Today, I received a new comment on an article I wrote sometimes ago on Tetrathiomolybdate: https://www.cancertreatmentsresearch.com/?p=249
I find the comment so relevant that I am going to publish it here, to increase its visibility:
My girlfriend started taking TM in late 2001 after her oncologist threatened to cut her off if she didn’t have mastectomies and a hysterectomy. She had several lumpectomies, cervical surgery and one ovary removed at that point, spread out from age 19 to age 30. I connected her with nurse Jan at the University of Michigan that was dispensing TM to the group of 30 + people with advanced cancer, and she benevolently supplied us with contact information of the supplier and the Tennessee pharmacist that made the caps and aided in communication between the staff at U of M, and my girlfriend’s doctor. The cancer was in remission for 3 months at which time we broke up. She maintained low copper levels for 6 more months with no evidence of cancer. However, she lapsed from taking the TM after losing her job. As related to me anecdotally, the cancer returned immediately and she needed to have lymph nodes removed. As an ex-boyfriend of a newly married woman I didn’t feel it was my place to grill her about the particulars. As I understand it, she has maintained treatment with TM ever since, and has had no additional cancer related events. Of note, she was able to become pregnant with her remaining ovary and now has a 10+ year old daughter. It was communicated to me that lapsing from taking the drug results in high spiking of copper levels; higher than before treatment began.
The rumor is it that University of Michigan licensed the drug to a group of doctor investors in California that put together an application to get TM approved for use in humans by the FDA. However, the application was botched and after great expense and time, the application was rejected for unknown, although allegedly frivolous reasons. Subsequently, the doctors fought, pointed fingers and lost interest in investing additional monies in the drug.
It has also been suggested that TM would be too readily available as a knock-off since it is just a metal salt. Ease of purchase without going through the doctor-prescription system would deprive the California doctors of their investment money. In 2000, after reading a WIRED magazine article on TM I found pricing for a 55 gallon drum of powdered industrial TM at around $300.
My personal opinion is that the drug is wildly effective for cancers that present tumors needing to be supplied with blood vessels in order to grow the tumor rapidly. TM’s cost is low, side effects are minimal and it may be used in parallel with other treatments without affecting them.
The downsides are:
-It takes a few weeks time to reduce copper levels to a level that stops the cancer from being able to construct a blood supply network.
-You can’t stop once you start or it’s thought that the cancer will come back with a vengeance.
-You might have to get back to work.
by David S
Thank you David for this valuable piece of information!
I only have one comment to the above, i.e. there is another downside and that is related to the fact that following Tetrathiomolybdate administration, patients can get sulfur burps that smell/taste like rotten eggs. This may be reduced or eliminated using concomitant administration of proton pump inhibitors such as Omeprazole. To me, this side effect is so irrelevant that I would go forward with Tetrathiomolybdate.
If you like to read the article on Tetrathiomolybdate, please click on the following link https://www.cancertreatmentsresearch.com/?p=249
Disclaimer:
This site is not designed to and does not provide medical advice, professional diagnosis, opinion, treatment or services to you or to any other individual. Through this site and linkages to other sites, I provide general information for educational purposes only. The information provided in this site, or through linkages to other sites, is not a substitute for medical or professional care, and you should not use the information in place of a visit, call consultation or the advice of your physician or other healthcare provider. I am not liable or responsible for any advice, course of treatment, diagnosis or any other information, services or product you obtain through this site. This is just my own personal opinion regarding what we have learned on this road.
OK but are you guys sure that there will be no developing of resistant to Tetrathiomolybdate ???
for treating cancer in my opinion the hardest thing to do is not dealing with the side effects !!!
its the resistant to these treatments that is very hard to deal with .
even a powerful drug like Salinomycin will not be effective after using it for a while
and the same thing is happening with the immunotherapy drugs
I’m always looking for those kind of treatments that cancer cannot develop any resistant to it once it works
———-
and by the way , what is this ?
http://www.huffingtonpost.com/entry/promising-therapy-sends-93-percent-of-incurable-cancer-into-remission_us_56c3cbf5e4b0c3c550531fe5
Hi Emad, I think it is difficult for cancer to develop resistance since most need vessels for supplies and that requires Copper.
How do you know Salinomycin will not be effective after using it for a while? I have seen only one paper suggesting that while all the others and my experience are suggesting the opposite.
I like the concept of immunotheraphy but I think today that is little understood and as a result difficult to control so that in many cases it may lead to increase of activity instead of reduction.
I read about Salinomycin becoming weak from here :
to be honest , I hope its not true
http://www.hindawi.com/journals/bmri/2012/950658/
read 7.2. Case 2 82-Year-Old Female Patient with Advanced and Metastatic (Pelvic Lymphatic Metastasis) Squamous Cell Carcinoma of the Vulva
about tetrathiomolybdate , it will be excellent if its hard for cancer to develop any resistant to it , I will try it with my mother as soon as I can
I know the article but I cannot find a reference to resistance. Can you please be more specific? Thanks.
Tetrathiomolybdate appears to be most effective against micrometastases, and sometimes ineffective against large tumors. So it might be used best as a maintenance therapy, or between chemotherapy cycles, if the blood formula has degraded badly and the patient needs time to recover.
Many anti-angiogenic drugs induce HIF-1a, which leads to increased stemness, but Tetrathiomolybdate degrades HIF-1a, also decreases invasiveness and promotes anoikis.
Tetrathiomolybdate inhibits mitochondrial complex IV and mediates degradation of hypoxia-inducible factor-1α in cancer cells.
http://www.ncbi.nlm.nih.gov/pubmed/26469226
Tetrathiomolybdate inhibits head and neck cancer metastasis by decreasing tumor cell motility, invasiveness and by promoting tumor cell anoikis.
http://www.ncbi.nlm.nih.gov/pubmed/20682068
Copper chelation leads to upregulation of glycolysis by cancer cells, so pairing a copper chelator with an inhibitor of glycolysis looks promising (a proton pump inhibitor, like omeprazole, could help).
Bioavailable copper modulates oxidative phosphorylation and growth of tumors.
http://www.ncbi.nlm.nih.gov/pubmed/24218578
Thanks Ovidiu.
OK Daniel , here :
Figure 4
http://www.hindawi.com/journals/bmri/2012/950658/fig4/
administration of both erlotinib + Salinomycin led to a significant tumor regression , huge decrease of the tumor markers
then after 3 months (with no treatments) the tumor grow back again , and the patient decided to take salinomycin only
but with Salinomycin alone , there was no more tumor shrinkage , only disease stabilization for 4 months
you can see it on the diagram , the tumor markers are raising slowly
isn’t that what’s always happening when there is a disease stabilization ? it’s a matter of time until the tumor wins and grows back again
I hope I’m wrong , I hate to see Salinomycin loosing a battle , but we should have a strategy in case salinomycin stops working
maybe 3BP is the best choice to boost the effect of Salinomycin , just like the SCLC patient who achieved a complete remission in 4 weeks
Emad I thought you are thinking of that fig but I just wanted to make sure. What I see there is the following: 1. chemo +Sal –> strong decline of the markers; 2. latter the markers start groing again; 3. Sal applied and leads to a marker decline but less than when combined with chemo; 4. latter markers start growing again.
So what I can conclude base on this is that:
1. Sal + Chemo leads to serious anticancer effect
2. Sal + Chemo at the dose used did not completely kill the tumor but given that the knowledge on application of Sal was limited, this was great result
3. Sal alone seems to be less but still effective (but that doesen’t mean that there is resistance developed which is the case for some of the conventional treatments)
Indeed, I am aware of the fact that Heidelberg believes Salinomycin needs to be applied with chemo or 3BP for the best effectiveness. And I can confirm that based on our personal experience.
But anyway, lets change the subject back to TM.
Both erlotinib and salinomycin are metabolized by CYP3A4, so co-administration may slightly increase the AUC for salinomycin.
But salinomycin is most effective against cancer stem-like cells, like the ones who have undergone EMT, and less effective against those with epithelial markers. On the other hand, erlotinib is not effective against cells that have undergone EMT, actually it favors EMT (a problem after 1-2 months of exposure), so there’s no surprise there’s synergy between erlotinib and salinomycin.
PS. Sorry for the off topic.
Guys, I think we can have a nice discussion here on Salinomycin and hopefully we may have some others jumping in to contribute as I will add some good fuel for that. When relevant, I may move the comments to the Salinomycin page or otherwise just add a link on that page for others to be able to get to this discussion.
Ovidiu, based on my practical experience (and that of others) I do not think the efectivness of the combination is due to the CYP3A4 inhibition. That can be easily verified when combining Sal with e.g. Ketoconazole which is a strong inhibitor of CYP3A4 (btw, Sal is inhibiting that too). However, also based on my practical experience I think you made a very relevant point in your comment that may help us to improve our knowledge. So I will share with you guys here some facts that may help us and the world have a breakthrough in understanding Salinomycin action.
Facts:
1. Salinomycin seems to be most effective in epithelial cancers
2. Salinomycin seems to work well when combined with Chemo (such as Cisplatin, Gemcitabine, Erlotinib and at least a few others) and/or 3BP
3. The Chemo and or 3BP has to be applied first and than Salinomycin after
4. Following the above, Salinomycin will lead to response that will decay in the following days of application if there is no other Chemo applied –> the effect fades away (I would not call this resistance)
5. If Chemo or 3BP is applied again than there is response again
6. Salinomycin must be applied at a delay of several days from Chemo and or 3Bp for the most intense response. That means that if Salinomycin is applied just after (e.g. during the same day) there may be no specific response to that
7. Following the Salinomycin effectiveness, cancer cells will die via necrosis – so there may be a strong immune reaction during the following days – blood measurements will show strong increase in LDH and others (e.g. potassium) for a few days suggesting tumor lysis
These were the facts and the fuel for our further discussion. The questions that follow are:
1. Why there is a need for chemo or 3BP “priming””
2. Why there is a response only when applying Sal after several days and not immediately
Now you understand why I was triggered by Ovidiu’s points. Following that, here are some assumptions that we need to verify (via references):
1. Salinomycin is sensitive to those cells that went through the EMT transition (already clearly known)
2. EMT transition is induced by some chemos and 3BP –> Do we know which are the chemos that induce EMT? Can we get a list of that here? Can 3BP induce such a transition? What would be the mechanism behind?
3. There is a time delay from the application of those chemos until the EMT transition happened. Do we know what is the average time depending on the chemos and/or the cancer cell type or any other aspect?
Lets have a team work to respond to the above questions! What do you guys think about that?
(Off course we should keep our mind open and think beyond EMT transition)
I tried earlier to post about erlotinib and STAT3 activation (favors EMT), with links, but my comment was rejected as spam.
Also about reverting TKI resistance with niclosamide or salinomycin.
There is no msg from you in my “spam” Ovidiu … maybe there were too many links in it? you can try to post again broken in a few comments?
Continuous exposure of non-small cell lung cancer cells with wild-type EGFR to an inhibitor of EGFR tyrosine kinase induces chemoresistance by activating STAT3.
http://www.ncbi.nlm.nih.gov/pubmed/25695284
Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells.
http://www.ncbi.nlm.nih.gov/pubmed/25065853
Anti-EGFR therapeutic efficacy correlates directly with inhibition of STAT3 activity.
http://www.ncbi.nlm.nih.gov/pubmed/24556630
Niclosamide overcomes acquired resistance to erlotinib through suppression of STAT3 in non-small cell lung cancer.
http://www.ncbi.nlm.nih.gov/pubmed/23894143
Salinomycin Promotes Anoikis and Decreases the CD44+/CD24- Stem-Like Population via Inhibition of STAT3 Activation in MDA-MB-231 Cells.
http://www.ncbi.nlm.nih.gov/pubmed/26528725
Thanks Ovidiu. How would you connect these points, STAT3 role, with the facts and our question above?
My point is that erlotinib resistance is different from resistance to cisplatin or paclitaxel.
It takes something like 4 weeks of erlotinib exposure to strongly induce STAT3, which favors chemoresistance and EMT.
Regarding the phenotypic transition caused by chemo, this happen in days, and here is a paper about docetaxel inducing a phenotypic cell state transition towards a favoured transient CD44HiCD24Hi chemotherapy-tolerant
state.
Temporally sequenced anticancer drugs overcome adaptive resistance by targeting a vulnerable chemotherapy-induced phenotypic transition.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4339891/
I also found another interesting article, possibly related to this, but it’s a bit difficult to digest…
http://www.ebiomedicine.com/article/S2352-3964(16)30005-6/abstract
Very good paper on the sequenced strategy … I will come back on STAT3 after some research.
Please note that I just added a new post based on the discussion above on Salinomycin so that we can focus the discussion and also to have a post where we can add things that we learn during our research and discussion. Here is the post https://www.cancertreatmentsresearch.com/?p=1098
Answering my second question above: the first paper showing the potentila of Salinomycin also showed that canecer cells pretreated with and that became resistent to Paclitaxel, had a 2x increase sensitivity to Salinomycin: “We observed that 4T1 cells treated with paclitaxel for 4 days and then allowed to recover in the absence of drug for 4 days (4T1-TaxR cells) were resistant to further paclitaxel treatment in comparison to parental 4T1 cells that had not been previously treated with paclitaxel (Figure 4G). In contrast, the 4T1-TaxR cells, while resistant to paclitaxel, displayed a 2-fold increase in sensitivity to treatment with salinomycin in comparison to parental 4T1 cells (Figure 4G). These observations demonstrate that treatment with paclitaxel selects for mesenchymal cancer cells that display increased resistance to paclitaxel while remaining sensitive to salinomycin treatment.” http://www.cell.com/cell/fulltext/S0092-8674(09)00781-8
Therefore, Paclitaxel pretreatment can increase the sensitivity to Salinomycin (after) treatment.
Following quietly …
Not quietly 🙂
Please note that I intend to move our discussion to a new post I just created https://www.cancertreatmentsresearch.com/?p=1098
Very interesting article Daniel.May be salinomycin should be added into the firstline treatment.
I think so Ergin but there is not much chance for that to happen since the only company working on Sal as a cancer drug (company called Verastem) have stopped the clinical trials with no communication to the public on why – this is very strange since any public company will state what is the reason when a drug goes out of their pipeline.
Whenever I read about Salinomycin , the main concern I can see about it is the toxicity
https://www.cancerresearchuk.org/about-cancer/cancer-chat/thread/salinomycin-and-mgo-treatment-any-experiences
like they fear it ?!
because it should be used in low doses, and any increased dose maybe dangerous , and also maybe because of tremor and increased heart rate people may fear it , even if its safe when used in the proper dose
unlike other chemicals like 3-BP or DCA which are silent and have no immediate side effects
its weird that many peoples talk about how these anti cancer drugs have bad side effects ! to me , compared to chemo its not bad at all !!!
like Ovidiu said , sorry for the off topic
I think TM should always be included in our anti cancer cocktail
the sulfur burps are not an issue , its still better than dying in my opinion
the little problem is the decrease in blood counts , maybe it will be a big problem if the WBCs fall nearly below the normal range, its not good al all even for a healthy person not just cancer patient
combining chemo with TM may increase the chance of this side effect ?
anyway , i can’t wait to get TM , i need it
I put a comment about TM but I can’t find it ?
I found it in “trash” and restore it – so you can see it above 🙂
Dear Emad.
I would like to know your feedback on TM.
Let us know,
Best wishes,
Alex
I didn’t use it with my mom
it can cause some drop on blood counts which is already a side effect of chemo , if my mother is not on chemo then most likely I will end up using it for sure as I believe it could really help
but I don’t know which is better as anti angiogenesis , TM or Thalidomide !??