Bortezomib puts some MM cells to sleep

April 3 2009 post. A recent post by an MMA list member caught my attention, so I took some time today to do a bit of research. Here goes. Apparently, many myeloma patients do not respond to Velcade. And those who do eventually relapse. Well, it appears that researchers may have found out why.

A study on Velcade and its effects on myeloma cells was published in “Cancer Research” in February 2009 (see abstract: http://tinyurl.com/czsn2e). Velcade by itself doesn’t kill every single myeloma cell in the body. Indeed, it apparently creates the conditions whereby quite a number of them are able to slip into a state of dormancy, just like ants that go to sleep in order to survive harsh winters in Finland, e.g. When the dormant cells resume their active state, boom!, myeloma rears its ugly head again.

 

But it seems that when salubrinal, a “selective inhibitor of enzymes that dephosphorylate EIF 2-alpha” (don’t ask!),  is added to Velcade, there are very few survivors. In other words, these two drugs together are able to wipe out almost all the ants in Fin…I mean, almost the entire population of dormant myeloma cells.

When I was about 2/3 of the way through the abstract, the following thought popped into my head: why not try to figure out how we can use this bit of information to kill our dormant myeloma cells via natural treatments, or at least keep them in a state of dormancy? Or…is that what we are doing right now with curcumin etc.? I began to look into this very matter earlier today but soon realized that I need a bigger chunk of free time to do a semi-decent job. Ant…I mean, and I need the full study. More to come…

April 4 2009 post. Sherlock (grazie!) sent me the full study mentioned in yesterday’s post. It’s “only” 8 pages long, so I thought I would give it a whirl.

 

In the Introduction, we can read that the use of prolonged bortezomib therapy has lead to the development of drug resistance. The subsequent paragraphs and quite a bit of online research added a bit to my understanding of how this process occurs.

 

In order to retain my sanity while going through this complex study, I tried to visualize the dormancy process. For this, I needed a hibernating creature. After considering polar bears, toads and snakes, I went back to my original example: ants. If there are any ant-lovers out there, I sincerely apologize in advance for comparing them to myeloma cells.

 

Let’s imagine a northern European State at the beginning of a very harsh Velcade winter. As it starts getting colder, the ants aka myeloma cells get cold, too, but quite a number of them have enough forewarning and are able to escape the increasingly frigid, Velcade killer temperatures by hiding inside their underground nests. Their metabolism starts slowing down. In this inactive state, they require no food. It’s clearly a good survival mechanism.

 

The stubborn ones that remain above ground don’t have a chance of surviving (not in my visualization, at least). As soon as the weather starts warming up, though, the dormant ants wake up again. If I sound obsessed with ants, yes, I suppose I am. Every spring, I find myself battling fiercely with an ant colony that has established itself in my front yard. I don’t mind their being there, don’t get me wrong, but at this time of year some of them desperately and stubbornly want to march through my house, I suppose in order to reach the back yard. So right now, grrr!, I don’t feel badly about identifying them as myeloma cells. But I digress…

 

Now for a more, er, scientific approach.

 

First, though, a look at proteasomes. These are large protein complexes that are found in both normal and cancer cells. The relevant (for us) information about proteasomes is that cancer cells depend on these proteins in order to proliferate, metastasize and survive. And, in fact, increased numbers of proteasomes can be found in the blood of myeloma patients.

 

So one way to kill cancer cells is to inhibit the cancer-friendly activity of proteasomes. Probably the best-known proteasome inhibitor is bortezomib (marketed as Velcade). When Velcade is injected into a patient’s body, it disrupts the proteasome’s activities. As a consequence (simply put), cancer growth is inhibited, and the cancer cells die.

 

Now we get to our full Velcade-dormant myeloma cell study. Proteasome inhibitors provoke what is called an “ER (which, unfortunately, has nothing to do with the dashing George Clooney but stands for “endoplasmic reticulum”) stress response” in myeloma cells. This type of “stress” kills between 50 and 70 % of them, according to the study…but at the same time it sends out certain survival signals to 30-50 % of these cells that are thus able to avoid apoptosis by slipping into a deep sleep (or, more scientifically, by becoming quiescent).

 

They basically stop growing. And, since Velcade attacks cells that are in the process of dividing rapidly (=typical of cancer cells), this is an excellent survival strategy, which, incidentally, is used also by other types of cancer cells, such as head and neck squamous carcinoma cells.

 

At any rate, these quiescent cells can be annihilated, the researchers discovered, by adding to Velcade another drug called salubrinal. The actual experiment is rather neat, so I will attempt to summarize the parts that I understand in a comprehensible fashion. The researchers identified the myeloma cells that survived the Velcade attack and washed them to remove the drug. I confess, I was a bit amused by the image of myeloma cells being washed…anyway, the researchers realized that these cells had stopped growing. They were fast asleep…the little buggers. Velcade was no threat to them.

 

Now, there is a tremendous amount of detail in the study. I am not interested in the intricate mechanisms that show exactly how myeloma cells avoid death, mechanisms that, to be quite honest, I can barely understand, such as CHOP induction and XBP-1 splicing. So, skip skip skip.

 

Let’s get to the part that describes what happens once salubrinal enters the picture. After 24 hours, treatment with salubrinal of the Velcade-surviving myeloma cells resulted in a more or less a 10-fold reduction in the number of viable cells. Hey, not bad! And even after 5 days, the cells that are still dormant were highly affected by salubrinal. Ah, an important titbit: salubrinal does not affect the control population.

 

And now we finally (wiping our sweaty brows) reach the Discussion part where we discover that, after administration of Velcade, 30-50 % of myeloma cells escape death by becoming inactive. The researchers argue that this is more likely due to treatment adaptation than to selection of a cell population genetically predisposed to undergo quiescence. But the fact that so many myeloma cells survive treatment with Velcade is the probable and unfortunate cause of disease recurrence.

 

The researchers also found that survival of the residual quiescent cells hinges on the down-regulation of eIF2a phosphorylation. Phospho-whaaat? Okay, let’s not get too bogged down by the details of this phospho-thingie process. What we need to know is that the strong phosphorylation of eIF2a is associated with apoptosis. In the Velcade-surviving myeloma cells, you see, eIF2a was attenuated, so that is probably a mechanism whereby the blasted surviving cells are able to avoid apoptosis. Well, let us leave it at that…for now.

 

In conclusion, the solution to the Velcade-caused “dormancy” problem, as we have seen, lies in the addition of salubrinal to the mix. Salubrinal can virtually eliminate the fraction of quiescent MM cells surviving proteasome inhibition by enhancing the above-mentioned, er, eIF2a phosphorylation.

 

Quick note: this combination treatment will apparently benefit only myeloma patients. It doesn’t work against other forms of cancer, such as chronic myeloid leukemia.

 

The study’s conclusion: In summary, we report that the induction of MM tumor cell quiescence and survival can be an undesirable side effect of proteasome inhibition. We also show that, by blocking eIF2a dephosphorylation, proteasome inhibitor efficiency can be maximized during acute treatment and that residual cells can be eliminated by nontoxic doses of salubrinal as a monotherapy for MM minimal residual disease after proteasome inhibition.

Now I need a few days to digest all this stuff…

22 thoughts on “Bortezomib puts some MM cells to sleep

  1. julie

    google myeloma dandelion theory … I think it speaks to the two different mechanisms of killing myeloma (encouraging apoptosis, the death of existing cells; and cutting off oxygen/nutrients to cells about to be born) that are characteristic of the two kinds of therapies (Velcade vs Revlimid, the imids and … oh I get this confused… the article explains it…) When they can get both things going at once, it should lead to death of existing cells and no more production of new cells. Like the dandelion root and head of the dandelion.

    Reply
  2. julie

    this new article speaks to a subset, to be sure, the quiescent cells. There is some indication that freezing stem cells kills them, that is part of why they are frozen after harvest in SCT.

    Reply
  3. Paula NZ

    After THREE weeks on Velcade/dex and cyclophosphamide my paraprotein IGg lambda which was stable at 19? for 4 1/2 yrs has dropped to 9.1.
    My albumin which dropped from 38 to 19 in 6 months before a kidney biospy to discover amyloidoisis, I
    that number also in THREE weeks has climbed back up to 31. The range is 38 – 55.

    Reply
  4. Julie Zimmer

    when doing SCT, the cells collected for use (reintroduced after the system is killed off, ground zero) are frozen. Freezing causes myeloma cells to burst. I would assume the dormant cells burst as well as the active cells. They freeze the harvested cells even if you are having your transplant immediately, for that reason.
    Curcumin potentiates Velcade, but not Revlimid – and revlimid works by a different mechanism, not proteasome inhibition. So I do think you are onto something. Again, google myeloma dandelion theory for support.

    Reply
    1. Margaret

      Hey Julie, where did you read that curcumin doesn’t potentiate Revlimid? The studies I have read prove the exact opposite. Thanks.

      Reply
      1. Julie Zimmer

        I’ll have to look – but I’ve watched for 5 years on this issue and have seen several mentions of the Velcade, recall zero on Rev…

        Reply
  5. Julie Zimmer

    Revlimid attacks angiogenesis – cuts off oxygen to growth – I think. But I’d have to look it up.

    Reply
  6. Julie Zimmer

    just a few:
    Curcumin Enhances Cytotoxic Effects of Bortezomib in …
    http://www.ncbi.nlm.nih.gov/...
    National Center for Biotechnology Information
    by QX Bai – ?2012 – ?Cited by 7 – ?Related articles
    Apr 16, 2012 – Curcumin Enhances Cytotoxic Effects of Bortezomib in Human Multiple Myeloma H929 Cells: Potential Roles of NF-?B/JNK. Qing-Xian Bai* …
    Sensitizing human multiple myeloma cells to the …
    http://www.ncbi.nlm.nih.gov/...
    National Center for Biotechnology Information
    by T Mujtaba – ?2012 – ?Cited by 8 – ?Related articles
    Oct 13, 2011 – Sensitizing human multiple myeloma cells to the proteasome inhibitor bortezomib by novel curcumin analogs. Mujtaba T, Kanwar J, Wan SB, …
    Curcumin And Multiple Myeloma: Preclinical And Early …
    http://www.myelomabeacon.com/…/curcumin-and-multi...
    The Myeloma Beacon
    Feb 17, 2010 – Curcumin has been garnering increased attention as a potential anticancer … confirmed curcumin’s ability to augment the effect of Velcade.
    Curcumin circumvents chemoresistance in vitro and …
    mct.aacrjournals.org/content/8/4/959.full
    by B Sung – ?2009 – ?Cited by 79 – ?Related articles
    Furthermore, in a nude mice model, we found that curcumin potentiated the antitumor effects of bortezomib (P < 0.001, vehicle versus bortezomib + curcumin; ..

    Reply
  7. Julie Zimmer

    evidently Agarwal had success with Rev/curc … what else have you found, Margaret??
    What about further investigations of curcumin for myeloma?

    Our lab has already used curcumin in vivo and in vitro with Revlimid® andwith VELCADE®, and we have demonstrated that Revlimid and VELCADEwork better when combined with curcumin

    Reply
  8. Julie Zimmer

    evidently Agarwal had success with Rev/curc … what else have you found, Margaret??

    … Agarwal’s response to a question: Our lab has already used curcumin in vivo and in vitro with Revlimid® andwith VELCADE®, and we have demonstrated that Revlimid and VELCADEwork better when combined with curcumin

    Reply
  9. Julie Zimmer

    apologies for mutliple posts… the question to Agarwal (in the snippet I copied) looked like part of my comment – messy cutting and pasting on my part…

    Reply
  10. Julie Zimmer

    Paula NZ,
    we had good luck with velcade and kidney numbers/albumin – after a crash, while on dialysis, Velcade cut the Lambda light chains down to size, enabling him to get off of dialysis – well, Velcade and Dex, but I credit the Velcade.. it doesn’t work for everyone, I know, but it continued to work for us (SCR) right up to having an SCT and now is in his back pocket for relapse (no maintenance at present, going on second year…)

    Reply
    1. Julie Zimmer

      currently on no therapies, taking small amount of curcumin, in SCR, LOVING not taking therapies… good QOL knock on wood, 2-year post SCT checkup in a few weeks…

      Reply
  11. Paula NZ

    Thanks Julie just read your other reply…yes I believe it is the Velcade also.
    I will post my 2nd month in 2 weeks…My kidney specialist said I had 60 damage on kidneys which is not much , he wrote to my doctor and said my numbers as in paraprotein was now NORMAL…it is 7 – 16 am at 14 after those three weeks.
    I am offered a stem cell transplant in about a year, but I at this stage do not want one, in fact I am going to try and get them to not do the whole 8 months Velcade, and stop in a few months and then watch..
    I have NO side effects except a little tired which is actually wonderful, so relaxed, and slightly swollen ankles…while they are getting the amyloidosis out of my body and kidneys..

    Reply
  12. Paula NZ

    Julie all the above sites you posted on curcumin etc are not available. SO I have not been able to access them.

    Reply
  13. julie zimmer

    Paula, not sure how th links got goofed up but that was just pulled off the top of a longer list from googling the terms curcumin and velcade (or mybe bortizimib,, mid?) I did the same for Revlimid but found only s few hits that seemed to be from Agarwal, M.D. Anderson researcher. but I only spent a minute and didn’t go far into the pages.

    Reply
  14. Paula NZ

    Thanks Julie, I have not been following your story, does your husband have amyloidosis or just the MM. re kidney/albumin connection?

    Reply
  15. julie

    he has severe back damage and full rods (twice, the first set broke due to lack of anterior support so they replaced them and added a cage in front) and has had the kidney crash/temporary dialysis (luckily temporary), no amyloidosis. His best friend had amyloidosis – made it 11 years, before the most recent therapies, but had an SCT very early. Hard to believe they both had/have MM. Now in SCR post SCT and no traceable minimal residual disease, taking curcumin – I’m wondering if his low dose (2-3 grams is the most I get him to take…) will cause a resistance and not do him any real good – never thought about the resistance possibility until this week. Mayo doc is cautiously on the bandwagon. I always thought I’d up him to 8 at the first sign of residual disease. Hope I don’t have to find that out real soon. we see Mayo doc in early July, regular quarterly appt.

    Reply
  16. julie

    Rhys, friend, made it 11 years with amyloidosis and early SCT., Velcade, REvlimid Van (my husband) is at almost 7 years past DX, had SCT at 5 years after minimal success on Revlimid and excellent success with Velcade – was in SCR going into SCT. We considered it consolidation and possible to go off of Velcade and Dex while they still worked for him. He was not happy with the side effects and QOL on the drugs.

    Reply

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