The role of E3 ubiquitin ligase Cbl proteins in β-elemene reversing multi-drug resistance of human gastric adenocarcinoma cells

• Published in: International journal of molecular sciences 2013-05, Vol.14 (5), p.10075-10089
• Main Authors: Zhang, Ye, Mu, Xiao-Dong, Li, En-Zhe, Luo, Ying, Song, Na, Qu, Xiu-Juan, Hu, Xue-Jun, Liu, Yun-Peng
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Cell Line, Tumor; Curcuma - chemistry; Doxorubicin - pharmacology; Doxorubicin - therapeutic use; Drug Resistance, Multiple - drug effects; Drug Resistance, Neoplasm - drug effects; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Proto-Oncogene Proteins c-cbl - metabolism; Sesquiterpenes - pharmacology; Sesquiterpenes - therapeutic use; Signal Transduction - drug effects; Stomach - drug effects; Stomach - metabolism; Stomach Neoplasms - drug therapy; Stomach Neoplasms - metabolism
• ISSN: 1422-0067; 1422-0067
• DOI: 10.3390/ijms140510075

Recent studies indicate that β-elemene, a compound isolated from the Chinese herbal medicine Curcuma wenyujin, is capable of reversing tumor MDR, although the mechanism remains elusive. In this study, β-Elemene treatment markedly increased the intracellular accumulation of doxorubicin (DOX) and rhodamine 123 in both K562/DNR and SGC7901/ADR cells and significantly inhibited the expression of P-gp. Treatment of SGC7901/ADR cells with β-elemene led to downregulation of Akt phosphorylation and significant upregulation of the E3 ubiquitin ligases, c-Cbl and Cbl-b. Importantly, β-elemene significantly enhanced the anti-tumor activity of DOX in nude mice bearing SGC7901/ADR xenografts. Taken together, our results suggest that β-elemene may target P-gp-overexpressing leukemia and gastric cancer cells to enhance the efficacy of DOX treatment.