title: Simultaneous targeting of P-gp and XIAP with siRNAs increases sensitivity of P-gp overexpressing CML cells to imatinib.
abstract: It is accepted that cancer chemoresistance may be due to overexpression of antiapoptotic proteins or P-gp. This study investigated the effect of downregulation of X-chromosome-linked inhibitor of apoptosis (XIAP) and of simultaneous downregulation of XIAP and P-gp on sensitivity to imatinib. The K562 and K562Dox (P-gp overexpressing) chronic myeloid leukemia cell lines were used and downregulation of target proteins was achieved with siRNAs. Targeting XIAP moderately enhanced sensitivity to imatinib in both cell lines. Simultaneous targeting of XIAP and P-gp further enhanced sensitivity to imatinib in the resistant K562Dox cells. In conclusion, simultaneous targeting of P-gp and XIAP increases sensitivity of P-gp overexpressing chronic myeloid leukemia cells to imatinib.
authors.affiliation: Cancer Biology Group, Institute of Molecular Pathology and Immunology of the University of Porto, Portugal.
authors.forename: Hugo
authors.initials: H
authors.lastname: Seca
authors.forename: Raquel T
authors.initials: RT
authors.lastname: Lima
authors.forename: José E
authors.initials: JE
authors.lastname: Guimarães
authors.forename: M
authors.initials: M
authors.lastname: Helena Vasconcelos
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D045744:Cell Line, Tumor; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D018390:Gene Targeting / Q000379:methods*; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism* / Q000628:therapy; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D034741:RNA, Small Interfering / Q000494:pharmacology*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D034741:RNA, Small Interfering; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D000068877:Imatinib Mesylate