title: Differential effects of drugs targeting cancer stem cell (CSC) and non-CSC populations on lung primary tumors and metastasis.
abstract: Cancer stem cells (CSCs) are thought to be responsible for tumor initiation and recurrence after chemotherapy. Targeting CSCs and non-CSCs with specific compounds may be an effective approach to reduce lung cancer growth and metastasis. The aim of this study was to investigate the effect of salinomycin, a selective inhibitor of CSCs, with or without combination with paclitaxel, in a metastatic model. To evaluate the effect of these drugs in metastasis and tumor microenvironment we took advantage of the immunocompetent and highly metastatic LLC mouse model. Aldefluor assays were used to analyze the ALDH+/- populations in murine LLC and human H460 and H1299 lung cancer cells. Salinomycin reduced the proportion of ALDH+ CSCs in LLC cells, whereas paclitaxel increased such population. The same effect was observed for the H460 and H1299 cell lines. Salinomycin reduced the tumorsphere formation capacity of LLC by more than 7-fold, but paclitaxel showed no effect. In in vivo experiments, paclitaxel reduced primary tumor volume but increased the number of metastatic nodules (p<0.05), whereas salinomycin had no effect on primary tumors but reduced lung metastasis (p<0.05). Combination of both drugs did not improve the effect of single therapies. ALDH1A1, SOX2, CXCR4 and SDF-1 mRNA levels were higher in metastatic lesions than in primary tumors, and were significantly elevated in both locations by paclitaxel treatment. On the contrary, such levels were reduced (or in some cases did not change) when mice were administered with salinomycin. The number of F4/80+ and CD11b+ cells was also reduced upon administration of both drugs, but particularly in metastasis. These results show that salinomycin targets ALDH+ lung CSCs, which has important therapeutic effects in vivo by reducing metastatic lesions. In contrast, paclitaxel (although reducing primary tumor growth) promotes the selection of ALDH+ cells that likely modify the lung microenvironment to foster metastasis.
authors.affiliation: Laboratory of Novel Therapeutic Targets, Division of Oncology, CIMA of the University of Navarra, Pamplona, Spain.
authors.forename: Leyre
authors.initials: L
authors.lastname: Larzabal
authors.forename: Nefertiti
authors.initials: N
authors.lastname: El-Nikhely
authors.forename: Miriam
authors.initials: M
authors.lastname: Redrado
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Savai
authors.forename: Alfonso
authors.initials: A
authors.lastname: Calvo
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000378:metabolism*; D051379:Mice; D009364:Neoplasm Recurrence, Local / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology; D011714:Pyrans / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D000095662:Polyether Polyketides
chemical_list: D000444:Aldehyde Dehydrogenase; D054377:Chemokine CXCL12; D017239:Paclitaxel; D011714:Pyrans; D019718:Receptors, CXCR4; D055748:SOXB1 Transcription Factors; C010327:salinomycin; D000095662:Polyether Polyketides