TY - JOUR
T1 - H6, a novel hederagenin derivative, reverses multidrug resistance in vitro and in vivo
AU - Yang, Yanting
AU - Guan, Daokun
AU - Lei, Lei
AU - Lu, Jing
AU - Liu, Jia Qi
AU - Yang, Gangqiang
AU - Yan, Chunhong
AU - Zhai, Rong
AU - Tian, Jingwei
AU - Bi, Yi
AU - Fu, Fenghua
AU - Wang, Hongbo
N1 - Funding Information:
This study was supported by Taishan Scholar Project, National Natural Science Foundation of China (nos. 81441130 , 81728020 ), Key Research Project of Shandong Province ( 2017GSF18177 ), State Key Laboratory of Drug Research ( SIMM1705KF-07 ), Graduate Innovation Foundation of Yantai University ( YDZD1716 ).
Funding Information:
This study was supported by Taishan Scholar Project, National Natural Science Foundation of China (nos. 81441130, 81728020), Key Research Project of Shandong Province (2017GSF18177), State Key Laboratory of Drug Research (SIMM1705KF-07), Graduate Innovation Foundation of Yantai University (YDZD1716).
Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2018/2/15
Y1 - 2018/2/15
N2 - Multidrug resistance (MDR) is a serious obstacle encountered in cancer treatment, in which the overexpression of P-glycoprotein (P-gp) plays an important role. Here, a novel α-hederagenin derivative, designated H6, was designed, synthesized and evaluated for its ability to reverse MDR. Our results showed that H6 could sensitize KBV and MCF7/T cells to paclitaxel and vincristine. Meanwhile, H6 could increase both rhodamine 123 and paclitaxel accumulation in MDR cells without affecting the expression of P-gp. Interestingly, siRNA knockdown of MDR1 further sensitized the cytotoxic activity of paclitaxel when co-administrated with H6. In addition, H6 could directly stimulate P-gp ATPase activity in vitro. Importantly, H6 enhanced the efficacy of paclitaxel against KBV cancer cell-derived xenograft tumors in nude mice. Finally, H6 showed high binding affinity with P-gp with a high docking score. Overall, we show H6 is a novel and potent MDR reversal agent, which has the potential to be administered in combination with conventional anticancer drugs.
AB - Multidrug resistance (MDR) is a serious obstacle encountered in cancer treatment, in which the overexpression of P-glycoprotein (P-gp) plays an important role. Here, a novel α-hederagenin derivative, designated H6, was designed, synthesized and evaluated for its ability to reverse MDR. Our results showed that H6 could sensitize KBV and MCF7/T cells to paclitaxel and vincristine. Meanwhile, H6 could increase both rhodamine 123 and paclitaxel accumulation in MDR cells without affecting the expression of P-gp. Interestingly, siRNA knockdown of MDR1 further sensitized the cytotoxic activity of paclitaxel when co-administrated with H6. In addition, H6 could directly stimulate P-gp ATPase activity in vitro. Importantly, H6 enhanced the efficacy of paclitaxel against KBV cancer cell-derived xenograft tumors in nude mice. Finally, H6 showed high binding affinity with P-gp with a high docking score. Overall, we show H6 is a novel and potent MDR reversal agent, which has the potential to be administered in combination with conventional anticancer drugs.
KW - H6
KW - Molecular docking
KW - Multidrug resistance
KW - P-glycoprotein
KW - α-Hederagenin
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U2 - 10.1016/j.taap.2018.01.015
DO - 10.1016/j.taap.2018.01.015
M3 - Article
C2 - 29408042
AN - SCOPUS:85041408451
SN - 0041-008X
VL - 341
SP - 98
EP - 105
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
ER -