Journal
TOXICOLOGY AND APPLIED PHARMACOLOGY
Volume 341, Issue -, Pages 98-105Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2018.01.015
Keywords
alpha-Hederagenin; H6; Multidrug resistance; P-glycoprotein; Molecular docking
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Funding
- Taishan Scholar Project, National Natural Science Foundation of China [81441130, 81728020]
- Key Research Project of Shandong Province [2017GSF18177]
- State Key Laboratory of Drug Research [SIMM1705KF-07]
- Graduate Innovation Foundation of Yantai University [YDZD1716]
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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 alpha-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.
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