title: Contribution of Abcc10 (Mrp7) to in vivo paclitaxel resistance as assessed in Abcc10(-/-) mice.
abstract: Recently, we reported that the ATP-binding cassette transporter 10 (ABCC10), also known as multidrug resistance protein 7 (MRP7), is able to confer resistance to a variety of anticancer agents, including taxanes. However, the in vivo functions of the pump have not been determined to any extent. In this study, we generated and analyzed Abcc10(-/-) mice to investigate the ability of Abcc10 to function as an endogenous resistance factor. Mouse embryo fibroblasts derived from Abcc10(-/-) mice were hypersensitive to docetaxel, paclitaxel, vincristine, and cytarabine (Ara-C) and exhibited increased cellular drug accumulation, relative to wild-type controls. Abcc10(-/-) null mice treated with paclitaxel exhibited increased lethality associated with neutropenia and marked bone marrow toxicity. In addition, toxicity in spleen and thymus was evident. These findings indicate that Abcc10 is dispensable for health and viability and that it is an endogenous resistance factor for taxanes, other natural product agents, and nucleoside analogues. This is the first demonstration that an ATP-binding cassette transporter other than P-glycoprotein can affect in vivo tissue sensitivity toward taxanes.
authors.affiliation: Program in Developmental Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA. EA_Hopper@fccc.edu
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Hopper-Borge
authors.forename: Timothy
authors.initials: T
authors.lastname: Churchill
authors.forename: Chelsy
authors.initials: C
authors.lastname: Paulose
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Nicolas
authors.forename: Joely D
authors.initials: JD
authors.lastname: Jacobs
authors.forename: Olivia
authors.initials: O
authors.lastname: Ngo
authors.forename: Yehong
authors.initials: Y
authors.lastname: Kuang
authors.forename: Alex
authors.initials: A
authors.lastname: Grinberg
authors.forename: Heiner
authors.initials: H
authors.lastname: Westphal
authors.forename: Zhe-Sheng
authors.initials: ZS
authors.lastname: Chen
authors.forename: Andres J
authors.initials: AJ
authors.lastname: Klein-Szanto
authors.forename: Martin G
authors.initials: MG
authors.lastname: Belinsky
authors.forename: Gary D
authors.initials: GD
authors.lastname: Kruh
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001853:Bone Marrow / Q000378:metabolism; D003561:Cytarabine / Q000494:pharmacology; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D017239:Paclitaxel / Q000494:pharmacology*; D043823:Taxoids / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D003561:Cytarabine; D000077143:Docetaxel; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017239:Paclitaxel; D043823:Taxoids; D014750:Vincristine; C498885:Abcc10 protein, mouse