Salinomycin kills cancer stem cells by sequestering iron in lysosomes

Trang Thi Mai, Ahmed Hamaï, Antje Hienzsch, Tatiana Cañeque, Sebastian Müller, Julien Wicinski, Olivier Cabaud, Christine Leroy, Amandine David, Verónica Acevedo, Akihide Ryo, Christophe Ginestier, Daniel

Birnbaum, Emmanuelle Charafe-Jauffret, Patrice Codogno

Presented by: Ardasher Mamadjonov

Introduction

What are Stem cells?

Stem cells are unspecialized human cells

that have the potential to differentiate

into any type of cell in the body to renew

and sustain our organs

https://www.foothillstherapy.com/2020/01/20/stem-cells-for-joint-pain/

What are Cancer Stem Cells(CSC’s)?Cancer stem cells are very similar to regular stem cells in a sense that they can differentiate and renew themselves. They are a small sub population in cancer mass that sustain the progression and spread of tumor. What makes them so dangerous is the fact that they are immune to common cancer therapies. So even if the tumor is shrinking with anti-cancer therapies the tumor will soon grow back.

https://www.sigmaaldrich.com/technical-documents/articles/biofiles/the-cancer-stem-cell.html

What is phenotypic high-throughput screening?

“Phenotypic screening is a strategy used in drug discovery to identify molecules with the ability to alter a cell’s phenotype.”

https://www.technologynetworks.com/drug-discovery/articles/the-role-of-phenotypic-screening-in-drug-discovery-293422

What is epithelial-to-mesenchymal transition(EMT)

“During embryogenesis, epithelial cells undergo extensive epigenetic reprogramming, allowing them to transdifferentiate and acquire physical properties of mesenchymal cells” basically skin cells become into cells that can differentiate like stem cells.

https://www.nature.com/articles/s41580-018-0080-4

What is salinomycin(Sal)

Salinomycin is a antibiotic that has recently been found to fight cancer stem cells. This is very important because it prevents cancer from relapsing, however because of its severe toxicity it was never really tested for humans.

Literature review

● Sal has been found to have therapeutic potential in humans and targeting cancer stem cells(Naujocat C, Steinhart R, 2012)

● A lot of prior work has been done to finding remarkable synthetic strategies ways to produce Sal derivations. Basically ways to molecularly edit Sal in order to get more efficient derivations. This is very useful because it would allow lower dosages to be used which reduce the toxicity of Sal.(Huczyński A, 2012)(Borgström B, 2013)

Purpose

Give evidence that a synthetic derivative of Sal, which was named ironomycin (AM5), exhibits a more potent and selective activity against breast cancer stem cells

Methodology● The researchers wanted to find more effective deregulation which would allow for

lower dosages reducing the toxicity of Sal. ● This was done by molecular editing of Sal using a chemoselective oxidation followed by

a stereoselective reductive amination led to Sal derivation of AM5 along with its methylated counterpart AM9 and which led to photocycloaddition yielding derivation of AM4

Figure 1

Methodology ...● Now the researchers needed to test it on Cancer stem cells but they are hard to isolate and maintain

in a culture making it almost impossible to screen small molecules for efficacy against these cells. So artificial induction of EMT was used to produce cells displaying properties similar to that of CSCs suitable for high-throughput phenotypic screening.

● They used a human mammary epithelial HMLER CD44high/CD24low cells (HMLER CD24low), a previously established model of human breast CSCs and another model of CSCs, namely iCSCL-10A2 cells

Cancer stem cells

Results The derivation AM5 displayed a ~tenfold higher potency against HMLER CD24low cells compared to Sal with a value of ~100 nM while maintaining selectivity over control cells

Figure 2= Potency of Sal derivations against HMLER CD24 low

Results...● The AM5 also selectively targeted the aldehyde dehydrogenase positive (ALDH+) the sub population

of the iCSCL-10A2 cells, which is another model of Cancer stem cells, more effectively than Sal.● It also exhibited less toxicity towards the normal breast cells

Figure 3= The selectivity of targeting iCSCL-10A2 cells

Results...● Sal and AM5 was more effective in reducing tumour growth in two early passage patient-derived

xenografts (PDXs)22, than the clinically approved drug docetaxel (Doc).

Figure 4= Reduction of the tumor size by derivation of Sal

● Most importantly the ratio of ALDH+ cells decreased and there were overall less cancer stem cells

Figure 5= The number of CSC’s before and after Sal derivations

Table 1= The ratios of CSC’s after using different Sal derivation

Discussions

“AM5 may provide the means to alter the epigenetic landscape for therapeutic benefits.” This gives a valuable strategy for one day being able to fight cancer more effectively.

Reference ● Cancer Stem Cells: New Targets for Cancer Therapy. (n.d.). Retrieved from

https://www.sigmaaldrich.com/technical-documents/articles/biofiles/the-cancer-stem-cell.htmly

● Dongre, A., & Weinberg, R. A. (2018, November 20). New insights into the mechanisms of epithelial–mesenchymal transition and implications for cancer. Retrieved from https://www.nature.com/articles/s41580-018-0080-4

● Foothills. (2020, January 20). Stem Cells for Joint Pain. Retrieved from https://www.foothillstherapy.com/2020/01/20/stem-cells-for-joint-pain/

● The Role of Phenotypic Screening in Drug Discovery. (n.d.). Retrieved from https://www.technologynetworks.com/drug-discovery/articles/the-role-of-phenotypic-screening-in-drug-discovery-293422

● Mai, T. T., Hamaï, A., Hienzsch, A., Cañeque, T., Müller, S., Wicinski, J., … Rodriguez, R. (2017, October). Salinomycin kills cancer stem cells by sequestering iron in lysosomes. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5890907/