title: The receptor tyrosine kinase inhibitor vandetanib activates Akt and             increases side population in a salivary gland tumor cell line (A253).
abstract: We and others have reported that cancer side population (SP) cells have             self-renewal and multidrug resistance capabilities. These phenotypes are similar             to those of cancer stem cells (CSCs), cancer stem-like cells and tumor-initiating             cells (TICs). It has also been reported that upregulation of the epidermal growth             factor receptor (EGFR) significantly increases the number of cancer SP cells,             conversely, molecular targeting of EGFR tyrosine kinases using specific kinase             inhibitors downregulates CSCs. Thus, we used flow cytometric analysis and cell             sorting to examine cancer SP cells in the SCA9.cl-15, WR21 and A253 cell lines             that originate from a salivary gland tumor (SGT). We successfully isolated cancer             SP cells from all of these cell lines. SP cells were detected following treatment             of these cell lines with the receptor tyrosine kinase inhibitors (RTKIs) lapatinib,             erlotinib and vandetanib. Several studies reported that RTKIs mostly reduced the             SP population in cancer cells. We did not observe any detectable morphological             differences between SP cells and non-SP cells. We found that the EGF RTKI lapatinib             decreased the number of cancer SP cells in all cell lines investigated; however,             the EGF RTKI erlotinib did not cause significant differences in the frequency             of cancer SP cells in these cell lines. Addition of vandetanib significantly increased             the number of cancer SP cells and upregulated the phosphorylated Akt. As far as             we know, this is the first report to show that one of the RTKIs, vandetanib, can             activate Akt and increase the number of cancer SP cells. It has been reported             that RTKIs could competitively inhibit ABC transporters and subsequently reduced             the number of SP cells. However, our observation indicated that signaling changes             induced by RTKIs could even activate Akt and induce the SP population. Investigation             of the SP phenotype of SGTs is important for the establishment of optimal cancer             therapy.
authors.affiliation: Oral Health Science Center HRC7, Tokyo Dental College, 1-2-2 Masago, Mihama-ku, Chiba City 261-8502, Japan. tazuma@tdc.ac.jp
authors.forename: Yuka
authors.initials: Y
authors.lastname: Fujishiro
authors.forename: Morio
authors.initials: M
authors.lastname: Tonogi
authors.forename: Hiromi
authors.initials: H
authors.lastname: Ochiai
authors.forename: Kenichi
authors.initials: K
authors.lastname: Matsuzaka
authors.forename: Gen-Yuki
authors.initials: GY
authors.lastname: Yamane
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Azuma
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D006801:Humans; D000077341:Lapatinib; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D012468:Salivary Gland Neoplasms; D058985:Side-Population Cells / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D010880:Piperidines; D011799:Quinazolines; D000077341:Lapatinib; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor; D051057:Proto-Oncogene Proteins c-akt; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C452423:vandetanib