Like I said in one of my earlier post (Ref), so far I investigated many potentially anti cancer treatments and out of this Salinomycin stands out. This is because when done well (sometimes done well just by chance) the administration of Salinomycin IV can lead to strong anti cancer effects that can be reflected in strong pain at the tumor side during and a few hours after the IV, strong immune response, blood parameters including markers affected. Everything indicates that if done well Salinomycin can lead to serious tumor necrosis (not apoptosis).
With this post, I would like to start a discussion around Salinomycin and the observations we and others made. The goal is to better understand the mechanism behind Salinomycin effectiveness so that it can be applied in the most effective manner. I hope that you, the visitor, will also contribute to this research and discussion.
Fuel for the discussion
Facts based on our experience and that of others applying Salinomycin in humans:
1. Salinomycin seems to be most effective in epithelial cancers (experience Heidelberg hospital)
2. Salinomycin seems to work well when combined with Chemo (such as Cisplatin, Gemcitabine, Erlotinib and at least a few others) and/or 3BP (experience Heidelberg hospital and other sources)
3. The Chemo and or 3BP has to be applied first and than Salinomycin after (other sources)
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) (other sources)
5. If Chemo or 3BP is applied again than there is response again (other sources)
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 (other sources)
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 (other sources)
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
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
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? I hope in time we will get more readers involved in this highly relevant discussion
(Off course we should keep our mind open and think beyond EMT transition)
Consolidating essentials emerging during our discussion – this list will continuously grow as we learn more
– cancer cells pretreated with and that became resistant to Paclitaxel, had a 2x increase sensitivity to Salinomycin (Ref)
– treatment of cancer cells with high concentration of taxanes results in the generation of ‘persister’ cells that are defined by a transition towards a Cancer Stem Cell like status – This shift correlates with the activation of the Src family kinase (SFK)/Hck pathway – post-treatment with a SFK/Hck inhibitor within a defined temporal window enhances cell death. Specifically the maximum of this activation that can be targeted with SFK/Hck inhibitor is between day 8th and day 11th from the application of taxanes (Ref.) So what this observation suggests is that chemo treatments like taxanes may induce chemoresistence but at the same time may make the cancer cells susceptible to other substances (in this case vulnerable to inhibition of SFK by kinase inhibitors) if those are administrated at the right time. Indeed this cancer stem like state seems to be transient so it needs to be targeted at the right time. This observation (i.e. chemo creating a transient state in which cancer cells is susceptible to other substances) is in perfect line with our observation where we have seen that Salinomycin administrated several days after chemo administration leads to best anti cancer effects.
– chemotheraphies that can prime cancer cells so that they respond to Salinomycin are: paclitaxel and doxetaxel, gemcitabine, eribulin, cisplatin, carboplatin, 3-bromopyruvate, temozolomide (Ref), carmustine (Ref), lomustine (Ref). I will add more to this list as soon as I learn about others.
Background information
Metastasis can be explained as a two-phase process: The first phase involves the physical translocation of a cancer cell to a distant organ, whereas the second encompasses the ability of the cancer cell to develop into a metastatic lesion at that distant site.
The first phase is connected to the epithelial-mesenchymal transition (EMT),a process important for embryonic development, that may be involved in many pathological processes such as wound healing, tissue fibrosis or cancer progression. Indeed, this is a process by which epithelial cells lose their cell polarity and cell-cell adhesion, and gain migratory and invasive properties to become mesenchymal stem cells; these are multipotent stromal cells that can differentiate into a variety of cell types. Some evidence suggests that cells that undergo EMT gain stem cell-like properties, thus giving rise to Cancer Stem Cells (CSCs). (Ref)
The EMT process in cell is driven by growth factors (EGF, PDGF, HGF) or other signaling proteins such as TGF-beta, sonic hedgehog (Shh), Wnt/beta-catenin and extracellular matrix (ECM) components that may stimulate cellular growth and migration. During cancer progression, the EMT process is necessary to the conversion of benign tumor to aggressive and highly invasive cancer.
The second phase, is a reverse process of the first one called mesenchymal-epithelial transition (MET) that may take place during the colonization of distant sites and metastatic cancer cells to again acquire the epithelial phenotype. Indeed, later in embryonic development, MET is crucial for gastrulation, angiogenesis, myoblast migration,bone remodeling, and nerve sprouting among others.[29] MET is essential for embryogenesis
Thus, EMT and MET form the initiation and completion of the invasion-metastasis cascade.
Not all cells undergo a complete EMT, i.e. losing their cell-cell adhesion and gaining solitary migration characteristics. Instead, most cells undergo partial EMT, a state in which they retain some cell-cell adhesion, and gain migratory traits, thus cells in this hybrid epithelial/mesenchymal phenotype are characterised by special properties such as collective cell migration. (Ref.)
It was suggested that there are coupled bistable switches mechanism, in which the SNAIL1/miR-34 double-negative feedback loop is responsible for the reversible switch and regulates the transition between epithelial and partial EMT, whereas the ZEB/miR-200 feedback loop is accountable for the irreversible switch and controls the transition between partial EMT and mesenchymal (Ref.).
Five main pathways have been found to trigger EMT-associated processes:
- tyrosine kinase receptors (epidermal growth factor, fibroblast growth factor, hepatocyte growth factor, platelet-derived growth factor, insulin-like growth factor),
- integrins,
- Wnt,
- NF-KB, a key regulator of the inflammatory response
- TGF-β pathways.
These pathways activate Akt, GSK3, Rho-GTPases, and SMAD signaling pathways. A distinct EMT pathway has also been recently described involving the protein tyrosine phosphatase Pez. (Ref.)
MET pathway plays an important role in the development of cancer through:
- activation of key oncogenic pathways (RAS, PI3K, STAT3, beta-catenin);
- angiogenesis (sprouting of new blood vessels from pre-existing ones to supply a tumor with nutrients);
- scatter (cells dissociation due to metalloprotease production), which often leads to metastasis
The amplification of the cell surface receptor MET in cancer often drives resistance to anti-EGFR therapies.
Relevant reference
2016: Acidosis enhances the ability of salinomycin to kill cancer cells and cancer stem cells
2009: Identification of Selective Inhibitors of Cancer Stem Cells by High-Throughput Screening – first paper indicatingteh anti-cancer potential behind Salinomycin
2012: Salinomycin as a Drug for Targeting Human Cancer Stem Cells – first paper indicating
2015: Temporally sequenced anticancer drugs overcome adaptive resistance by targeting a vulnerable chemotherapy-induced phenotypic transition – paper indicating that chemo may turn the cancer cells in to stem cells like resistent to chemo (and that state and related resistance may be lost in about a month). Based on this knowledge, applying two different drugs one after each other at specific points in time (associate with the transition of the cells) may improve the anti tumor outcome
2004: The kiss of death – a paper on the advantages of necrotic cell death
2014: Sequential Salinomycin Treatment Results in Resistance Formation through Clonal Selection of Epithelial-Like Tumor Cells – this paper essentially argues that cancer cells may become resistant to Salinomycin if they will undergo a MET transition towards epithelial state. If that is the case, MET inhibitors will help to inhibit this transition. Otherwise treatment with chemo should restore sensitivity to Salinomycin via an induction of EMT which will bring the cells again into mesenchymal state – a cancer stem like state.
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 learn on this road.
A few observations:
– the EMT is not a binary event, in practice cancer cells can be found on various levels of transformation between epithelial and mesenchymal.
– while some chemo can upregulate some EMT related markers, they may downregulate others, also some newer chemo can revert EMT.
– not only chemo interferes with EMT, but other not-cancer-related medications, supplements and also the tumor microenvironment.
– salinomycin can upregulate some EMT markers, like Snail and vimentin, at least in some cancers.
– from the paper “Phenotypic Plasticity Determines Cancer Stem Cell Therapeutic Resistance in Oral Squamous Cell Carcinoma”, resistance to salinomycin can be driven by “plasticity”, defined as the ability undergo both EMT and EMT (not all cells that do EMT can do MET too). They found such cells to be sensitive to Thapsigargin. It’s possible that a MET inhibitor applied after salinomycin to also increase cell killing.
My advice is to contact the authors of the “Temporally sequenced…” paper and ask if they would like to deepen the study, by adding thapsigargin or a MET inhibitor after salinomycin.
Sorry for the typo in previous comment, “EMT and EMT” should be “EMT and MET”.
From the paper referenced above, pEMT-P (resistant to paclitaxel, cisplatin and salinomycin) had upregulated expression of the EMT markers Vimentin and Zeb1 and downregulated expression of the epithelial marker E-cadherin.
Apricoxib may be effective against this resistant line, because “apricoxib treatment induced a dose-dependent reversal of epithelial-mesenchymal transition (EMT), as shown by robust upregulation of E-cadherin and the virtual disappearance of vimentin and ZEB1 protein”.
Epithelial-mesenchymal transition increases tumor sensitivity to COX-2 inhibition by apricoxib.
http://www.ncbi.nlm.nih.gov/pubmed/22678114
This paper may be very much in line with your idea for using MET inhibitors after salinomycin https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4311025/
The main statement is that “Salinomycin Is More Effective against Cancer Cells with Mesenchymal Traits” and that moving towards epithelial state will become “resistant” to Salinomycin but susceptible to chemo again. Again, it makes sense that Heidelberg hospital thinks that the best is to alternate Salinomycin with Chemo as you will move the cancer cells from one state to the other in a continuous cycle while at each of these two states (epithelial or mesenchymal phenotypes) using an effective drug against that specific state.
So again, good idea to use MET inhibitors. If that is not available, chemo might also be enough to constantly put cancer cells back into a state of susceptibility to Salinomycin.
I created a new section above to start explaining a little about what is EMT, MET, etc.
Indeed, EMT is not binary event. Also some chemo may up regulate EMT while other not, even Sal may up regulate some EMT related markers … same applies for some supplements (when they are taken in high enough dose). But to be honest, looking at all these aspects things become more and more complex which is a clear sign to me that we are going away from the path that will lead to answers. So instead of trying to understand all the signaling pathways affected by various chemos and supplements, I propose that we consider the chemos that are know to prime cancer cells to a response to Salinomycin. After that we see what are the main pathways that are affected when exposing the cancer cells to those chemos and finally, see if there are mechanisms that are common between all these. Then we can search for other (less toxic) elements that can affect the same pathways.
So far, I know that based on human results paclitaxel and doxetaxel, gemcitabine, eribulin, cisplatin and carboplatin, 3-bromopyruvate are priming cancer cells for response to salinomycin. So the next question is what all these have in common? Specifically, I am wondering why 3BP is a primer too.
can Salinomycin be taken as a prevention drug to prevent recurrence.
I see it as helpful when using it in that way. But of course applied by somebody who has experience and training since it can be lethal.
Kind regards,
Daniel
a little question :
can low doses of chemotherapy up regulates EMT just like high doses ? if the answer is yes , then it should be easy to treat cancer for long time with less side effects and with good prognosis
but if the answer is no , then its better to find other options that can up regulate EMT (like 3BP) , patients cannot tolerate chemo for long time 🙁
The general rule is to avoid, if possible, anything that upregulates EMT, because it favors chemoresistance and metastasis.
But EMT eventually happens anyway, without specific treatments that downregulate it, so here the discussion is how to use a bad development like EMT against cancer.
Daniel, based on your experiences, do you have a best guess for optimum time between chemo/3BP etc. and Sal? You mention the 8th to 11th day after taxane therapy. Many chemos are infused at seven day intervals (my wife’s case) so, can halfway between chemo sessions (at 3 or 4 days) still be effective? Maybe the oncologist should be brought into the loop to consider temporary longer intervals between chemo (say- 16 days) to accommodate Sal. On the other hand, I suppose it’s up to my wife and I as to whether we take more time between chemo.
http://www.eurekaselect.com/113568/article
Looks like Temozolomide, Carmustine, and Lomustine can prime (brain) cancers for salinomycin.
I don’t know much about the others, but Temozolomide is an alkalyting agent. So I’m not sure where that puts it with the other chemotherapeutic drugs you’ve compiled.
Very good paper Meech. Thanks. It is very much in line with our observations + it adds to the list of substances that can prime cancer cells to Salinomycin response … which is great. I will comment asap. Maybe others can already comment.
Looks like we have a good idea for a very effective protocol !
3BP , chemo , 3BP , Salinomycin(half or full dose) , repeat …
can we put this in a real protocol or is it still early ?
and what else I’m thinking about is low dose chemo , will it do the job in making Salinomycin responding very well ?
————-
great discussion by the way 🙂
The best would be 3BP for a few days and after that Salinomycin half dose until response and when response add the other half dose to hit stronger. What is not yet clear to me is if 3BP alone is enough and/or chemo is needed. I think there is a good chance that 3BP alone is enough for priming and that would be great because both 3BP and Salinomycin IVs can be done without depending on hospitals, i.e. we an do it at home.
This is our real protocol now 🙂
We just verified by CT scan and the tumor part that was affected by Chemo shows up as not evolving possibly already death?
Hi Daniel, can you possibly expand on the final sentence and what you mean by that? Has the tumour regressed on radiological imaging or is it stable or?
And what do you mean by “that was affected by chemo”?
Also, does Sal have to be IV? I’d like to obtain some but I have no experience in interveneous injections or drips.
Thanks in advance!
Thanks for the response, Daniel.
Meech, my wife and I enlisted an in-home nurse to teach us IV/sterile techniques. I now feel I’m much more on top of sterile issues than what I see in the chemo room We started infusing IV-C with peripheral vein catheters but found her installed port was much better. I feel very confident selecting IV over oral where that’s better.
Daniel, remember that most SOC chemo is destructive to healthy cells. In fact, when resistance develops you end up attacking healthy cells while tumors grow unaffected, a great argument for agents that selectively attack cancer while sparing healthy cells.
I have exactly the same experience: the sterility is much better at home than in many hospitals …
I do have two good friends who are MDs and a good friend’s girlfriend who is a phlebotomist. I suppose I can get help from them.
Regarding Salinomycin storage conditions: S. C. B. Sal shipping box states “REFRIGERATE- DO NOT FREEZE” S. C. website says “STORE AT -20°C” Sigma Aldrich shows “Store at 2-8° C”. Anyone have good info?
Stored at -20C (both powder and solution) remains effective.
First of all, thanks Daniel for the existance of this place:
Regarding sal, has someone experience of oral use? Is a macrolide, for animals, with a range of 40-60ppm. Bioavality is the big question.
HI Jandro, thank you for the feedback. Regarding Sal there was someone on a forum who used Sal orally but based on my calculation he used too much. I wrote in the comments section of this post https://www.cancertreatmentsresearch.com/salinomycin/ why I think taking it orally is dangerous.
Hi Daniel, can you send me how to prepare Sal Sodium solution?
Hi, I did responded to your e-mail –> first you need to explain why you need the info and how you are going to use it since Sal is a dangerous tool when not used correctly. Do you have a dr. to support? Please respond first. Kind regards, Daniel
Dear Daniel, I sent an e-mail, but there was no response i.e. I didn’t receive anything. Could you resend it? Thanks
Hello.I have a question. my girlfriend,have a synovial sarcoma with a lot of bone and pleural metastasis .She has a very good condition. She s on iv vit.c high dose and selenium.
She is doing ipt now three times a week. I will add doxorubicin and ifosfamide. The question is can I do ipt with chemo 2 times a week when I am using sal ? If I am doing in the first day chemo plus 2dgp+ 3bp,next day 3bp ,in the third day sal. ( Can I add sal plus 3bp?) And next day after sal is ok to do ipt or should be a little break until next ipt ? Thank you 🙂
Hi Radu,
While my comments come always with the Disclaimer on this website, it’s impressive to see what you are doing for your girlfriend. I am very sorry you two have to go through this, but I am happy you can access such treatment options next to the conventional ones.
Regarding the treatment strategy, if I would have to build around Chemo, I would do it like this:
– Day 0: Before Chemo I would do fasting as possible – some are doing one day others 3 days, depending on each one
– Day 1: Chemo, and immediately after chemo I would do a one hour 2DG IV at 500mg total dose for a patient of about 60kg. After that I would switch to 2DG metronomic during 24 to 48 hours (to be discussed soon)
– Day 2: continuation of 2DG metronomic
– Day 3: brake
– Day 4: 3BP (max 2mg/kg dose) followed by 2DG (500mg in one hour IV)
– Day 5: Sal (max 200ug/kg dose) followed by 2DG (500mg in one hour IV)
– Day 6: 3BP (max 2mg/kg dose) followed by 2DG (500mg in one hour IV)
– Day 7: Sal (max 200ug/kg dose) followed by 2DG (500mg in one hour IV)
– Day 8: 2DG metronomic
– Day 9: continuation of 2DG metronomic started a day earlier
This could be one cycle in my mind. The above and related timing has various aspects in mind that I observed during all these years and also considering half times of drugs.
Depending on how the patient is feeling, another cycle can be started after this.
This IV cycle has to be supported by various supplements and drugs. I will soon write about that, but what comes to mind now is the need for using
– Tetrandrine daily (a drug used in China to enhance chemo – found at Chinese pharmacies) as autophagy inhibitor.
– Chloroquine 250mg capsule once a week
– Oxygen therapies will help
– Metformin during this time (but not a few days before chemo) is expected to help but due to 2DG glyco blocker, there may be a risk of too low glucose for some people
– Local hyperthermia integrated in the above schedule will help in my view
Due to fundamental reasons I just learned yesterday from a Univ Professor, and that will be discussed at a latter point, the strategy discussed here https://www.cancertreatmentsresearch.com/reduce-cholesterol-in-cancer-cells-to-fight-cancer/ may work in synergy with some of the substances included in the above schedule.
This treatment may trigger Tumor Lysis, so watching the patient including blood test of e.g. LDH, Potassium, Natrium, Calcium, Phosphate, Uric Acid, etc. is important. I discussed TLS here https://www.cancertreatmentsresearch.com/tls/
I would not interfere with the above strategy by adding Selenium since it is not clear what we can expect.
Altering the above strategy:
The above schedule includes several strategies I have learn during the years that could be effective. On the other hand, if I would want to use chemo 2x/week as you mentioned, I would give priority at maintaining the concept of adding 2DG immediately after chemo at least in a metronomic fashion. The point with Salinomycin on the other hand is to be implemented at day ~4 to ~8, in respect to a chemo cycle since I have seen that seems to be relevant for response. On this line, we could do Chemo+2DG on Day 1 and 2 and next on Day 4 and 5. Next we could implement Sal on Day 5 (next to 2DG metro) and on Day 7 (followed by 2DG IV in one hour as discussed above). In this case, 3BP+2DG could be included in Day 6 and Day 8. However, I think this would be a bit too intensive for the patient and stressing the patient is worse than giving the best treatments. In other words, happiness and positive attitude of the patient is key and stands above any treatment (since stress is triggering inflammation, high cortisol, high blood glucose level and tumor growth).
I hope this helps. If there are questions please let me know and for all reading this please also read the Disclaimer https://www.cancertreatmentsresearch.com/home/disclaimer/
Kind regards,
Daniel
Daniel…you take a stone from my hearth . I thank you very much.
I am thinking to do ozone therapy in day 1-2-4-5-7 what do you think ?
I have sarted laetrile 9g a day for almost 2 weeks…should I continue until day 21 ?(I have read that should be used 21 days in a raw).
Dear Radu, please take good care with everything you do. The linkto the Disclaimer was not a mistake but would like you and everyone visiting this page to read it. This is like driving. If we drive well we get to the destination, but when we move fast a small mistake can have huge impact. That’s why we need to be careful with everything.
Regarding B17, from my point of view it is on a second level of priority. It’s a nice to have not a must have in my view.
All the best!
Daniel
Hi Radu, now I see the first link was not the right one 🙂 Thanks.
I think it s an error with the first link becuase it’s to disclaimer
Hi Daniel .
The first link is wrong ,is right where you say you just learn something of a university professor
Hi Marcos. Thanks. The link is replaced.