• July 22, 2019

    Discovery of functional binding protein for salinomycin could open new research in targeting neuroblastoma stem cells

The American Cancer Society identifies neuroblastoma as “by far the most common cancer in infants (less than 1-year-old).” According to the latest statistics, neuroblastoma accounts for about 6 percent of all cancers in children, with an estimated 800 new cases identified each year in the United States.

The average age of children when they are diagnosed is about 1 to 2 years. While traditional therapies have proven effective in targeting cancer cells, they have yet to demonstrate full efficacy in targeting and killing cancer stem cells. Despite being a very small population of the total tumor cells, stem cells are the driver that triggers tumor regrowth and therapeutic resistance. Researchers at Baylor Scott & White Medical Center – Temple recently published findings in the Journal of the American Chemical Society that could help unlock more treatment options for neuroblastoma patients by identifying a direction for treatment strategies specifically targeting cancer stem cells.  

Beyond salinomycin’s use as an anticoccidial agent, the monocarboxylic chemical is known for its ability to increase cancer cell sensitivity to radiation and chemotherapy. Examining salinomycin’s functionality and its potential involvement in the development of more effective therapeutic neuroblastoma treatment strategies were at the root of research taken on by Erxi Wu, Ph.D. and the team Baylor Scott & White Research Institute.

Researchers first defined the neuroblastoma-cancer stem cell (CSC) markers through an analysis of identified expression levels in neuroblastoma patient tumors. The team then utilized integrated strategies, such as chemical proteomics and chromatin immunoprecipitation (ChIP)-qPCR assays, to examine salinomycin’s neuroblastoma effectiveness, as well as to drill down on the action mechanism at play in an attempt to identify the chemical’s binding protein target and its clinical relevance to neuroblastoma.

“Salinomycin has been shown to kill breast cancer stem cells with 100-fold potency compared to paclitaxel, for example. Its potential capabilities are known, however, its intracellular direct binding target had been unclear,” said Wu, Baylor Scott & White Research Institute’s principal investigator on this study. “By utilizing integrated strategies, we identified that nucleolin (NCL) was a salinomycin binding target and a critical regulator involved in human neuroblastoma stem cells activity.”

The team’s broader findings were as follows:

  1. Salinomycin suppressed neuroblastoma cells, neuroblastoma CSCs, and reduced CD34+ neuroblastoma cell presence
  2. Higher NCL levels may correlate to poor neuroblastoma prognostic outcomes
  3. Salinomycin suppressed CD34 expression via disruption of the interaction between NCL and the CD34 promoter

Discovery of a connection between NCL and salinomycin represents a notable potential paradigm shift in cancer research. “We believe that the NCL is related to cancer stem cells and our data bear this theory out,” said Wu. “If our further investigation into this idea is successful, the discovery could open promising new research direction for more effective cancer treatments and milestones.”

The published paper can be found at: https://pubs.acs.org/doi/10.1021/jacs.8b12872