title: Synergistic therapeutic effect of cisplatin and phosphatidylinositol 3-kinase (PI3K) inhibitors in cancer growth and metastasis of Brca1 mutant tumors.
abstract: Drug resistance and cancer metastasis are two major problems in cancer research. During a course of therapeutic treatment in Brca1-associated tumors, we found that breast cancer stem cells (CSCs) exhibit an intrinsic ability to metastasize and acquire drug resistance through distinct signaling pathways. Microarray analysis indicated that the cytoskeletal remodeling pathway was differentially regulated in CSCs, and this was further evidenced by the inhibitory role of reagents that impair this pathway in the motility of cancer cells. We showed that cisplatin treatment, although initially inhibiting cancer growth, preventing metastasis through blocking cytoskeletal remodeling, and retarding CSC motility, eventually led to drug resistance associated with a marked increase in the number of CSCs. This event was at least partially attributed to the activation of PI3K signaling, and it could be significantly inhibited by co-treatment with rapamycin. These results provide strong evidence that cytoskeletal rearrangement and PI3K/AKT signaling play distinct roles in mediating CSC mobility and viability, respectively, and blocking both pathways synergistically may inhibit primary and metastatic cancer growth.
authors.affiliation: From the Genetics of Development and Disease Branch.
authors.forename: Athanassios
authors.initials: A
authors.lastname: Vassilopoulos
authors.affiliation: From the Genetics of Development and Disease Branch.
authors.forename: Cuiying
authors.initials: C
authors.lastname: Xiao
authors.affiliation: From the Genetics of Development and Disease Branch.
authors.forename: Cristine
authors.initials: C
authors.lastname: Chisholm
authors.affiliation: Microarray Core Facility, and.
authors.forename: Weiping
authors.initials: W
authors.lastname: Chen
authors.affiliation: From the Genetics of Development and Disease Branch.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Xu
authors.affiliation: From the Genetics of Development and Disease Branch.
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Lahusen
authors.affiliation: Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Carole
authors.initials: C
authors.lastname: Bewley
authors.affiliation: From the Genetics of Development and Disease Branch, chuxiad@bdg10.niddk.nih.gov.
authors.forename: Chu-Xia
authors.initials: CX
authors.lastname: Deng
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D019398:Genes, BRCA1; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D000081082:Phosphoinositide-3 Kinase Inhibitors
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D002945:Cisplatin
keywords: Breast Cancer; Cancer Stem Cells; Cytoskeleton; Drug Resistance; PI3K Signaling; Tumor Metastases