Proteasome inhibitor MG132 reverses multidrug resistance of gastric cancer through enhancing apoptosis and inhibiting P-gp.
Multidrug resistance (MDR) is a major impediment to the effective chemotherapy of many human malignancies. Although much effort has been devoted to develop new drugs for overcoming MDR, until now, still no useful method of reversing MDR, suitable for clinical use, has emerged from this large quantity of work. Some researchers have reported that proteasome inhibitors could induce apoptosis in a variety of cancer cells. In the present study, we found that, in vincristine-resistant human gastric cancer cell line SGC7901/VCR, proteasome inhibitor MG132 was an effective inducer of apoptosis, and also had the capacity of downregulating the expression of anti-apoptotic Bcl-2 and MDR1 (P-gp), by which MG132 resensitized tumor cells to the apoptosis induced by anticancer drugs. Data presented by drug sensitivity assay further demonstrated that MG132 could reverse the resistant phenotype of gastric cancer cells effectively through both enhancing drug-induced apoptosis and inhibiting P-gp. The further study of the effectiveness and safety of proteasome inhibitor in vivo may be helpful for developing a new possible strategy to treat gastric cancer MDR.
Zhang
Yafei
Y
State Key Laboratory of Cancer Biology & Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Shi
Yongquan
Y
Li
Xiaohua
X
Du
Rui
R
Luo
Guanhong
G
Xia
Lin
L
Du
Wenqi
W
Chen
Bei
B
Zhai
Huihong
H
Wu
Kaichun
K
Fan
Daiming
D
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D013274:Stomach Neoplasms / Q000201:enzymology / Q000378:metabolism*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D019253:Proto-Oncogene Proteins c-bcl-2; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde