Low intensity ultrasound promotes the sensitivity of rat brain glioma to Doxorubicin by down-regulating the expressions of p-glucoprotein and multidrug resistance protein 1 in vitro and in vivo.
The overall prognosis for malignant glioma is extremely poor, and treatment options are limited in part because of multidrug resistant proteins. Our previous findings suggest low intensity ultrasound (LIUS) can induce apoptosis of glioma cells. Given this finding, we were interested in determining if LIUS could help treat glioma by inhibiting multidrug resistant proteins, and if so, which pathways are involved. In this study, the toxicity sensitivity and multidrug resistance proteins of glioma induced by LIUS were investigated using CCK-8, immunohistochemistry, immunofluorency, and RT-PCR in tissue samples and cultured cells. LIUS inhibited increase of C6 cells in an intensity- and time-dependent manner. The toxicity sensitivity of C6 cells increased significantly after LIUS sonication (intensity of 142.0 mW/cm(2)) or Doxorubicin (DOX) at different concentration, particularly by the combination of LIUS sonication and DOX. The expressions of P-gp and MRP1 decreased significantly post-sonication at intensity of 142.0 mW/cm(2) both in vitro and in vivo. The expressions of p110 delta (PI3K), NF-κB-p65, Akt/PKB, and p-Akt/PKB were downregulated by LIUS sonication and DOX treatment separately or in combination at the same parameters in rat glioma. These results indicate that LIUS could increase the toxicity sensitivity of glioma by down-regulating the expressions of P-gp and MRP1, which might be mediated by the PI3K/Akt/NF-κB pathway.
Department of Ultrasound, China Medical University affiliated First Hospital, Shenyang, Liaoning, China. zhenshcc@163.com
Zhen
Z
Zhang
Ke
K
Xu
Yonghua
Y
Bi
Guibo
G
Yu
Siwei
S
Wang
Xun
X
Qi
Hongshan
H
Zhong
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D048430:Cell Shape; D003131:Combined Modality Therapy; D015536:Down-Regulation / Q000528:radiation effects; D004317:Doxorubicin / Q000494:pharmacology* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000528:radiation effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D015870:Gene Expression / Q000528:radiation effects; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D013010:Sonication; D013016:Sound
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C421109:multidrug resistance-associated protein 1