June 18 2007 post: Here we go again. First it was mint leaves, now it’s olive leaves. Yesterday I was looking up something entirely different when I came across oleanolic acid, which is a triterpenoid (how’s that for a mouthful?) compound extracted from plant sources and food (even seedless raisins, I read). But it is also extracted from olive leaves (olea = olive). Olive leaves? Yes, I read that correctly: the leaves of Olea europaea, the common olive tree. I couldn’t stop reading, since I live in a country, indeed a region, famous for its delicious extra virgin olive oil (rightly so). Plus, my cousin is an extra virgin olive oil taster (yes, just like a sommelier, except she tastes and judges olive oil), and our wonderful extra virgin olive oil is given to us by a friend who owns an olive grove here in Tuscany.
So, just for the heck of it, I googled oleanolic acid and myeloma and, wouldn’t you know it?, there it was: a study on an olive leaf extract and MM cells, co-authored by Dr. Kenneth Anderson and published in “Molecular Cancer Therapeutics” in 2004. The full study can be read at: http://tinyurl.com/2okvod It is quite technical, but the conclusion is clear: a synthetic version of oleanolic acid, known as CDDO-Im, induced apoptosis in myeloma cells.
I called my husband, who laughed “boy, those MM cells get killed by practically anything, don’t they?” (Don’t we wish?!!!) But it (almost) seems to be true: any plant extract that I have looked up so far, and that has been tested in vitro against MM cells, appears to have an apoptotic effect on these malignant cells. Hmmm. Anyway, back to us and the oleanolic acid-MM study. In the Introduction, we can read that Chemoresistant MM cells have also been reported to inactivate anticancer drugs more efficiently than chemosensitive MM cells […]. In this regard, increases in the expression of glutathione (GSH) or the activity of GSH-related enzymes in MM cells has been associated with resistance to anticancer drugs […]. Novel treatment approaches that overcome such chemorefractory mechanisms may therefore be effective in the treatment of MM. CCDO-Im reduces the levels of GSH, which leads to the apoptosis of MM cells. The study continues: we analyzed the effects of the CDDO C-28 imidazolide ester (CDDO-Im) on MM cells. CDDO-Im is a potent inducer of apoptosis in MM cell lines and primary MM cells. Potent inducer of apoptosis in MM cells? What??? Hold on a sec, I’ll be right back. I am just going to pop over to ask my neighbour for some olive leaves from his gorgeous olive tree (see photo)! I could juice them! (Just kidding or am I? 
) 
Other effects of oleanolic acid. It has anti-inflammatory, hepatoprotective and anti-hyperlipidemic properties, see this 1995 study: http://tinyurl.com/2aa7vm It has anti-HIV activity, according to this 1999 study: http://tinyurl.com/ypahk9, and wound-healing potential (http://tinyurl.com/ytczrr). A 1999 study (http://tinyurl.com/2rhdpu) tells us that it suppresses the abilities of various inflammatory cytokines, such as IFN-, interleukin-1, and tumor necrosis factor-, to induce de novo formation of the enzymes inducible nitric oxide synthase (iNos) and inducible cyclooxygenase (COX-2) in mouse peritoneal macrophages, rat brain microglia, and human colon fibroblasts. CDDO will also protect rat brain hippocampal neurons from cell death induced by beta-amyloid.
A 2003 study suggests that it be used in breast cancer therapy: http://tinyurl.com/338z7b. It also “can provide a cheap and accessible source of additive to conventional treatment of hypertension, complicated by stenocardia and cardiac failure” (http://tinyurl.com/yo2pvv). There seems to be no end to its potential. Oh, it also fights the bacteria that cause cavities and gum disease, so make sure you include oleanolic acid-containing raisins in your diet. Oleanolic acid can also be found in medicinal herbs such as ligustrum, forsythia, and swertia, which are used in China to treat hepatitis. I will stop here, but there would be much more.
Last but not least, according to the IMF website (http://tinyurl.com/3dlsmr), Johns-Hopkins and Dartmouth are testing oleanolic acid, which is now in the preclinical stage. In fact, this excellent bit of news is hot off the press, see the May 22 issue of the Myeloma Minute: http://tinyurl.com/22faba!
February 13 2008 post (update): This morning I was going to write a post about a new plant extract that was found to kill myeloma cells in vitro, but then I received a peculiar Google Alert, so I am going to post about that instead: today’s edition of the Tamil Star (http://tinyurl.com/ywbegh) reports that, contrary to popular belief ( = raisins cause cavities), raisins fight cavities and gum disease thanks to these phytochemicals: “oleanolic acid, oleanolic aldehyde, betulin, betulinic acid, and 4-(hydroxymethyl)-2-furfural.”
January 26 2009 update. The blog reader (thanks, PvM!) who sent me all the cytogenetic studies on myeloma also provided me with a few studies on the cancer-killing compounds found in olive oil. Even though I have already dealt with the anticancer properties of olives, see my page on oleanolic acid, which is extracted mainly from olive leaves, I hadn’t seen this particular study, published in November 2008 in “The Journal of Nutrition” (full study: http://tinyurl.com/cprfho) and carried out by an Italian team from the University of Perugia, the lovely provincial capital of one of my favourite Italian regions, Umbria.
The researchers examined the effect of a virgin olive oil phenol extract (PE) on proliferation, the cell cycle distribution profile, apoptosis, and differentiation of the human promyelocytic cell line HL60. Phenols, incidentally, are rather acidic chemical compounds. Curcumin, for instance, is a phenolic compound from turmeric; so is capsaicin (<chilli peppers). And olive oil happens to be full of antioxidant phenolic compounds.
An interesting point: there is a clear association between the consumption of olive oil and a reduced risk of certain types of cancer: breast, ovary, prostate, colon and larynx. Olive oil has also been shown to suppress spontaneous liver tumorigenesis in mice and reduce skin carcinogenesis when applied topically both before and after exposure of mice to UV light. Hmmm, I didn’t know that…well, well…
In this study, the researchers incubated the leukemic cell line HL60 with PE, the above-mentioned olive oil extract (a complex mixture of phenols)…and, abracadabra!, after a few days, 100% were NECROTIC, even at rather low concentrations. One hundred percent! Put simply, PE not only inhibited proliferation of the leukemic cells but also killed them.
The researchers state (my emphasis) that Another important result of the present investigation is that PE can induce differentiation in HL60 cells. Although several previous studies showed that phenols present in wine and tea can induce differentiation in promyelocytic cell lines, as well as in other systems, to the best of our knowledge, our results are the first to show such an effect exerted by phenols from olive oil. Important, indeed!
Another significant excerpt: the researchers state that there is still no evidence that olive oil can protect against leukemia. But, they add, In the present study, a clear anticancer activity of some phenolic compounds isolated from olive oil was demonstrated. Such activity was evident at phenol concentrations relatively higher than those observed in vivo after a normal daily intake of olive oil; however, it is possible that the regular low life-time intake of olive oil results in an overall protective effect.
I grew up in Italy, which has a national obsession, rightly so!, with high quality (=extra virgin) olive oil. I can give up lots of things, but it would be almost impossible for me to live without olive oil. It’s more important to me than chocolate! But, thinking back on all the years that I lived in the U.S. and Canada, I almost certainly used very little olive oil, and certainly not the high-quality stuff that we get now from Italian friends who have their own organic olive grove. It made me wonder…
Of course there are a lot of Italians with leukemia and myeloma, so I don’t mean to imply that my years without the protective effect of olive phenols led me to develop MGUS and then SMM. But wouldn’t it be interesting (impossible, I know!) to see how many Italian leukemic patients have a high versus low olive oil intake? Oh well, just a silly thought…
Anyway, this was certainly an interesting study. Another related one, sent by the same blog reader (thanks again, PvM!), examines the metabolism of olive oil phenols in humans. Since the full study is available online (http://tinyurl.com/cfjl6f), I will mention only that we absorb a great deal of the olive oil we swallow…and this bit of information could be useful for a future olive oil/curcumin experiment, since, as we know, curcumin dissolves in fats and oil. To be honest, the thought of experimenting with olive oil had crossed my mind some time ago, and I know some blog readers already mix curcumin with olive oil, but I hadn’t considered it very seriously because of the omega 6/3 ratio. But now…well, we shall see…
Interesting titbit: a 2007 Spanish study (see: http://tinyurl.com/dbfg7q) showed that the phenolic compounds in olive oil, just like curcumin, killed eight strains of H. pylori (see my page on H.pylori and MGUS), even three that were resistant to antibiotics. Based on their results, these researchers think that olive oil might be used as a chemopreventive agent for peptic ulcer or gastric cancer, but this bioactivity should be confirmed in vivo in the future. Extraordinary…
Wow – so much high quality research and information here. Thank you for sharing your work.