title: Piperine, a piperidine alkaloid from Piper nigrum re-sensitizes P-gp, MRP1 and BCRP dependent multidrug resistant cancer cells.
abstract: Over-expression of P-gp, MRP1 and BCRP in tumor cells is one of the important mechanisms leading to multidrug resistance (MDR), which impairs the efficacy of chemotherapy. P-gp, MRP1 and BCRP are ABC (ATP-Binding Cassette) transporters, which can expel a variety of lipophilic anti-cancer drugs and protect tumor cells. During a screening of MDR reversal agents among alkaloids of various structural types, a piperidine alkaloid, piperine (a main piperidine alkaloid in Piper nigurm) was identified as an inhibitor. Piperine can potentiate the cytotoxicity of anti-cancer drugs in resistant sublines, such as MCF-7/DOX and A-549/DDP, which were derived from MCF-7 and A-549 cell lines. At a concentration of 50 μM piperine could reverse the resistance to doxorubicin 32.16 and 14.14 folds, respectively. It also re-sensitized cells to mitoxantrone 6.98 folds. In addition, long-term treatment of cells by piperine inhibits transcription of the corresponding ABC transporter genes. These results suggest that piperine can reverse MDR by multiple mechanisms and it may be a promising lead compound for future studies.
authors.affiliation: College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, People's Republic of China.
authors.forename: Sen
authors.initials: S
authors.lastname: Li
authors.forename: Yu
authors.initials: Y
authors.lastname: Lei
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Jia
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Michael
authors.initials: M
authors.lastname: Wink
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Ma
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D000470:Alkaloids / Q000302:isolation & purification / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D052117:Benzodioxoles / Q000302:isolation & purification / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D029222:Piper nigrum / Q000737:chemistry*; D010880:Piperidines / Q000302:isolation & purification / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000302:isolation & purification / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000470:Alkaloids; D000970:Antineoplastic Agents; D052117:Benzodioxoles; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D010880:Piperidines; D053284:Polyunsaturated Alkamides; C116614:ABCG2 protein, human; C008922:piperine; C421109:multidrug resistance-associated protein 1