Multidrug resistance-associated protein 7 expression is involved in cross-resistance to docetaxel in salivary gland adenocarcinoma cell lines.
The aim of the present study was to clarify whether ATP binding cassette transporters are refractory factors in head and neck cancers. For in vitro and in vivo chemotherapeutic studies, we used the following head and neck cancer cell lines: a mouse oral squamous cell carcinoma (SCC) cell line, Sq-1979; a human SCC cell line, SCCHA; a mouse salivary gland adenocarcinoma (SGA) cell line, NR-PG; and a human SGA cell line, HSY. We used a vinca alkaloid anticancer drug, vincristine (VCR), as a chemotherapeutic anticancer drug. To determine the cause of multidrug resistance, Western blot analysis, reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry of xenografted tumors in nude mice, drug efflux analysis, and drug efflux inhibitory assays were performed. VCR-treated cell lines, Sq-1979/VCR, SCCHA/VCR, NR-PG/VCR, and HSY/VCR, intensively expressed multidrug resistance (MDR) gene 1 mRNA and multidrug resistance associated protein (MRP) 1 mRNA. MRP7 mRNA and protein were expressed in NR-PG/VCR and HSY/VCR cells, but not in Sq-1979/VCR and SCCHA/VCR cells. In each cell clone of NR-PG/VCR and HSY/VCR, MRP7 mRNA was induced by VCR treatment, suggesting an acquired resistance to VCR in the context of MRP7 expression. In the in vivo chemotherapeutic nude mice model, VCR-treated xenografted SCCHA and HSY cells expressed MDR1 and MRP1. Moreover, MRP7 expression was immunohistochemically found in xenografted HSY cells of VCR-injected tumor-bearing mice, but not in SCCHA cells. Furthermore, doxorubicin accumulation was increased and drug cross-resistance to docetaxel decreased in HSY/VCR in the presence of a competitive MRP7 inhibitor, 17-beta-estradiol-(17-beta-D-glucuronide). These results indicate that MDR1 expression, MRP1 expression, and MRP7 expression are refractory factors in head and neck cancer chemotherapy and suggest that induction of MRP7 expression is involved in drug resistance to natural products, especially to docetaxel in SGA.
Naramoto
Hiroko
H
Department of Oral and Maxillofacial Surgery, Matsumoto Dental University School of Dentistry, Nagano 399-0781, Japan.
Uematsu
Takashi
T
Uchihashi
Takayuki
T
Doto
Ryosuke
R
Matsuura
Takashi
T
Usui
Yohei
Y
Uematsu
Setsuko
S
Li
Xianqi
X
Takahashi
Masahiro
M
Yamaoka
Minoru
M
Furusawa
Kiyofumi
K
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000077143:Docetaxel; D018432:Drug Resistance, Multiple; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis*; D009368:Neoplasm Transplantation; D012333:RNA, Messenger / Q000378:metabolism; D012468:Salivary Gland Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D043823:Taxoids / Q000494:pharmacology*
D000970:Antineoplastic Agents; D000077143:Docetaxel; D004958:Estradiol; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; D043823:Taxoids; C421142:ABCC10 protein, human; C025483:estradiol-17 beta-glucuronide