Salinomycin, a promising anticancer stem cell agent

The antibiotic Salinomycin, used in animal feed to kill pathogens, is another repurposed or off-label anti-cancer drug that seems very capable of killing cancer stem cells. It is already used as such in some European countries.

What is Salinomycin?

Salinomycin is a natural ionophore. What’s an ionophore? It helps the ease of movement of  compounds (ions) across membranes and into cells. For example, hydroxychloroquine is popularly known as an ionophore that carries virus-killing zinc into cells.

Salinomycin is a polyether membrane ionophore from the bacterium Streptomyces albus. It exhibits a broad spectrum of antimicrobial activity against certain parasites, gram-positive bacteria, viruses, protozoa and some fungi (1). 

Salinomycin is an antibiotic and widely used in veterinary medicine (since the 1970s) as a feed additive to control coccidiosis in poultry, the single-cell parasitic disease of the intestinal tract, and also as a non-hormonal growth promoter. The latter use is good for the farmer as less feed is needed for animal growth. However, it may well not be good for you. One problem is that low-level antibiotic feeding leads to antibiotic-resistance in pathogens; another is the low level effect on human health with regular consumption of meat or, for example, milk. 

The use of antibiotics purely for growth promotion purposes was banned in the European Union in 2006 and in the USA in 2017. The WHO are reviewing Antibiotic-Resistant genes in the human microbiome as a cause for illness and disease.

Salinomycin and cancer stem cells

Cancer stem cells (CSCs) are present in every tumour at 3-5% of cells. Some cancers have more, in terms of numbers and types, than others - notably pancreatic, brain and prostate cancers. Cancer stem cells are resistant to conventional drug treatments but are known to be the source of cancer recurrence.

CSCs are defined as cancer-initiating cells and have been linked to self survival, angiogenesis, tumour initiation, and recurrence.. Some experts even think it is CSCs that can seed to distant parts of the body and cause metastases (2). 

In 2009, researchers identified Salinomycin from a lengthy screening process involving 16,000 compounds as being the only one capable of killing CSCs - they stated that it was potentially 100 times more effective than paclitaxel for breast cancer (3).

Salinomycin is known to carry potassium, sodium, magnesium and calcium into cancer cells resulting in cancer cell death - certainly, the buildup of calcium was known at that time to kill certain pathogens. However by 2014 it had also been shown to affect certain cancer pathways increasing DNA damage, cell death and inhibiting the Wnt signalling pathway in various cancers. 

In a 2019 mRNA screening study (4), Salinomycin was shown to be only one of three potential compounds for eradicating breast CSCs. The other two compounds were mifepristone and jQ1 which inhibits the BET cancer protein. Indeed, the clinical findings supported this screening process, especially where Salinomycin was used with jQ1.

In research with mice given breast cancer TNBC, salinomycin combined with a non-selective histone deacetylase inhibitor showed potent effects in stopping cancer cell growth, inhibiting apoptosis and arresting the cell cycle (5). A drug named LBH589 was used; it is now named Panobinostat and used for multiple myeloma.

For anyone who wishes to read more there is a 2022 research review (6). The researchers list an array of actions with different cancer signalling pathways: the inhibition of Wnt and MAPK pathways,  the initiation of autophagy, the decrease of adenosine triphosphate (ATP) levels along with the elevation of reactive oxygen species (ROS) production, the sequestration of iron in lysosomes, the triggering of DNA damage and prevention of DNA repair, the induction of endoplasmic reticulum (ER) stress, and the suppression of CSC marker expression via the interaction with its cellular binding target nucleolin. 

(There will be a test later!!! Just joking)

Usage of Salinomycin with cancer

We do have patient usage in Poland where all the early work was done. Breast cancer and sarcoma are targets, but theoretically any cancer might be treated.

At the end of the day, this is an antibiotic and will damage your microbiome. Is it better than Doxycycline. From what we know, probably. Doxycycline did not register in either of the two screening studies.

What’s the dose? That needs to be checked. Certainly overdosing caused death in Turkeys.

References

1.  Effects of antibiotics upon the Gut Microbiome; A review of the literature; Theocharis Konstantinidis et al; Biomedicines 2020, 8(11), 502;

2. A medicinal chemistry perspective on salinomycin as a potent anticancer and anti-CSCs agent;  Micha Antoszczak; European Journal of Medicinal Chemistry, Vol 164, 15 Feb 2019, pg 366-377.

3. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA, Lander ES. Cell. 2009;138:645–659

4. A genome-wide RNAi screen reveals essential therapeutic targets of breast cancer stem cells; Abir Arfaoui et al; EMBO Mol Med; 2019 Oct;11(10):e9930.  

5. Targeting breast cancer stem cells in triple-negative breast cancer using a combination of LBH589 and salinomycin; Masaya Kai et al; Breast Cancer Res Treat; 2015 Jun;151(2):281-94

6. Salinomycin as a potent anticancer stem cell agent: State of the art and future directions; Dan Qi et al; Med Res Rev. 2022 May; 42(3): 1037–1063.