Synergistic antitumor effect of TRAIL in combination with sunitinib in vitro and in vivo.
The present data showed that sunitinib potentiated the in vitro and in vivo anticancer capabilities of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), also known as Apo2 ligand. Interactions between sunitinib and TRAIL were examined in colon cancer SW620 cells and lung cancer 95-D cells. The average combination index (CI) values of the anti-proliferation abilities on each cancer cell line were less than 1.0, demonstrating the synergism of the combination of sunitinib and TRAIL. Western blot experiments indicated that TRAIL and sunitinib synergistically enhanced apoptosis by simultaneously activating the extrinsic and intrinsic pathways. The decrease in the expression levels of anti-apoptotic proteins cFLIP, XIAP and Mcl-1 were probably involved in this apoptosis enhancement. Furthermore, treatment of colon cancer SW620-bearing nude mice with sunitinib plus TRAIL resulted in more significant tumor growth inhibition (52.8%), comparing with the moderate inhibition in TRAIL-treated (35.3%) or sunitinib-treated groups (26.7%) (p<0.05). These results indicate that the combination of TRAIL with sunitinib seems highly encouraging and warrants further investigation in a clinical setting.
School of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Wanjing
W
Ding
Tianyu
T
Cai
Hong
H
Zhu
Rui
R
Wu
Chongxing
C
Tu
Liuqing
L
Yang
Wei
W
Lu
Qiaojun
Q
He
Bo
B
Yang
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D000077210:Sunitinib; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
D007211:Indoles; D011758:Pyrroles; D053221:TNF-Related Apoptosis-Inducing Ligand; D000077210:Sunitinib