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Published on: October 14, 2016
Salarin C inhibits the maintenance of chronic myeloid leukemia progenitor cells
E Del Poggetto1, M Tanturli1, N Ben-Califa2
1a Department of Experimental and Clinical Biomedical Sciences "Mario Serio" ; Universita degli Studi di Firenze ; Florence , Italy.
Abstract:
We previously showed that incubation of chronic myeloid leukemia (CML) cells in very low oxygen selects a cell subset where the oncogenetic BCR/Abl protein is suppressed and which is thereby refractory to tyrosine kinase inhibitors used for CML therapy. In this study, salarin C, an anticancer macrolide extracted from the Fascaplysinopsis sponge, was tested as for its activity on CML cells, especially after their incubation in atmosphere at 0.1% oxygen. Salarin C induced mitotic cycle arrest, apoptosis and DNA damage. Salarin C also concentration-dependently inhibited the maintenance of stem cell potential in cultures in low oxygen of either CML cell lines or primary cells. Surprisingly, the drug also concentration-dependently enforced the maintenance of BCR/Abl signaling in low oxygen, an effect which was paralleled by the rescue of sensitivity of stem cell potential to IM. These results suggest a potential use of salarin C for the suppression of CML cells refractory to tyrosine kinase inhibitors.
Insights
Salarin C, a novel compound, combats chronic myeloid leukemia (CML) by targeting drug-resistant CML stem cells. This macrolide restores sensitivity to tyrosine kinase inhibitors, offering new hope for CML therapy.
Area of Science:
- Oncology
- Pharmacology
- Cell Biology
Background:
- Chronic myeloid leukemia (CML) cells under low oxygen conditions develop resistance to tyrosine kinase inhibitors (TKIs).
- This resistance is linked to the suppression of the BCR/Abl oncogenic protein.
Purpose of the Study:
- To investigate the activity of salarin C, an anticancer macrolide, against CML cells, particularly those adapted to low oxygen environments.
- To determine salarin C's effect on BCR/Abl signaling and TKI sensitivity in CML stem cells.
Main Methods:
- Incubation of CML cell lines and primary cells in 0.1% oxygen.
- Treatment with varying concentrations of salarin C.
- Assessment of cell cycle arrest, apoptosis, DNA damage, and stem cell potential.
- Monitoring of BCR/Abl signaling and sensitivity to imatinib (IM).
Main Results:
- Salarin C induced cell cycle arrest, apoptosis, and DNA damage in CML cells.
- It inhibited stem cell potential maintenance in low-oxygen conditions.
- Surprisingly, salarin C restored BCR/Abl signaling and imatinib sensitivity in these resistant cells.
Conclusions:
- Salarin C demonstrates potent anti-leukemic activity against CML cells, including drug-resistant populations.
- The compound's ability to restore TKI sensitivity suggests its potential as a therapeutic agent for refractory CML.
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