Andrographolide and parthenolide kill myeloma stem cells

February 14, 2018 / Margaret / Leave a comment

My andrographolide-researching blog reader also sent me the link to a 2011 U.S. study on the effects of parthenolide (remember PTH? Remember DMAPT? Yeah, I haven’t written about it in a long time…making mental notes right now…) and andrographolide on myeloma stem cells: goo.gl/3e6Nk5

That’s right…on MYELOMA STEM CELLS.

Problem: only the abstract is available for free online. With the help of a fab friend, however, I was able to read the full study, but I have to be careful about copyright issues, even though it irks me that you have to pay for studies that could be of vital importance to us. Of course, I DO understand that journals need to survive. And so…well, let’s have a look, without going into too much detail. Compromises…

Incidentally, this is the first study discussing “a natural product with anti-CSC activity in myeloma” (CSC = cancer stem cell).

As we all know, the main problem with myeloma is RELAPSE. Relapse is caused by the tough myeloma stem cells, the cells that can clone themselves, the really bad thugs that escape being killed by chemotherapy. The chemo drugs used in myeloma target the general plasma cell population, that is, the cells that cannot reproduce themselves, BUT they are NOT able to eliminate our myeloma stem cells. So no matter how many chemo bombs we throw at our myeloma, there will always be a handful of nasty ruffians in hiding, ready to come out and start proliferating again at some point.

This study shows that parthenolide AND andrographolide do just that: they go after the ruffians. The abstract calls them two “potent anti-MM-CSC agents.”

Potent…I like that!

Okay, I’m going to see if I can extract some gems from the full study.

As we’ve seen, it’s not enough to target the circulating plasma cells. If we want to get rid of the myeloma weed, we must go after the stem cells, the “clone troopers” (Star Wars, anyone? 😉 No, I’m not really a fan, but I do remember that expression…). The only way to prevent relapses is to kill the cloners!

Parthenolide is the first extract to be discussed. In addition to being a powerful NF-kappaB inhibitor, parthenolide (PTH from now on) kills the stem cells of myeloma and of acute myelogenous leukemia, without killing the normal hematopoietic cells, the good guys, which produce red/white blood cells and platelets. One big problem has been PTH’s has low solubility in water (but remember DMAPT? It’s water soluble… but these researchers don’t mention DMAPT, except in their References…anyway…).

Andrographolide (AGR from now on) hasn’t been studied as much as PTH. However, it’s more soluble in water compared to PTH. That is very good news…

The researchers point out that melphalan and bortezomib “are not curative” (their words, not mine), because they don’t target the MM stem cells.

But, they add, that’s what PTH and AGR do…

One of the coolest things about this study, IMO, is that the researchers used a 3-D tissue culture of rBM, which is basically a reconstruction of a bone marrow microenvironment (rBM stands for reconstructed bone marrow). They also used 2-D cell cultures. They were able to confirm that the main target of PTH and AGR were the myeloma stem cells.

Clearly, more research is needed…more testing…but I’d say that this study shows how promising these two extracts are. We need to rip out the myeloma weeds…without harming ourselves in the process…

Testing promising natural extracts is a step in the right direction.

Are our official myeloma organizations going to do something about this very important study??? C’mon!!!!!!

A new anti-myeloma substance: andrographolide

February 13, 2018 / Margaret / 1 Comment

A blog friend (thank you!!!) sent me the link to a few studies on andrographolide, extracted from a medicinal plant called Andrographis paniculate, native to South Asian countries and also known as the “king of bitters.” The leaves and underground stems of this plant are used for about a million purposes: to prevent and treat colds and the flu, to treat digestive disorders (diarrhea, colic, stomach pain and so on), liver conditions (jaundice, liver damage caused by medications), infections (all sorts, from pneumonia to rabies, even HIV/AIDS), and skin conditions.

The list is seemingly endless and even includes snake bites, loss of appetite, kidney problems, hemorrhoids, worms (ugh). It has antibacterial, anti-inflammatory, antiviral, anti-tumor, anti-fungal, and immune regulatory, properties. It also protects the gallbladder and the liver. Oh, and apparently it is good for the heart, too!

But the main reason I’m writing about this seemingly amazing substance today is because it has ANTI-MYELOMA properties. What I really like about this new (new to me!) substance is its “low toxicity and low cost.”

Luckily for us, the main andrographolide-MM study, published in 2015, is available for free online, so you can read it, too. The whole shebang can be found here: goo.gl/Z9CaVF

Incidentally, this is the first study to discuss the effect of andrographolide on myeloma cells…

According to the abstract, these two Chinese researchers showed that andrographolide reduced the proliferation of MM cells and increased their death rate (apoptosis) by inhibiting the NF-kappaB pathway that we’ve learned so much about in all these years.

Results: as mentioned in the abstract: 1. andrographolide blocks the proliferation of myeloma cells; 2. It also KILLS them (“induces apoptosis”). And that’s really all we need to know, although the study offers other important details, too.

Let’s look at one of them, since it is connected to an item of MUCH interest that pops up later in the study: andrographolide reduces the levels of the TLR4 protein and of the NF-kappa B pathway in myeloma cells.

Discussion: andrographolide also inhibits angiogenesis, which is so important for the survival and wellbeing of myeloma cells, so that’s good to know, too.

Now we get to the above-mentioned importance of the TLR4 protein. TLR4 is apparently involved, not in a good way!!!, with a tumor’s microenvironment and has a lot of power over immune cells. So, if its activity can be blocked, that’s very good news. With andrographolide, this can be accomplished…

I mentioned TLR4 in one of my earliest posts, written in 2007: TLRs, or toll-like receptors, play a key role in the immune system. Back then, I was interested in the fact that TLR4 is inhibited by…yes…curcumin. This all makes sense, eh?

Anyway, definitely a very interesting substance. I’ll be looking at more studies on this topic in the next few days. I think it might deserve more than just ONE post. Right now it’s at the top of my list of stuff I intend to test…

“The bone-marrow niche in MDS and MGUS: implications for AML and MM.” Part 3.

February 7, 2018 / Margaret / Leave a comment

Final post on the Dana-Farber study.

–Another thing mentioned in my 2013 post (see my Jan 31 2018 post for the link) is mentioned in this Dana-Farber study, too: PD-1, which stands for programmed cell death protein 1. Blocking the activity of this protein, which is highly expressed by MM cells, helps our immune system react against the cancerous cells. The Dana-Farber study informs us, however, that the conventional agents used to block PD-1 have been found to be toxic and not very effective, so the patient studies are currently on hold.

But guess what? Curcumin blocks PD-1, without any toxic side effects. Of course, curcumin isn’t a drug, so we cannot expect it to work like one. But it’s one MORE thing that curcumin does.

–There is another target called CXCL12, a chemokine protein (don’t ask!) secreted by stromal cells that helps myeloma cells become drug resistant, among other bad things. If CXCL12 is inhibited in early stages, however, progression to myeloma can be delayed or even prevented.

28 patients with relapsed or refractory MM participated in a relatively recent clinical trial testing bortezomib, dexamethasone, and something called olaptesed pegol whose target is CXCL12. There was a “clinical benefit rate” for 75% of these patients. Not sure what that means, and we are also told nothing about the patients’ quality of life, stuff that I imagine is of HUGE interest to all of us. Oh well.

My comment: curcumin inhibits CXCL12.

I don’t want to go overboard with too many details. So let’s get to the study’s conclusions.

This group of researchers maintains that targeting the myeloma-friendly bone marrow microenvironment is crucial. It might prevent disease progression to myeloma and increase the effectiveness of conventional treatments after progression has taken place.

But the research is in an early stage…more studies are needed.

In the meantime, I say, let’s stick to the “Watch and Wait” strategy (while taking non-toxic stuff and having a normal, splendid life). Until you have CRAB symptoms, it’s the best strategy on the market today.

Incidentally, why don’t we rename “Watch and Wait” with something that sounds more proactive? I mean, most of us aren’t just sitting back and just waiting for a brick to fall on our heads, right? We’re doing something!!!

So, any suggestions?

Living with two active kittens

February 6, 2018 / Margaret / Leave a comment

This morning, after re-reading the last bit of Dr. Biswas’ EBV-MM thesis, I began looking at another area of research, concerning myeloma, of course. But then I decided to take a break and write a KITTEN POST. The kittens are asleep right now, so I have some time to do that…

Let’s see. We let the kittens out of their quarantine room on Saturday, December 30, 2017. They had been in that room, full of games and a floor-to-ceiling cat tower, since the beginning of November, when we first brought them home. It took almost two months for them to get their clean bill of health: no more giardia (!), no more ear mites, and their booster shots. They were finally ready to meet the others, the adult cats.

When we opened that door, it was like opening the front door and letting two little kids go outside in the snow for the first time in their lives. Pandora and Pixie were bouncing all over the place, full of enthusiasm, happiness, and fun…A joy to behold.

As for our adult cats, they didn’t quite know what to do at first. In the beginning, they just stayed on our bed (where they’d been napping, as usual), pretending to ignore the ruckus, the thundering noise of small paws rushing about madly on our cotto floors, exploring the house…

When they finally realized the noise (and the noise creators) wasn’t going to go away, most of them simply disappeared. Prezzemolo hid downstairs, in a small room under the kitchen, for two days…

But cats have to eat, right? And the cat bowls are all in our open kitchen/dining room area. That’s when the growling and hissing started. Hiss hiss growl growl hiss growl, whack. Yes, there was an occasional whack, too…

Thus far, the cat who is having the most difficult time dealing with the arrival of the two kittens is Peekaboo (10 years old). She still goes after them every chance she can get and growls at them even when they aren’t even near her. And they are really afraid of her.

She doesn’t hurt them, mind you. No claws out, no scratches, nothing. It’s all just a lot of noise. When Peekaboo manages to chase Pixie into a corner, though, the screeches they emit still make me jump out of my chair and practically hit the ceiling. So LOUD!!!

The noise has been lessening, though…I think it’s simply because the kittens are getting better at avoiding Peekaboo.

The others are behaving much better towards the new girls in town. Pinga, in particular. I’m not saying they are cuddling just yet, but now and again we do have six cats lying on our bed, peacefully (minus Peekaboo, of course). So it’s going to be fine.

And I have to say that Pandora and Pixie are two of the happiest kittens I’ve ever had. They’re amazingly curious, and they do everything together, even when it comes to using the litter box (as they get bigger, though, I imagine that will stop!).

They follow me around like teeny tiny dogs. Everything I do is absolutely fascinating to them. The laundry, making the bed, oh just anything! And they are so helpful (not). It’s mostly okay, except when I’m cooking. They still don’t understand what “NO!,” “Go AWAY!,” or “GET DOWN!” mean. And even when I get them off the counter and put them on the floor, they’re back up within nanoseconds.

So fast!!! 😛

It was when Stefano was away on a business trip in mid January that I realized the only way I’d be able to eat ANYTHING would be for me to STAND UP IN THE KITCHEN, holding my plate as far from the counters as possible. These two little critters may be small, but they are also strong and athletic. And, as mentioned, QUICK.

And no, it wasn’t because they were hungry. They’re never hungry. They always have dry (kitten) food at their disposal, and I feed them wet food at least twice a day, plus treats on occasion. No, it’s because they are CURIOUS. They want to know what I’m up to, what I’m eating, they want to know EVERYTHING. 🙂

And even when it’s the two of us, Stefano and I are no match for those Olympic jumpers, and dinner at the dining room table can become quite challenging. If we get distracted, we end up with a paw smack in the middle of our plate or with a kitten stuffing her silly little face down into our glasses.

There are only two of them, but at mealtimes it’s like having an army of Pandoras and Pixies. Fast and determined, those two!!!

But who’s complaining? I certainly am NOT. Pandora and Pixie are the most adorable creatures on Earth. And they are soooo endearing. Early in the morning Pixie comes up to my face and wraps herself around my neck like a (very warm) scarf, putting one of her paws over my ear (so I won’t hear the alarm go off? How considerate!). I put my arm around her and hug her close, and she begins purring. Irresistible.

They cannot replace Puzzola and Piccolo, the two cats we lost last summer, but they have definitely made their way into our shattered hearts.

And they are helping us heal…For sure! 🙂

P.S. Some of these photos were taken with my cellphone and didn’t come out as well as I’d hoped. And by the way, if you’re wondering why these are mostly shots of the kittens sleeping or at rest, the reason is simple: almost impossible to get a decent photo these two in motion…they’re almost as bad as puffins in flight! 😉 But…I’m trying!

Does myeloma run in the family?

February 2, 2018 / Margaret / 18 Comments

Ever since I began doing research on myeloma, one of my certainties–although with something like myeloma you can never be absolutely certain!!!–has been that myeloma is NOT a hereditary disease. Yes, of course, I’ve read about a few patients who had relatives with myeloma, but…only a few.

If you do an online search, you will find that not much is known about the causes of myeloma. A few known ones are things such as pesticide exposure, past exposure to radiation, genetic changes that turn our plasma cells into MM cells…stuff like that. The family connection seems to be a minor one…

Today, however, I read a Science Daily article that suggested otherwise. As you can see for yourself (goo.gl/jPgDtS), the article begins like this: “Researchers have identified two gene regions that contribute to multiple myeloma, an inherited cancer…”

SAY WHAAAAAT??? MYELOMA…AN INHERITED CANCER?

The Science Daily article picked this up from a newly published gene mapping study that I won’t even try to read today (my brain is still reeling from that “inherited” business). If you’re interested and find technical jargon as fascinating as my kittens find me doing practically anything 😉 , go right ahead and have a look: goo.gl/bTgGmW

Still stunned, I immediately began digging and found a few relatively new studies on the apparent inheritance factor. A 2013 “Leukemia” study uses the expressions “familial clustering” and “genetic predisposition” in its abstract, but the full study isn’t available for free online, so I wasn’t able to check it out. For what it’s worth, here’s the link (to the abstract): goo.gl/kr2Fq2

According to another study published in 2016 (see goo.gl/nNqqJh), full study available online, “Results from this pooled analysis provide compelling evidence to support hypotheses that genetic inheritance plays a role in the aetiology of MM.” The risk is greater if you have a first-degree relative with myeloma, non-Hodgkin lymphoma, Hodgkin lymphoma, or leukaemia.

But is that enough evidence? I mean, can we really define myeloma as an “inherited cancer”?

Of one thing I am certain: nobody in my family has MGUS, let alone MM. I’m the first (and last, since I don’t have any children, apart from the marvelous furry ones, of course!). Besides, based on my most recent readings, I am 100% positive that EBV started my myeloma.

I think there are too many potential causes out there, there’s too much we just don’t know (for example, the bone marrow microenvironment wasn’t even considered to be an important player in myeloma until a decade ago), for us to be able to define myeloma as a hereditary type of cancer. Or…am I wrong?

I’d be really interested to know how many of you have myeloma (or leukemia/lymphoma) in the family…

“The bone-marrow niche in MDS and MGUS: implications for AML and MM.” Part 2.

January 31, 2018 / Margaret / 2 Comments

Back to the Dana-Farber study that I wrote about a couple of days ago.

The section titled “Therapeutic opportunities” is interesting. How to prevent progression, that is. As you can imagine, the chef’s daily special consists only of conventional treatments. For example, the authors make a reference to the Spanish study (Mateos et al) that I have repeatedly condemned here on the blog. The Spanish researchers–some with strong ties to the big pharmaceutical companies (hello???)–tested lenalidomide and dexamethasone on a group of SMM patients. The study claims to have prolonged progression-free survival and even overall survival in those patients…without ever taking into consideration QUALITY OF LIFE. Sorry, but I have no patience for statistical studies that play with people’s lives…

That said, the trend toward early intervention is clearly taking off, as the Dana-Farber study points out. Very unfortunate, IMO.

And there is no way to stop it, except that we, the patients, can say just say NO. Of course, if you have CRAB symptoms, that’s another matter. But, in the absence of the CRABs, WHY TAKE THE CHANCE OF WORSENING YOUR QUALITY OF LIFE?

Makes zero sense.

And there’s another thing that bothers me: where’s the proof that the overall survival of someone with SMM was extended thanks to these conventional treatments? Do the Spanish researchers have crystal balls that give them the exact times of death for their patients, both with AND without treatment? Oh, right, no, that’s what their STATISTICS tell them. Based on the patients’ “high-risk” data (see yesterday’s post).

I’m not saying that statistics can’t be useful in certain circumstances, mind you. But in these cases, when someone with no CRABs is deciding on whether to agree to early treatment, or not!, they can be harmful. If I had agreed to begin conventional treatments in 2005, I don’t know where I would be today (according to my former hematologist, I’d be dead…would have died in 2010…didn’t happen, OBVIOUSLY!!!…I’m still here, still splendid 😉 , still no CRABs, still no conventional treatments…).

Sorry for the rant. Okay, let’s calm down and try to understand the rationale of early intervention from the Dana-Farber study perspective. The researchers say that if the number of osteoblasts (bone-forming cells) can be increased in the early stages of myeloma, myeloma cells cannot proliferate. That’s good to know. There are non-toxic ways to do that, btw, but let’s keep to the study…

Mice that were injected with nanoparticles loaded with bortezomib before being contaminated with MM cells lived longer than non-injected mice. The researchers give another example in which early treatment of an antiangiogenic antibody was used on mice. Okay, but we’re talking about mouse models here. The reality, as the researchers themselves admit at the end of this paragraph, is that “…the use of antiangiogenic agents other than thalidomide and other immunomodulatory agents has not been shown to be successful in patients with MM.”

Not successful in patients.

So much for that.

Then there’s immunotherapy, which we have heard and read a lot about in the last few years. You may have heard about the anti-CD38 antibody known as daratumumab, which activates the immune system.

Anyway, it’s in this paragraph that I found a remarkable admission.

But first, let me say that ever since I joined online myeloma support groups, one of the key issues we discussed was what how to deal with our immune system. Should we stimulate it, thereby possibly stimulating our myeloma cells, too? Or should we avoid anything that stimulates the immune system? The consensus usually drifted toward the former approach. I wrote a post about this in 2013: http://margaret.healthblogs.org/2013/10/20/long-term-survival-in-myeloma-is-finally-linked-to-a-robust-immune-system-and-my-new-discovery/

I’ve had mixed feelings about it throughout the years, but my gut has always told me that it makes no sense to keep our immune system weak.

And here, in this paragraph, I finally have my answer (vindication!!!): “Indeed, trials involving these antibodies provide the first proof of concept that activation of the immune system has therapeutic benefits in patients with MM.”

After years of not knowing what to do, we finally know that having a strong immune system is GOOD.

Quelle surprise…not.

“The bone-marrow niche in MDS and MGUS: implications for AML and MM.”

January 29, 2018 / Margaret / 1 Comment

Remember the post I wrote back in December 2014 about myeloma subpopulations and the bone marrow microenvironment? Probably not…so here’s the link: http://margaret.healthblogs.org/good-or-bad-for-myeloma/first-do-no-harm-myeloma-subpopulations/

The main point is that not much is known about the interactions between the myeloma subpopulations living in our bone marrow, how they compete for survival and so on…

Therefore, the only conclusion, in my opinion, is that going in with conventional bombs and blasting the heck out of this microenvironment doesn’t seem to be the best strategy for those of us with MGUS and SMM…certainly not until we know a LOT more about what goes on inside this complex and, I would add, delicate setting.

Luckily, there have been more studies on this topic since my 2014 post, including this recent Dana Farber one, titled “The bone-marrow niche in MDS and MGUS: implications for AML and MM.” A blog reader sent me the link (thanks!): goo.gl/Ew3K4A

The full study isn’t available for free online, but I was able to read it thanks to a good friend. Okay, let’s have a look at it…

We know that MM is preceded by MGUS and by an intermediate stage called SMM.

Progression, that is, the “clonal evolution” of myeloma, takes place between MGUS and MM. But, the researchers add, some of the characteristics of myeloma can be found, “at lower frequencies,” at the MGUS and SMM stages. For example, the gene deletions.

Therefore, they say, it is the development of neoplastic “subclones” in the earlier stages that probably leads to the progression to myeloma.

This development wouldn’t be able to take place without the help of the bone marrow microenvironment, which therefore must be targeted in order to prevent progression as well as increase the effectiveness of conventional treatments once the stage of MM has been reached.

As I was reading this study, full of technical jargon that I could barely grasp, I began imagining the bone marrow microenvironment as a marketplace where strong nasty myeloma hooligans live and operate in coexistence with other, not-so-harmful, silly myeloma characters, as well as a bunch of normal folks, our normal cells.

Problem: myeloma clones have the ability of turning the marketplace into a toxic environment that helps them grow and proliferate.

A lot depends on how the marketplace reacts to these attempted changes. If it is weak and yields to the MM hooligans, it will become full of “weeds.” If it resists, it will be full (well, perhaps not entirely!) of crowds of happy customers, what the researchers call a “physiologically useful crop of mature blood cells,” that is, normal blood cells.

Now, a NORMAL marketplace contains all sorts of custome…I mean, all sorts of cells, including osteoclasts, macrophages, endothelial cells and, don’t you love this one?, sympathetic neurons. Lots of different cells that live happily ever after in this lovely area of the body.

Too many details here…okay, we don’t need to know this stuff…skip skip skip.

Certain cells (the above-mentioned stromal cells, e.g., after they have gone over to the dark side) become responsible for helping myeloma develop. Furthermore, whenever myeloma cells initiate a disruption, things that should be sleeping (in technical terms: in a quiescent state) wake up (remember EBV?). Not good.

Disruptions also cause tumor suppressor genes, such as Rb1, to be…suppressed. Also not good!

The end result of all the disrupting and suppressing, without any reaction from the immune system, is that the BM microenvironment becomes myeloma-friendly, and MM stem cells can begin proliferating, helped along by processes such as angiogenesis (remember all my posts on VEGF?).

As you can imagine, the study doesn’t mention anything remotely non-conventional. But some of its findings are interesting, so let’s keep reading.

Ah, another thing occurs: immunosuppressive cells arrive in the marketplace and make such a ruckus that T cells and B cells are completely overwhelmed and can’t function properly. This means, of course, that myeloma cells are no longer being sought and destroyed by our immune system.

The study therefore gives us a lesson in progression. First and foremost, as we’ve just seen, myeloma cells learn how to avoid being annihilated by the immune system. They then create what the researchers call an “immunosuppressive environment” where the immune system defenders are no longer able to function normally. Other types of important cells present in this now-toxic environment are also affected, such as stromal cells.

When MGUS progresses to SMM and then MM, immunosuppression is one of the main culprits. In fact, I recently read a study that discussed this problem, concluding that patients with SMM whose other immunoglobulins—in my case, e.g., IgA and IgM—are suppressed are more at risk of developing myeloma. *

The questions are: can we stop this process? How? And…when?

In 2014 (and before), my opinion was to “watch and wait” for as long as possible. Until CRAB symptoms appear. My opinion hasn’t changed in all these years. Indeed, it hasn’t changed today.

“Watch and wait” doesn’t mean sitting around and moping and doing nothing but watch TV series all day long. It means being proactive, doing research, enjoying life, taking something that doesn’t have any toxic side effects and that has been shown at least in vitro to be anti-myeloma, such as curcumin. And so on. There’s lots of stuff we can do in this stage…

Okay, I think this is enough for one day. After almost falling asleepzzz myself, I decided to divide this post into three parts…or perhaps only two.

So…more on this topic tomorrow! Ciao!

P.S. The study also discusses the evolution from MDS to AML, but I didn’t really look at that part, of course, since it’s not my main focus…

* P.P.S.S. While it’s true that my IgA and IgM are suppressed (barely “alive,” in fact!), it’s also true that they’ve been pretty much at the same tiny level for years now. So yes, I am in the high risk category BUT I am still here, leading a normal life, no CRAB symptoms…

Living proof that being at “high risk” doesn’t have to be as scary as it sounds…right? 🙂