Salarin C inhibits the maintenance of chronic myeloid leukemia progenitor cells.
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.
a Department of Experimental and Clinical Biomedical Sciences "Mario Serio" ; Universita degli Studi di Firenze ; Florence , Italy.
E
E
Del Poggetto
a Department of Experimental and Clinical Biomedical Sciences "Mario Serio" ; Universita degli Studi di Firenze ; Florence , Italy.
M
M
Tanturli
b Department of Cell and Developmental Biology; Sackler Faculty of Medicine ; Tel Aviv University ; Tel Aviv , Israel.
N
N
Ben-Califa
c Hematology Unit; "Careggi" University Hospital ; Florence , Italy.
A
A
Gozzini
a Department of Experimental and Clinical Biomedical Sciences "Mario Serio" ; Universita degli Studi di Firenze ; Florence , Italy.
I
I
Tusa
a Department of Experimental and Clinical Biomedical Sciences "Mario Serio" ; Universita degli Studi di Firenze ; Florence , Italy.
G
G
Cheloni
a Department of Experimental and Clinical Biomedical Sciences "Mario Serio" ; Universita degli Studi di Firenze ; Florence , Italy.
I
I
Marzi
a Department of Experimental and Clinical Biomedical Sciences "Mario Serio" ; Universita degli Studi di Firenze ; Florence , Italy.
M G
MG
Cipolleschi
d School of Chemistry ; Tel Aviv University ; Tel Aviv , Israel.
Y
Y
Kashman
b Department of Cell and Developmental Biology; Sackler Faculty of Medicine ; Tel Aviv University ; Tel Aviv , Israel.
D
D
Neumann
a Department of Experimental and Clinical Biomedical Sciences "Mario Serio" ; Universita degli Studi di Firenze ; Florence , Italy.
E
E
Rovida
a Department of Experimental and Clinical Biomedical Sciences "Mario Serio" ; Universita degli Studi di Firenze ; Florence , Italy.
P
P
Dello Sbarba
D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism* / Q000473:pathology*; D018942:Macrolides / Q000494:pharmacology*; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000187:drug effects*; D010100:Oxygen / Q000494:pharmacology
D018942:Macrolides; C571877:salarin C; D016044:Fusion Proteins, bcr-abl; D010100:Oxygen
BCR/Abl suppression; Chronic Myeloid Leukemia; drug-resistance; hypoxia; imatinib-mesylate; leukemia stem cells; tyrosine kinase inhibitors