Polyoxypregnanes as safe, potent, and specific ABCB1-inhibitory pro-drugs to overcome multidrug resistance in cancer chemotherapy in vitro and in vivo

doi:10.1016/j.apsb.2020.12.021

	Polyoxypregnanes as safe, potent, and specific ABCB1-inhibitory pro-drugs to overcome multidrug resistance in cancer chemotherapy in vitro and in vivo
	Wu, Xu 1,2,7; Yin, Chun 1,2; Ma, Jiang 1,2; Chai, Stella 1,2; Zhang, Chunyuan 1,2; Yao, Sheng 2,3,4; Kadioglu, Onat 5; Efferth, Thomas 5; Ye, Yang 2,3,4; To, Kenneth Kin-Wah 6
刊名	ACTA PHARMACEUTICA SINICA B
	2021-07-01
卷号	11 期号:7 页码:1885-1902
关键词	Multidrug resistance ABCB1 Polyoxypregnane Combination chemotherapy Marsdenia tenacissima
ISSN号	2211-3835
DOI	10.1016/j.apsb.2020.12.021
通讯作者	To, Kenneth Kin-Wah(kennethto@cuhk.edu.hk) ; Lin, Ge(linge@cuhk.edu.hk)
英文摘要	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. (C) 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences.
资助项目	Health and Medical Research Fund (HHSRF, Hong Kong SAR, China) from Food and Health Bureau, HKSAR[08090481] ; One-off Funding for Joint Lab/Research collaboration (Hong Kong SAR, China) from the Chinese University of Hong Kong[3132968] ; School of Biomedical Science, the Chinese University of Hong Kong (China)
WOS关键词	P-GLYCOPROTEIN EXPRESSION ; MARSDENIA-TENACISSIMA ; TARIQUIDAR XR9576 ; PHARMACOKINETICS ; INHIBITION ; REVERSAL ; PACLITAXEL ; CARCINOMA ; STEROIDS ; CURCUMIN
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
WOS记录号	WOS:000677639400011
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/298253]
专题	中国科学院上海药物研究所
通讯作者	To, Kenneth Kin-Wah; Lin, Ge
作者单位	1.Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Hong Kong 999077, Peoples R China 2.Chinese Acad Sci, Joint Res Lab Promoting Globalizat Tradit Chinese, Hong Kong 999077, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, Nat Prod Chem Dept, Shanghai 201203, Peoples R China 5.Johannes Gutenberg Univ Mainz, Dept Pharmaceut Biol, D-55099 Mainz, Germany 6.Chinese Univ Hong Kong, Fac Med, Sch Pharm, Hong Kong 999077, Peoples R China 7.Southwest Med Univ, Sch Pharm, Dept Pharmacol, Lab Mol Pharmacol, Luzhou 646000, Peoples R China
推荐引用方式 GB/T 7714	Wu, Xu,Yin, Chun,Ma, Jiang,et al. Polyoxypregnanes as safe, potent, and specific ABCB1-inhibitory pro-drugs to overcome multidrug resistance in cancer chemotherapy in vitro and in vivo[J]. ACTA PHARMACEUTICA SINICA B,2021,11(7):1885-1902.
APA	Wu, Xu.,Yin, Chun.,Ma, Jiang.,Chai, Stella.,Zhang, Chunyuan.,...&Lin, Ge.(2021).Polyoxypregnanes as safe, potent, and specific ABCB1-inhibitory pro-drugs to overcome multidrug resistance in cancer chemotherapy in vitro and in vivo.ACTA PHARMACEUTICA SINICA B,11(7),1885-1902.
MLA	Wu, Xu,et al."Polyoxypregnanes as safe, potent, and specific ABCB1-inhibitory pro-drugs to overcome multidrug resistance in cancer chemotherapy in vitro and in vivo".ACTA PHARMACEUTICA SINICA B 11.7(2021):1885-1902.