This was accomplished through the biochemical modulating the genetic processes of these natural killer cells.
Another, more recent study found that nobiletin inhibits the growth of lung cancer cells through a process called notch signalling.
Researchers from West Virginia’s Alderson Broaddus University found that nobiletin isolated from citrus peels inhibited the growth of two types of prostate cancers. This was accomplished through another complex genetic modulation, including the blocking of VEGF.
Researchers from Taiwan’s Chung Shan Medical University also studied the effects of nobiletin on leukemia cells. In this study they found that nobiletin blocked the proliferation of the leukemia cells. This means that the citrus peel extract blocked the growth of leukemia.
Researchers from Japan’s Nakamura Gakuen University found that nobiletin blocked the growth of three different types of breast cancers. Once again the mechanisms were complex, but in general, they suppressed the growth of the cancer cells through genetic switching.
Research from Japan’s Kansai University and Mukogawa Women’s University tested nobiletin on non-small-cell lung cancer cells. Once again, they found the citrus peel extract inhibited the growth of the cancer cells in laboratory tests.
Research from Japan’s Nakamura Gakuen University, studied several human lines of breast cancer cells. These included the cell lines MCF-7, HER2-positive SK-BR-3, and triple-negative MDA-MB-468. These represent a significant swath of potential breast cancers that occur among women.
The researchers found the citrus peel extract nobiletin inhibited the growth of all three breast cancer lines, with the most being the MDA-MB-468 cell line. This was extracted from a 51-year old African American woman with adenocarcinoma – breast cancer.
The significant point about this study is that the citrus peel extract blocked tumor growth on a dose-dependent manner. This means the effect was definite – the more dose, the greater the inhibition.
The inhibition was also time-dependent. This means the effect continued over the duration of the treatment.
Liver and stomach cancers halted by citrus peel extracts
It doesn’t stop there. Sichuan University researchers studied human liver cancer cell lines with nobiletin and found the extract halted the growth of SMMC-7721 tumor cells.
In this study also, the tumor inhibition effect was found to be dose-dependent. The greater the nobiletin dose, the more tumor cells died.
Researchers from Korea’s Jeju National University tested nobiletin against human stomach cancer cells. Again they used a human gastric cancer cell line, the SNU-16 cell line.
Again they found that the citrus peel extract halted the growth of the cancer cells, against in a dose-dependent manner. When the researchers tested the nobiletin together with the chemotherapy drug 5-fluorouracil, the cancer-killing effect was increased as compared with the chemotherapy drug alone.
This strategy of combining nobiletin with chemotherapy drugs has been tested in other studies. For example, nobiletin research from Japan’s Osaka University of Pharmaceutical Sciences found that the citrus extract nobiletin inhibits the growth of non-small-cell lung cancer in human cells.
Non-small-cell lung cancer often escapes chemotherapy solutions. The researchers tested two human non-small-cell lung cancer cell lines A549 and H460. They tested paclitaxel and carboplatin with the cancer cells and then added nobiletin in combination and found that the nobiletin killed the non-small lung cancer cells the chemotherapy missed.
Other cancers, such as leukemia, have also been found to be potentially treated with nobiletin.
Mechanisms of nobiletin’s anticancer effects
In many of these studies, the mechanisms involved in the citrus peel extract’s ability to halt the cancer growth was the stimulating or modulating a genetic change that helps the body kill tumor cells.
In other words, the citrus peel extract actually stimulates the body’s own mechanisms for killing cancer cells.
Even the healthiest of us must deal with cancer cells all the time. A cancerous cell growth will occur quite often. But a healthy body will initiate what is called apoptosis – the killing of the cancer cell. This is initiated through the Bcl-2 protein and others – typically driven by the immune system.
But when our body and its immune system is overburdened, the cancer growth can get out of hand.
Liver health and nobiletin
We can now add liver health to the above benefits of nobiletin. Recently researchers from Japan’s College of Life Sciences in Kusatsu produced a nobiletin extract from the peels of the chinpi fruit – Citrus unshiu.
They then tested liver cells in a laboratory and found using chromatography that the nobiletin stimulated a healing process among the cells by limiting the produced nitric oxide and stimulated a genetic change (blocking iNOS) that produced a healing effect.
The researchers concluded from this finding that nobiletin has a healing effect upon the liver:
“The suppression of iNOS induction by nobiletin suggests that nobiletin may be responsible for the anti-inflammatory effects of citrus peels and have a therapeutic potential for liver diseases.”
Cholesterol and orange peels
A new study has found that a polymethoxylated flavonoid called nobiletin found in orange peels reduces very low density cholesterol (VLDL and LDL) levels. The researchers, from the Robarts Research Institute of London and Ontario, found that the secretion of LDL and VLDL by human liver cells was significantly inhibited by nobiletin.
They also found that the polymethoxylated flavonoid, with a chemical structure of 3’4’5,6,7,8-hexamethoxyflavone, reduced VLDL levels found in insulin resistance and atherosclerosis.
LDL and VLDL are implicated in cardiovascular disease, because they promote something called lipid peroxidation, which damages the arteries.
This confirms the research by Agricultural Research Service (ARS) scientists who found that 3’4’3,5,6,7,8-heptamethoxyflavone (HMF), another citrus polymethoxylated flavone, inhibited a precursory protein called apoprotein B found within low-density lipoprotein (LDL).
John Manthey, a chemist for the ARS from the USDA’s Winter Haven lab, is a leading citrus peel researcher. He has been researching the orange oils within orange peels for several years.
Citrus peel constituents
Citrus peels contain several polymethoxylated flavonoids (PMFs). Nobiletin is a O-methylated flavone. It renders a hydroxyl group that mediates a reaction called O-methylation. Methylation allows for the donation of methyl groups, which provide radical-neutralizing effects, as well as the inhibition of lipid peroxide-friendly LDL cholesterol apoprotein B. Other O-methylated flavones include tangeritin (first found in tangerine oil), wogonin (found in the herb baikal scullcap), and sinensetin, found in the Java tea herb Orthosiphon stamineus.
Citrus peels can contain as much as 70% oil. The oil contains a number of other healthful components including limonene and linalool. Limonene is monoterpene known for its antimicrobial and radical-scavenging abilities.
Most applications of citrus remove the peel and toss it out. In a good year, over 700,000 tons of peel solids will be discarded or sold for feed.
Eating the rind and the citrus fruit like an apple is obviously one strategy. Another strategy would be to just peel or slice off the very outer rind and leave as much of the inner peel as possible. The bitterness of the peel may take a bit to get used to, but after awhile it will take on a taste of its own and complement the sweeter inner fruit.
Another compound found in citrus peels is modified citrus pectin. Other research finds MCP helps the body detoxify and boosts immune function. Citrus peels also inhibit bacteria according to other research.
Ma X, Jin S, Zhang Y, Wan L, Zhao Y, Zhou L. Inhibitory effects of nobiletin on hepatocellular carcinoma in vitro and in vivo. Phytother Res. 2014 Apr;28(4):560-7. doi: 10.1002/ptr.5024. Epub 2013 Jul 1,
Chen C, Ono M, Takeshima M, Nakano S. Antiproliferative and apoptosis-inducing activity of nobiletin against human breast cancer cell lines. Anticancer Res. 2014 Apr;34(4):1785-92.
Uesato S, Yamashita H, Maeda R, Hirata Y, Yamamoto M, Matsue S, Nagaoka Y, Shibano M, Taniguchi M, Baba K, Ju-ichi M. Synergistic antitumor effect of a combination of paclitaxel and carboplatin with nobiletin from Citrus depressa on lung cancer cell lines. Planta Med. 2014 Apr;80(6):452-7. doi: 10.1055/s-0034-1368321.
Hsiao PC, Lee WJ, Yang SF, Tan P, Chen HY, Lee LM, Chang JL, Lai GM, Chow JM, Chien MH. Nobiletin suppresses the proliferation and induces apoptosis involving MAPKs and caspase-8/-9/-3 signals in human acute myeloid leukemia cells. Tumour Biol. 2014 Dec;35(12):11903-11. doi: 10.1007/s13277-014-2457-0.
Meiyanto E, Hermawan A, Anindyajati. Natural products for cancer-targeted therapy: citrus flavonoids as potent chemopreventive agents. Asian Pac J Cancer Prev. 2012;13(2):427-36.
Moon JY, Cho M, Ahn KS, Cho SK. Nobiletin induces apoptosis and potentiates the effects of the anticancer drug 5-fluorouracil in p53-mutated SNU-16 human gastric cancer cells. Nutr Cancer. 2013;65(2):286-95. doi: 10.1080/01635581.2013.756529.
Chen J, Creed A, Chen AY, Huang H, Li Z, Rankin GO, Ye X, Xu G, Chen YC. Nobiletin suppresses cell viability through AKT pathways in PC-3 and DU-145 prostate cancer cells. BMC Pharmacol Toxicol. 2014 Oct 24;15:59. doi: 10.1186/2050-6511-15-59.
Saito T, Abe D, Nogata Y. Polymethoxylated flavones potentiate the cytolytic activity of NK leukemia cell line KHYG-1 via enhanced expression of granzyme B. Biochem Biophys Res Commun. 2015 Jan 16;456(3):799-803. doi: 10.1016/j.bbrc.2014.12.027.
Gao XJ, Liu JW, Zhang QG, Zhang JJ, Xu HT, Liu HJ. Nobiletin inhibited hypoxia-induced epithelial-mesenchymal transition of lung cancer cells by inactivating of Notch-1 signaling and switching on miR-200b. Pharmazie. 2015 Apr;70(4):256-62.
Mulvihill EE, Assini JM, Lee JK, Allister EM, Sutherland BG, Koppes JB, Sawyez CG, Edwards JY, Telford DE, Charbonneau A, St-Pierre P, Marette A, Huff MW. Nobiletin attenuates VLDL overproduction, dyslipidemia, and atherosclerosis in mice with diet-induced insulin resistance. Diabetes. 2011 May;60(5):1446-57.
Manthey JA, Bendele P. Anti-inflammatory activity of an orange peel polymethoxylated flavone, 3′,4′,3,5,6,7,8-heptamethoxyflavone, in the rat carrageenan/paw edema and mouse lipopolysaccharide-challenge assays. J Agric Food Chem. 2008 Oct 22;56(20):9399-403.