Identification of selective inhibitors of cancer stem cells by high-throughput screening.
Screens for agents that specifically kill epithelial cancer stem cells (CSCs) have not been possible due to the rarity of these cells within tumor cell populations and their relative instability in culture. We describe here an approach to screening for agents with epithelial CSC-specific toxicity. We implemented this method in a chemical screen and discovered compounds showing selective toxicity for breast CSCs. One compound, salinomycin, reduces the proportion of CSCs by >100-fold relative to paclitaxel, a commonly used breast cancer chemotherapeutic drug. Treatment of mice with salinomycin inhibits mammary tumor growth in vivo and induces increased epithelial differentiation of tumor cells. In addition, global gene expression analyses show that salinomycin treatment results in the loss of expression of breast CSC genes previously identified by analyses of breast tissues isolated directly from patients. This study demonstrates the ability to identify agents with specific toxicity for epithelial CSCs.
Gupta
Piyush B
PB
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.|Broad Institute of MIT and Harvard, Cambridge, MA 02142.
Onder
Tamer T
TT
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.|Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142.
Jiang
Guozhi
G
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.|Broad Institute of MIT and Harvard, Cambridge, MA 02142.
Tao
Kai
K
Department of Anatomy and Cell Biology, Tufts University School of Medicine and Molecular Oncology Research Institute, Tufts Medical Center, Boston MA 02111.
Kuperwasser
Charlotte
C
Department of Anatomy and Cell Biology, Tufts University School of Medicine and Molecular Oncology Research Institute, Tufts Medical Center, Boston MA 02111.
Weinberg
Robert A
RA
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.|Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142.|MIT Ludwig Center for Molecular Oncology.
Lander
Eric S
ES
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.|Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142.|Broad Institute of MIT and Harvard, Cambridge, MA 02142.|Department of Systems Biology, Harvard Medical School, Boston, MA 02115.
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000188:drug therapy; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D017239:Paclitaxel / Q000494:pharmacology* / Q000627:therapeutic use; D011714:Pyrans / Q000494:pharmacology* / Q000627:therapeutic use; D000095662:Polyether Polyketides
D000970:Antineoplastic Agents; D017239:Paclitaxel; D011714:Pyrans; C010327:salinomycin; D000095662:Polyether Polyketides
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