Response of brain specific microenvironment to P-glycoprotein inhibitor: an important factor determining therapeutic effect of P-glycoprotein inhibitor on brain metastatic tumors.
P-glycoprotein (P-gp), a factor responsible for the multidrug resistance of tumors, is specifically expressed in brain microenvironment. To test its roles in brain metastatic tumor chemoresistance, we implanted the paclitaxel-sensitive melanoma cell line, K1735, into the skin or brain of mice and examined its paclitaxel resistances. When implanted into the skin, paclitaxel inhibited tumor growth, however, it had no inhibitory effect on cells implanted into the brain. The paclitaxel resistance of the brain K1735 tumors was eliminated by combined treatment with a P-gp inhibitor, HM30181A, and paclitaxel. Previously we found that there is a defined therapeutic window for combined treatment of brain tumors with HM30181A and paclitaxel. To determine whether it is due to responses of the brain microenvironment we measured changes in P-gp expression and function of brain endothelial cells in response to HM30181A treatment in vitro and in vivo. They were significantly increased by high-dose HM30181A treatment and it was related with the therapeutic effect loss of high-dose HM30181A treatment. Therefore, P-gp in the brain microenvironment has crucial roles in the brain metastatic tumor chemoresistance and brain microenvironment responses to P-gp inhibitor treatment should be considered in the development of brain endothelial cell-targeted chemotherapy using P-gp inhibitor.
Joo
Kyeung Min
KM
Department of Neurosurgery, Samsung Medical Center and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Gangnam-Gu, Seoul 135-710, Korea.
Song
Sang Yong
SY
Park
Kwan
K
Kim
Mi Hyun
MH
Jin
Juyoun
J
Kang
Bong Gu
BG
Jang
Mi Jung
MJ
Lee
Gwan Sun
GS
Kim
Maeng Sup
MS
Nam
Do-Hyun
DH
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology
C521083:4-oxo-4H-chromene-2-carboxylic acid (2-(2-(4-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl)-phenyl)-2H-tetrazol-5-yl)-4,5-dimethoxyphenyl)amide; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001578:Benzopyrans; D007546:Isoquinolines; D013777:Tetrazoles; D017239:Paclitaxel