Potentiation by alpha-tocopheryl succinate of the etoposide response in multidrug resistance protein 1-expressing glioblastoma cells.
Multidrug resistance protein 1 (MRP1) is one of the representative members of the ATP-binding cassette superfamily of transporters that is involved in resistance to chemotherapeutic agents in cancer patients. MRP1 functions as an efflux pump of drugs, primarily those conjugated to glutathione (GSH). Decreases in the intracellular concentration of GSH have been shown to enhance the response of MRP1-overexpressing cells to MRP1-substrate drugs by limiting the available drug-GSH conjugates. We report here that alpha-tocopheryl succinate (TOS), a vitamin E analogue, decreased intracellular GSH concentration and blocked MRP1 function in glioblastoma cells. Functional blockade by TOS of MRP1 was confirmed by the enhanced accumulation of etoposide (VP-16), an MRP1-substrate drug. As a result, co-treatment of TOS with VP-16 or treatment with liposomes containing both TOS and VP-16 greatly enhanced the response of MRP1-expressing glioblastoma cells to VP-16. TOS may be a promising adjuvant for enhancing the therapeutic efficacy of VP-16 in patients with MRP1-expressing glioblastomas.
Kang
Young-Hwa
YH
Research Institute, National Cancer Center, 809 Madu-Dong, Ilsan-gu, Goyang, Gyeonggi 411-769, South Korea.
Lee
Eunmyong
E
Youk
Hee-Jeong
HJ
Kim
So Hee
SH
Lee
Hyun Jang
HJ
Park
Yong-Geun
YG
Lim
Soo-Jeong
SJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects* / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005047:Etoposide / Q000008:administration & dosage / Q000378:metabolism; D005909:Glioblastoma / Q000378:metabolism*; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008081:Liposomes; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D008081:Liposomes; D014810:Vitamin E; D005047:Etoposide; D005978:Glutathione