From the stems ofMarsdenia tenacissima two new polyoxypregnanes were isolated, their structures were elucidated by 1D, 2D-NMR as 11α,12β-di-O-tigloyl-tenacigenin B （1） and tenacigenoside E （2）.
Multidrug resistance(MDR)mediated by ATP binding cassette subfamily B member 1(ABCB1)is significantly hindering effective cancer chemotherapy.However,currently,no ABCB1-inhibitory drugs have been approved to treat MDR...Multidrug resistance(MDR)mediated by ATP binding cassette subfamily B member 1(ABCB1)is significantly hindering effective cancer chemotherapy.However,currently,no ABCB1-inhibitory drugs have been approved to treat MDR cancer clinically,mainly due to the inhibitor specificity,toxicity,and drug interactions.Here,we reported that three polyoxypregnanes(POPs)as the most abundant constituents of Marsdenia tenacissima(M.tenacissima)were novel ABCB1-modulatory pro-drugs,which underwent intestinal microbiota-mediated biotransformation in vivo to generate active metabolites.The metabolites at non-toxic concentrations restored chemosensitivity in ABCB1-overexpressing cancer cells via inhibiting ABCB1 efflux activity without changing ABCB1 protein expression,which were further identified as specific non-competitive inhibitors of ABCB1 showing multiple binding sites within ABCB1 drug cavity.These POPs did not exhibit ABCB1/drug metabolizing enzymes interplay,and their repeated administration generated predictable pharmacokinetic interaction with paclitaxel without obvious toxicity in vivo.We further showed that these POPs enhanced the accumulation of paclitaxel in tumors and overcame ABCB1-mediated chemoresistance.The results suggested that these POPs had the potential to be developed as safe,potent,and specific pro-drugs to reverse ABCB1-mediated MDR.Our work also provided scientific evidence for the use of M.tenacissima in combinational chemotherapy.展开更多
文摘From the stems ofMarsdenia tenacissima two new polyoxypregnanes were isolated, their structures were elucidated by 1D, 2D-NMR as 11α,12β-di-O-tigloyl-tenacigenin B （1） and tenacigenoside E （2）.
基金supported by Health and Medical Research Fund(HHSRF Project No.08090481,Hong Kong SAR,China)from Food and Health Bureau,HKSAROne-off Funding for Joint Lab/Research collaboration(Project code:3132968,Hong Kong SAR,China)from the Chinese University of Hong KongSeed Fund for Joint Establishments from School of Biomedical Science,the Chinese University of Hong Kong(China)
文摘Multidrug resistance(MDR)mediated by ATP binding cassette subfamily B member 1(ABCB1)is significantly hindering effective cancer chemotherapy.However,currently,no ABCB1-inhibitory drugs have been approved to treat MDR cancer clinically,mainly due to the inhibitor specificity,toxicity,and drug interactions.Here,we reported that three polyoxypregnanes(POPs)as the most abundant constituents of Marsdenia tenacissima(M.tenacissima)were novel ABCB1-modulatory pro-drugs,which underwent intestinal microbiota-mediated biotransformation in vivo to generate active metabolites.The metabolites at non-toxic concentrations restored chemosensitivity in ABCB1-overexpressing cancer cells via inhibiting ABCB1 efflux activity without changing ABCB1 protein expression,which were further identified as specific non-competitive inhibitors of ABCB1 showing multiple binding sites within ABCB1 drug cavity.These POPs did not exhibit ABCB1/drug metabolizing enzymes interplay,and their repeated administration generated predictable pharmacokinetic interaction with paclitaxel without obvious toxicity in vivo.We further showed that these POPs enhanced the accumulation of paclitaxel in tumors and overcame ABCB1-mediated chemoresistance.The results suggested that these POPs had the potential to be developed as safe,potent,and specific pro-drugs to reverse ABCB1-mediated MDR.Our work also provided scientific evidence for the use of M.tenacissima in combinational chemotherapy.
