Margaret's Corner

Siede la terra dove nata fui
su la marina dove ‘l Po discende
per aver pace co’ seguaci sui.
Amor, ch’al cor gentil ratto s’apprende
prese costui de la bella persona
che mi fu tolta; e ‘l modo ancor m’offende.
Amor, ch’a nullo amato amar perdona,
mi prese del costui piacer sì forte,
che, come vedi, ancor non m’abbandona.
Amor condusse noi ad una morte:
Caina attende chi a vita ci spense.

Totally off-topic today. Sometimes we need that. Or I do, at least!

A while ago I read online that Roberto Benigni, an Italian actor and film director, is the equivalent of a double shot of espresso coffee. I agree. Some of you may remember him excitedly jumping onto the backs of seats during the 1999 Academy Award ceremony after his La vita è bella, or Life is beautiful won three Oscars. Deservedly so, in my opinion.

Anyway, I am writing about Benigni because yesterday evening he put on an extraordinary one-man show on TV (Rai Uno, one of the Italian state channels). Absolutely brilliant. After a bit of contemporary political satire, Benigni, using his unique expressive communication style, launched into a passionate and eloquent explanation of the Divine Comedy’s 5th Canto. For two and a half hours, he barely stopped to take a breath. Fantastico. I was glued to the screen. Verse by verse, at times word by word, Benigni described every detail of this famous Canto, which centers on the tragic story of two lovers, Paolo Malatesta and Francesca da Rimini. He put into plain language the most intricate and difficult passages and concepts, at times drawing on current Italian social and political events to make his point more clearly. Keep in mind that Dante Alighieri wrote the Divine Comedy in vernacular Italian at the beginning of the 14th century, so this wasn’t as easy as it sounds.

I would like to note that I went through the Italian public school system (yep, I am one of those odd bilingual creatures), where I studied Dante’s Divine Comedy. I also examined each and every verse while doing research for my Ph.D. thesis (don’t ask! ). My interest, however, has always been superficial…related to schoolwork. But yesterday evening Benigni infected me with his fervour. I want to reread the Divine Comedy.

Benigni ended his performance by reciting the entire 5th Canto from memory. Now, I am no lover of poetry, but this final part brought tears to my eyes. Benigni’s declamation came from the gut, it had feeling, it had passion. Last year, for his interpretation of Dante, Benigni was nominated for the Nobel prize in literature. He didn’t win, but in my opinion, he should have. Grazie, Roberto!

Peekaboo came home yesterday and is doing well. I went to pick her up at the vet’s at 5 PM. I had to keep her separated from the other cats until this morning so I put her in my parents’ room. She was not very steady on her feet and kept bumping into things (the litter box, the furniture ). I stayed with her until Stefano got home, then we took turns eating dinner so that one of us could be with her (we tried to leave her alone, but she howled). I know, only big-time cat lovers will understand this! I spent the night in my parents’ room with Peekaboo, and Stefano slept with the other cats in our room. We have so rarely slept apart in all the years we have been together so, yes, last night was very odd. Anyway, Peekaboo was very happy to be home, nestled in my lap all evening, purring like mad and batting her blue eyes at me. She even did something she has never done before: she kneaded my legs. Cutie pie. This morning she isn’t jumping around like she normally does, but she seems just fine. A bit subdued, that’s all. To be expected.

I have a ton of things to post about, lots of news, but new things keep popping up in my e-mail box just as I think I have finished doing all my research and writing. Aaargh! So I have more reading to do today. In the meantime, I will post about a new clinical trial: http://tinyurl.com/2ap4k8 Yesterday the Geron Corporation announced that it has enrolled the first myeloma patient in its GRN163L clinical trial. GRN163L is a novel inhibitor of telomerase, an enzyme that is expressed in all major types of cancer cells. This enzyme is essential for malignant cell growth and is absent or expressed transiently at low levels in most normal adult tissues. The most interesting aspect of this trial, however, as a MMA list member pointed out yesterday, is that GRN163L has been shown to target cancer STEM cells. Just like DMAPT (from parthenolide or feverfew). Now, if we can get rid of cancer stem cells, the ones that are resistant to conventional treatments and that cause cancer (myeloma, too, of course) to recur well, let’s just digest the implications of THAT statement…!

Today another MMA list member posted about a study in this month’s issue of “Blood” discussing how the Notch signaling pathway, a new one to me!, protects myeloma cells from apoptosis (death). You can read the abstract here: http://tinyurl.com/ysv9gg Well, I immediately, as usual!, googled Notch signaling and curcumin, and to my surprise (I wonder WHY I am still surprised…!), I found that, yes, apparently curcumin inhibits this signaling pathway (important, by the way, for cell to cell communication), see this 2006 abstract on pancreatic cancer cells in vitro: http://tinyurl.com/2cjgpr See also this December 2007 abstract on leukaemic cells: http://tinyurl.com/2hp5z2 I don’t have time to do more research on Notch and curcumin today (busy in other fields…), but it’s always good to come across another good reason to be taking the orange powder! Yeah!

Tomorrow I am taking Peekaboo to the vet to be spayed. I hate to put her through the trauma, but there is no help for it. So I am a bit distracted, well, even a bit distraught, right now. I know that this is for her own good, and the others are spayed/neutered, too, but I just want it to be all over, and have her back safe and sound with me. I took a few photos of her sweet trusting little face earlier this afternoon, as though she will look at me differently from now on, with mistrust or even hatred! I know, I know, I am being silly. But it was an excuse to take lots of photos. This one is my favourite.

Change of subject. Today, as I was driving home from work, I thought about how much I have come to love my students. They are sooo entertaining. In fact, I am beginning to suspect that at least a couple of them must have attended drama school at some point in the past. Their funny nonverbal communication skills include comical faces, animated gesticulation, rapid speech (usually in Italian, as much as I try to forbid it!)…in short, everything you would expect from the stereotypical image of an excited Italian. And more! When one of my students makes a mistake, she rolls her eyes and flails her arms about, finally throwing her head down on the table (with an audible bonk!). Another screws up her face in pretend agony, then bursts into peals of infectious laughter. I should really start taking notes (or making videos!) for my upcoming bestselling book titled “Laughing English.”

I thought that my intermediate English students would be happy today at the news that I wanted to tell them a joke (mostly in the past tense, which is what we are studying at the moment) instead of doing grammar. A joke versus grammar? Where’s the competition? But, oh no, they began protesting loudly that they couldn’t understand jokes even in Italian (yeah, likely story!). Silly beans! I mean, I had to CONVINCE them to listen to the joke! In the end, they did understand it (one of my blog jokes, actually), including the irregular forms of the past tense, AND they liked it. Yes, it was a fun lesson. We all enjoyed it.

Last but certainly NOT least, Stefano got some excellent news today regarding his job. YIPPEEEEEE!!! I can’t wait for him to get home and tell me all the details. Fidget fidget…fidget! We have some celebrating to do later this evening. Oh, if only I weren’t taking my baby to the vet tomorrow morning…!!!

As promised, here is the chapter on glucuronidation. First, what IS it? According to Wikipedia, Glucuronidation, the conversion of chemical compounds to glucuronides, is a method that organisms use to assist in the excretion of substances that cannot be used as an energy source. Glucuronic acid is attached via a glycosidic bond with the substance, and the resulting glucuronide, which has a much higher water solubility than the original substance, is eventually excreted by the kidneys. So glucuronidation is used by the body usually to get rid of toxic substances.

What happens once we have swallowed curcumin? A blog reader has already explained this process to us, but let’s have a look at what the MD Anderson researchers write: Once absorbed, curcumin is subjected to conjugations like sulfation and glucuronidation at various tissue sites. They discuss a study published in Life Sciences in 2000 (abstract: http://tinyurl.com/3ybfhm): in rats, it would appear that orally administered curcumin is absorbed from the alimentary tract and present in the general blood circulation after largely being metabolized to the form of glucuronide/sulfate conjugates. Curcumin sulfate and curcumin glucuronide were identified in the colorectal tissue of colorectal cancer patients who ingested curcumin capsules. Metabolites, by the way, are substances produced during digestion. Okay, so once ingested, curcumin is transformed into these metabolites. But are these substances completely useless as far as cancer patients are concerned?

On page 7 we read the following: Whether curcumin metabolites are as active as curcumin itself is, unfortunately, not clear. While most studies indicate that curcumin glucuronides and THC are less active than curcumin itself, there are other studies which suggest that they may actually be more active than curcumin. THC is tetrahydrocurcumin, one of the major metabolites of curcumin. The section on curcumin metabolites concludes: “The lack of availability of curcumin glucuronides and related compounds contributes to a continued lack of clear understanding of the relative pharmacologic activities of observed curucmin metabolites.” So we don’t have a clear answer. Yet.

Are there ways of addressing all of the problems dealing with poor absorption, rapid metabolism and elimination? Sure there are! The MD Anderson team suggests that Nanoparticles, liposomes, micelles, and phospholipid complexes are other promising novel formulations, which appear to provide longer circulation, better permeability, and resistance to metabolic processes. So, no doldrums! (I like that word…)

The researchers examine studies on piperine, a known inhibitor of hepatic and intestinal glucuronidation. According to a 1998 study published in Planta Medica (abstract: http://tinyurl.com/2eb84u), in humans receiving a dose of 2 g curcumin alone, serum levels were either undetectable or very low. Concomitant administration of piperine, however, produced 2000% increase in bioavailability. Conclusion: The glucuronidation inhibiting effect of piperine and the established lesser activity of curcumin glucorinides will indicate that inhibition of glucuronidation by piperine may be the major mechanism by which it increases the bioavailability of curcumin.

Quercetin is also mentioned. Yippeeeee! (I am already taking it, you see ). In a clinical study published in 2006, five familial adenomatous polyposis (FAP) patients with prior colectomy received curcumin (480 mg) and quercetin (20 mg) orally three times a day. The polyps decreased in number and size (60.4% and 50.9%, respectively) after approximately six months. See full study: http://tinyurl.com/3b46wd

Okay, all of this may sound discouraging, but it really isn’t, in my view. Of course, it’s also true that I don’t get discouraged easily! Seriously, though, in my opinion there are ways we can make curcumin more bioavailable. Some methods may work better for some of us, but the important thing is that those methods EXIST. On this topic…have a look at what this 2005 Clinical Cancer Research study (full study: http://tinyurl.com/2cugub) on head and neck squamous cell carcinoma (HNSCC) has to report: In the nude mice studies, we compared two different methods of delivery of curcumin: intratumoral injection and topical application of the curcumin paste onto the tumor. To our knowledge, we are the first to attempt in vivo studies using curcumin paste in nude mice. Use of this method of delivery could overcome the problem of low bioavailability encountered in studies of oral curcumin in colorectal and other cancers in mice and in humans. Now, ok, this method wouldn’t work with myeloma (but couldn’t curcumin be injected right into plasmacytomas?), but it sounds promising for solid tumour cancers and of course skin cancer. As you know, I have tested a few bioavailability methods on myself: some worked, some didn’t, and I am awaiting the results from my most recent tests so the jury is still out on my most recent experiment. A few days ago, though, Stefano suggested that I quit experimenting and start focusing instead on the methods that have already worked for me. He’s right. Besides, if my IgG level goes up anymore, I will have to adopt Don’s kitchen sink approach!

There is more food for thought in the MD Anderson study, but I need a change, so I will work on something different now. Speaking of working, drat, I still have to prepare my classes for tomorrow! YIKES! Ciao!

In my November 22nd post, I mentioned a newly published MD Anderson study, co-authored by Prof. Aggarwal (abstract: http://tinyurl.com/35w4mn). Thanks to Sherlock (grazie mille!), I was able to read the full study, which I have read but must read again, as it is filled with so many significant details etc. My original post turned out to be too long, so I will divide it into chapters, at least two.

Titled Bioavailability of Curcumin: Problems and Promises, the study was published in the November 14th issue of Molecular Pharmaceutics. It begins with an overview of curcumin, which, as we know by now, has been shown to exhibit antioxidant, anti-inflammatory, antimicrobial, and anticarcinogenic activities. Additionally, the hepato- and nephro-protective, thrombosis supressing, myocardial infarction protective, hypoglycemic, and antirheumatic effects of curcumin are also well established. Even at high doses, up to 12 grams a day, curcumin is well tolerated. I know I have written all this before, but I think it’s good to go over known information sometimes.

Curcumin’s main problem, as we (again!) know, is bioavailability: studies over the past three decades related to absorption, distribution, metabolism and excretion of curcumin have revealed poor absorption and rapid metabolism of curcumin that severely curtails its bioavailability. The serum levels of curcumin are extremely low. Let us keep in mind, though, that the UK Phase I Clinical Trial of Oral Curcumin (full study: http://tinyurl.com/32kwok), which tested regular curcumin (C3 Complex without bioperine) on patients with advanced colorectal cancer, ends with the following statement: The findings of the study presented here lead us to conclude that the systemic pharmacological properties of a daily dose of 3.6 g of curcumin are suitable for its evaluation in the prevention of malignancies at sites other than the gastrointestinal tract. 3.6 grams. Very little, compared to the 8 grams that I am taking. This Phase I clinical trial in fact showed that consumption of 3.6 g of curcumin daily generates detectable levels of parent compound and conjugates in plasma and urine, where the parent compound was curcumin, of course. The study contains headache-causing (for a non-scientific brain!) amounts of details, but, unless I am much mistaken, a few are lacking, which I would be curious to know, for instance: 1. what time of day was curcumin taken by the patients and 2. did they take it on a full or empty stomach?

Speaking of time of day, as I was reading through the description of all the studies cited by the MD Anderson team, a BIG question popped into my head. Relevant or not, here it is. Remember my November 11th post on circadian rhythms, in particular the part about human versus rat testing? Well, here’s a memory refresher: Despite this evidence of variation, drug research is almost always done during daylight hours, when the humans leading the studies are awake and alert. And in the animal testing stage, it’s almost always done with mice and rats, which are nocturnal €”the middle of our day is the middle of their night. This can lead to gross misestimations of the effectiveness and toxicity of a drug intended for humans. My question: could circadian rhythms possibly affect the curcumin testing being conducted on mice and rats? And what about the curcumin testing on humans? What if these tests were conducted at different times of the day and night? Would there be differences in the results? My feeling is that there would be. Take a look at this sentence in the MD Anderson study: the serum levels of curcumin in rats and in human are not directly comparable. Hmmm. Well, okay, that makes sense on all sorts of levels, of course, even though I enjoy a bite of cheese probably as much as a mouse does , BUT could this divergence also be due, at least in part, to daylight testing on nocturnal animals? Another point. We don’t know what time of day or under what circumstances the human subjects in these trials took their dose of curcumin. And, for instance, we are informed that some folks developed diarrhea but others didn’t. Did both groups take curcumin at the same time? All this information would indeed be interesting to have. Okay, I realize that I’m in over my head here, and that my suspicions may turn out to be irrelevant rubbish. I must read the MD Anderson study again, and look up all the studies, one by one (yeah, that’s likely to happen… ). Ok, enough about circadian rhythms.

The MD Anderson researchers point out that the issue of curcumin levels found in body tissues has been relatively ignored. Interesting, I thought. One of the few studies dealing with body tissues dates to 1980 (abstract: http://tinyurl.com/3a93ko). I quote from the MD Anderson study: after oral administration of 400 mg of curcumin to rats only traces of unchanged drug were found in the liver and kidney. At 30 min, 90% of curcumin was found in the stomach and small intestine, but only 1% was present at 24 h. The team points out also that Although many curcumin analogues are found to show improved biological activity over curcumin, specific evaluations of structural analogues and/or derivatives of curcumin to show improved tissue and plasma distribution are lacking. More studies are needed!

There is lots more, including mentions of substances we can take to enhance the bioavailability of curcumin and novel bioavailability methods, some of which I have mentioned in previous posts. But this post is getting to be too long, so I will stop here for now. In chapter two, I will discuss glucuronidation!