Salinomycin is as an antimicrobial and anticoccidial antibiotic. In 2009, a groundbreaking result was published in the scientific journal Cell (Ref), showing that Salinomycin can be effective in killing the cancer stem cells (CSC), the cancer cell population that is responsible for chemo resistance and metastasis. Although the study was focused on breast cancer, Salinomycin will do the same in most epithelial cancers.
In my opinion, this is one of the most effective anti cancer substance I am aware of, that can trigger an intensive anticancer response. However, somehow, the intensive response doesn’t happen always and it is not clear why. It seems that Sal works best in epithelial cancers. Example of epithelial cancers are cancers of endocrine glands (e.g. adrenal, thyroid, pituitary), breast, ovarian, lung, etc. Cancers that develop in epithelial cells are called carcinomas (Carcinoma is the term used for a malignant epithelial tumor). About 80-90% of cancers are this type. (Ref.)
Besides is wide effectiveness in various types of cancers, another strong point of Salinomycin is that even if it will not kill the cancer cells, it is a potent inhibitor of the ABC transporter P-glycoprotein/MDR1 in different cancer cells. Ref1 Ref2 This means that Sal will turn cancers that are or have become insensitive to chemo therapies, into cancers that will be again sensitive to chemo.
Soon after its discovery, in 2009, it has been patented by a company founded by the scientists who discovered the anti cancer effects of Sal. The company is also supported by Harvard University and MTI. Its name is Verastem. In their product portfolio, Salinomycin goes under VS-507 name while being promoted as an Wnt Inhibitor.
Update 27.02.2016: My understanding of Salinomycin today, based on personal view and that of others:
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 may 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 or little 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 (TLS). TLS can be dangerous if too much cancer is killed at once so it needs to be manged carefully.
Note that the above are extremely valuable conclusions following my intensive search for answers on this topic and identifying patterns.
Strangely enough, it seems that Salinomycin is not anymore on the pipeline of Verastem???
Salinomycin as a drug for targeting human cancer stem cells.
“Salinomycin was therapeutically applicated €œfirst-in-man€ in 2010, in the context of a pilote clinical trial with a small cohort of patients with metastatic breast, ovarian, and head and neck cancers. Intravenous administration of 0.20-0.25 mg/kg salinomycin every second day for three weeks resulted in partial regression of tumor metastasis and showed only minor acute and long-term side effects, but no severe acute and long-term side effects observed with conventional chemotherapeutic drugs.”
“As shown in Figure 3, systemic salinomycin therapy induced a marked regression of the subcutaneous thoracal metastases. A biopsy of the regressive subcutaneous thoracal metastases was obtained after 12 cycles of salinomycin therapy, and the specimen was investigated by molecular histopathology. As determined by TdT-mediated dUTP nick end labeling (TUNEL) histopathology, ~85% of the cells had undergone apoptosis. Moreover, the serum levels of the tumormarkers Ca 15-3 (cut off <31€‰U/mL) and CEA (cut off <3.4€‰ng/mL) declined from 14.3 U/mL and 50.8€‰ng/mL before salinomycin therapy to 7.2 U/mL and 15.5€‰ng/mL after salinomycin therapy, respectively. Intravenous salinomycin therapy resulted in minor acute side effects, including tachycardia and mild tremor for 30€“60€‰min. after administration but lacked severe and long-term side effects observed with conventional chemotherapeutic drugs, such as myelodepression, neutropenia, alopecia, nausea and vomiting, or gastrointestinal, thromboembolic, and neurological side effects. Similar results of salinomycin-induced partial tumor and metastasis regression were obtained in three other patients with metastatic breast cancer, one patient with metastatic ovarian cancer, and one patient with metastatic head and neck squamous cell carcinoma.” Ref.
Case 1: SCLC: Cancer Treatment Institute of Colombia Demonstrates Unprecedented Results Using Unique Cancer Drug Combination of 3-Bromopyruvate and Salinomycin for Treatment of Multiple Types of Cancer
With masses in both lungs and a depressed platelet count, the prognosis for the patient was poor; he had previously undergone standard chemoradiotherapy, but the cancer returned within three months. His attending physician recommended against additional treatments. At Cancer Treatment Institute of Colombia, the patient received 21 total rounds of salinomycin and 3-BrPA, delivered on alternating days. Chest CT scans four weeks later confirmed the total disappearance of SCLC. Just as encouraging was that the patient experienced no significant adverse reactions during his treatment.
Case 2: Adrenal cancer – to be added
I am sure there will be many to come.
Potassium ionophore, specifically targeting the cancer stem cells (CSC). As a result, it will induce an efflux of K+ from mitochondria and cytoplasm. While the CSC killing mechanism is not that clear to the scientists, here you can read a bit more about the possible mechanism.
One potential mechanism: Salinomycin treatment led to increased cytosolic Na+concentration, which consequently resulted in elevated cytosolic Ca2+ by means of Na(+)/Ca(2+) exchangers (NCXs) in the plasma membrane as well as the mitochondria. Elevated Ca(2+) then leads to calpain activation, which triggers caspase-dependent apoptosis involving caspases 12, 9 and 3. In addition, cytochrome c released from depolarized mitochondria directly activates caspase 9. (Combined inhibition of calpain and the mitochondrial NCXs resulted in significantly decreased cytotoxicity and was comparable to caspase 3 inhibition.) Ref.
Salinomycin induces activation of autophagy, mitophagy and affects mitochondrial polarity: differences between primary and cancer cells. Ref
Salinomycin, a polyether ionophore antibiotic isolated from Streptomyces albus, has been shown to kill CSCs in different types of human cancers, most likely by interfering with ABC drug transporters, the Wnt/Î²-catenin signaling pathway, and other CSC pathways. Ref
Salinomycin to selectively target €œCD133+€ cell subpopulations: http://link.springer.com/article/10.1245%2Fs10434-011-1561-2
Has been shown to kill CSCs in different types of human cancers, most likely by interfering with ABC drug transporters, the Wnt/Î²-catenin signaling pathway, and other CSC pathways http://www.ncbi.nlm.nih.gov/pubmed/23251084
The in vitro IC50 of salinomycin varies, depending on the source, cell type used and treatment period (Ref.).
Here is a new (2017) paper discussing various anti cancer mechanism of Salynomicin: http://journals.sagepub.com/doi/full/10.1177/1010428317695035 and below is a figure from the article, indicating the various mechanisms:
Update Sept 2017: A recent Nature Chemistry papers proposing a new mechanism related to Salinomycin’s anti cancer action: https://www.nature.com/nchem/journal/vaop/ncurrent/full/nchem.2778.html
This mechanism could sit at the basis of all the other mechanisms that have been previously identified.
In this paper it is suggested that Salinomycin is accumulating and sequestering iron in lysosomes. When the cells are left without Iron in cytosol, they will trigger the degradation of ferritin in lysosomes, leading to further iron loading in the lysosomes. Iron-mediated production of reactive oxygen species promoted lysosomal membrane permeabilization, activating a cell death pathway consistent with ferroptosis.
Here is a nice recent paper on Lysosomes as Oxidative Targets for Cancer Therapy https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5516749/
To understand what Ferropoptosis is, you can read this paper: https://www.nature.com/cdd/journal/v23/n3/full/cdd2015158a.html
If indeed, this is the main mechanism responsible for Sal anti cancer mechanism, Iron Chelation prior to Sal treatments should be avoided. Indeed this paper suggest that Iron chelators can stop ferroptosis (Ref.). Opposite to that, Iron ionophores such as Disulfiram may help Salinomycin enhance this anti-cancer mechanism.
Interestingly, Chloroquine was suggested to work well with Salinomycin (Ref.) but due to a different reason. Based on the above, I can imagine Chloroquine can support the ferroptosis induced by Salinomycin due to a possibly similar action on Iron in the lysosames (Ref.)
This substance can be lethal if administrated at higher doses than it should. If on the other hand the administration dose is correct, as demonstrated by the articles above, there is a dose window where cancer cells are killed while the normal cells are not affected.
A case of accidental inhalation and swallowing of about 1mg/kg by a 35 years/old man leading to sever acute toxicity with acute nausea, photophobia, leg weekness, blod preasure elevation, chronic creatinine kinase elevation and muscle pain http://www.ncbi.nlm.nih.gov/pubmed/15107902
Note that this is about 4x higher dose than that used for cancer treatment.
Short term side effects have been reported and to my knowledge those may be: 30-60 min tremor after the administration, short term impact on peripheral view, fever after the administration, pain in the tumor area.
Inhibition of Na(+)/Ca(2+) exchangers (NCX) prevents salinomycin-induced neuropathy. Blocking mitochondrial Na(+)/Ca(2+) exchangers does not impair antineoplastic efficacy. Ref
Existing ion channel blockers, such as amiodarone, dronedarone, bepridil, aprindine, and cibenzoline, have been found to have an NCX inhibitory action. (Ref.)
Administration (Intra Venous – IV)
So far I am aware of two other administration protocols:
- Protocol as published in 2012 by the scientists from Heidelberg, Germany. This protocol has been administrated to multiple patients (4 cases published in one paper) with good results in all cases. The protocol used was suggesting the following:
– one cycle is defined by 12 intravenous administrations, in alternative days (i.e. a total of 24 days)
– each IV would consist of 0.200mg/kg to 0.250mg/kg Salinomycin (i.e. 10mg Salinomicyn in and IV for a person of 50kg receiving a 0.200mg/kg dose)
– the cycles may be repeated after a few months
- A more intensive protocol I heard of being used:
– one cycle is defined as 4 weeks treatment, 5 days/week (Monday to Friday)
– each IV would consist of 0.250mg/kg to 0.300mg/kg Salinomycin
– the cycle should be repeated 4x with one month break between each
- However, in other cases 0.180mg/kg to 0.200mg/kg is enough to trigger an immune response during the following 3-4 days, that includes episodes of fever and pain at the tumor site.
Substance used: Salinomycin >98%. This is relatively expensive and the total cost of material required for one cycle treatment is about 3500 euro.
Note that there is another version of Salinomycin i.e. Sodium Salt >90% which may be 10x cheaper. However its effectiveness in humans is unknown.
Also note that on the web we will find easy to buy 24% purity (which typically is Sodium Salt version). This is used for treatment of animals.
So, the best seems to be Salinomycin base version (CAS Number 53003-10-4) as it seems that this was used before in the published cases, but Salinomycin Sodium Salt (CAS Number 55721-31-8) may also be relevant.
Tumor acidosis enhances cytotoxic effects and autophagy inhibition by salinomycin on cancer cell lines and cancer stem cells. http://europepmc.org/abstract/med/27248168
Improving Sal effectiveness:
While there is a lot of research indicating that Salinomycin can overcome multi drug resistance, there is also research indicating that Salinomycin is a substrate of P-glycoprotein and P-glycoprotein over expression may also limit Salinomycin brain penetration as well as oral bio-availability (Ref.). Here is another example of research indicating that MDR1 overexpression leads to resistance to Salinomycin https://www.researchgate.net/publication/279529617_Drug_Transporter-Mediated_Protection_of_Cancer_Stem_Cells_From_Ionophore_Antibiotics
However, I do know based on genetic profiling of my wife’s tumor (but also specific literature) that she had a high MDR1 over expression level. And we did saw strong response to Salinomycin. So our results may also be related with some of the drugs and supplements she was taking, with MDR1 inhibition capabilities. Those are e.g. sometimes Verapamil, sometimes Ketokonazole. As a result, when there is no response to Salinomycin treatment, P-glycoprotein inhibitors such as Verapamil, Ketoconazole, or Tetrandrine should be administrated prior and/or during the Sal treatment.
Since MDR1 pump is ATP driven, lowering ATP prior to Sal treatment should also improve effectiveness. Using Metformin and/or Doxicycline would then help. Same applies for Phlorizin and 2DG. Note: we always used Metformin and sometimes Doxicycline. These will slow down mitochondria.
I will share my research on this asap.
Source & Cost
Chemical suppliers such as Sigma. Salinomycin base version (CAS Number 53003-10-4). Material cost is a few thousands euro/dollars for one cycle (12 IVs) depending on your weight.
Synergies & Antagonsists
2-DG, 3BP, other glycolisis inhibitors: http://www.ncbi.nlm.nih.gov/pubmed/25912307
HDAC inhibitors (e.g. Valproic acid): http://www.ncbi.nlm.nih.gov/pubmed/24351423
Autophagy Inhibitors (e.g. Chloroquine): http://www.ncbi.nlm.nih.gov/pubmed/23670030
Therapeutic compositions and related methods of use
Based on this the formulation was found to remain stable in normal saline up to 24 hours at room temperature.
Preclinical drug metabolism and pharmacokinetics of Salinomycin, a potential candidate for targeting human cancer stem cells
Concomitant administration of Ketoconazole (KTC) on SAL pharmacokinetics: KTC, being a selective CYP3A4 inhibitor increased the systemic exposure of SAL significantly to 7-fold in AUC0-Î± and 3-fold increase in Cmax of SAL in rats with concomitant KTC administration.
Glucose starvation-mediated inhibition of salinomycin induced autophagy amplifies cancer cell specific cell death
Our in vitro studies further demonstrate that the combined use of 2-Fluoro 2-deoxy D-glucose, or 2-deoxy D-glucose with Salinomycin is lethal in cancer cells
HDAC inhibitors enhance the lethality of low dose salinomycin in parental and stem-like GBM cells.
Collectively our data demonstrate that the lethality of low nanomolar concentrations of salinomycin are enhanced by HDAC inhibitors in GBM cells and that increased death receptor signaling together with reduced mitochondrial function are causal in the combinatorial drug necro-apoptotic killing effect.
Salinomycin induces cell death with autophagy through activation of endoplasmic reticulum stress in human cancer cells. In conclusion, these findings provide evidence that combination treatment with salinomycin and pharmacological autophagy inhibitors will be an effective therapeutic strategy for eliminating cancer cells as well as cancer stem cells.
Metformin and salinomycin as the best combination for the eradication of NSCLC monolayer cells and their alveospheres (cancer stem cells) irrespective of EGFR, KRAS, EML4/ALK and LKB1 status. In conclusion, METF in combination with SAL could be a promising treatment option for patients with advanced NSCLC irrespective of their EGFR, KRAS, EML4/ALK and LKB1 status.
Specific targeting of neurotoxic side effects and pharmacological profile of the novel cancer stem cell drug salinomycin in mice. Inhibition of the mitochondrial Na(+)/Ca(2+) exchanger partially prevented the development ofsalinomycin-induced neuropathy in vivo, an approach which did not reduce salinomycin‘s antineoplastic efficacy in vitro.
Salinomycin treatment reduces metastatic tumor burden by hampering cancer cell migration. Our findings clearly show that salinomycin can strongly inhibit cancer cell migration independent of the induction of cell death. We furthermore demonstrate for the first time that salinomycin treatment reduces metastasis formation in vivo, strengthening its role as promising anti-cancer therapeutic.
The cancer stem cell selective inhibitor salinomycin is a p-glycoprotein inhibitor. Treatment of the MDR cell lines with salinomycin restored a normal drug sensitivity of these cells.
Salinomycin and Other Ionophores as a New Class of Antimalarial Drugs with Transmission-Blocking Activity http://aac.asm.org/content/59/9/5135.full
Dual targeting of androgen receptor and mTORC1 by salinomycin in prostate cancer. http://www.ncbi.nlm.nih.gov/pubmed/27557496
Androgen receptor (AR) and PI3K/AKT/mTORC1 are major survival signals that drive prostate cancer to a lethal disease. Reciprocal activation of these oncogenic pathways from negative cross talks contributes to low/limited success of pathway-selective inhibitors in curbing prostate cancer progression. We report that the antibiotic salinomycin, a cancer stem cell blocker, is a dual-acting AR and mTORC1 inhibitor, inhibiting PTEN-deficient castration-sensitive and castration-resistant prostate cancer in culture and xenograft tumors. AR expression, its transcriptional activity, and androgen biosynthesis regulating enzymes CYP17A1, HSD3β1 were reduced by sub-micro molar salinomycin. Estrogen receptor-α expression was unchanged. Loss of phosphorylated AR at serine-81, which is an index for nuclear AR activity, preceded total AR reduction. Rapamycin enhanced the AR protein level without altering phosphoAR-Ser81 and CYP17A1. Inactivation of mTORC1, evident from reduced phosphorylation of mTOR and downstream effectors, as well as AMPK activation led to robust autophagy induction. Apoptosis increased modestly, albeit significantly, by sub-micro molar salinomycin. Enhanced stimulatory TSC2 phosphorylation at Ser-1387 by AMPK, and reduced inhibitory TSC2 phosphorylation at Ser-939/Thr-1462 catalyzed by AKT augmented TSC2/TSC1 activity, which led to mTORC1 inhibition. AMPK-mediated raptor phosphorylation further reduced mTOR’s kinase function and mTORC1 activity. Our novel finding on dual inhibition of AR and mTORC1 suggests that salinomycin is potentially active as monotherapy against advanced prostate cancer.
Salinomycin: A new paradigm in cancer therapy http://journals.sagepub.com/doi/full/10.1177/1010428317695035
The primary hurdle in the treatment of cancer is acquisition of resistance by the tumor cells toward multiple drugs and selectively targeting the cancer stem cells. This problem was overcome by the chemotherapeutic property of recently discovered drug salinomycin. Exact mechanism of action of salinomycin is not yet known, but there are multiple pathways by which salinomycin inhibits tumor growth. Salinomycin decreases the expression of adenosine triphosphate–binding cassette transporter in multidrug resistance cells and interferes with Akt signaling pathway, Wnt/β-catenin, Hedgehog, and Notch pathways of cancer progression. Salinomycin selectively targets cancer stem cells. The potential of salinomycin to eliminate both cancer stem cells and therapy-resistant cancer cells may characterize the compound as a novel and an efficient chemotherapeutic drug.
Clinics Treating Patients with Salinomycin
Columbia: Advanced Medical Therapeutics
My review: Unknown
US: Advanced Rejuvenation Institute
My review: Unknown
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