title: Piperlongumine for Enhancing Oral Bioavailability and Cytotoxicity of Docetaxel in Triple-Negative Breast Cancer.
abstract: Very low oral bioavailability due to extensive pre-systemic metabolism and P-gp efflux has constrained the oral metronomic chemotherapy of docetaxel (DTX). There is tremendous need of compounds facilitating oral delivery of DTX. The research was aimed to investigate the effect of piperlongumine (PPL) on human liver microsomal metabolism, Caco-2 permeability, and cytotoxicity of DTX in triple-negative breast cancer cell lines. Reduction in testosterone and DTX metabolism (twofold increase in half-life) by PPL was comparable to the standard CYP3A4 inhibitor, cyclosporine A. P-gp efflux ratio of DTX across caco-2 monolayer was reduced from 2.37 to 1.52 on co-incubation with PPL. The IC50 value of DTX was reduced three to five times and combination index values in all the cell lines were below 0.6. PPL at non-cytotoxic concentration showed significant enhancement of the antimigration effect of DTX. Expression of tumor markers such as survivin, bcl2, C-myc, and cyclin D1 were downregulated to a great extent with enhanced p53 expression when treated with combination instead of individual drug. Co-treatment with PPL led to 1.68-fold enhancement in DTX bioavailability in SD rats. PPL could be a potential candidate in overcoming the obstacles associated with oral DTX delivery with synergistic anticancer activity.
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida 32307.
authors.forename: Ketan
authors.initials: K
authors.lastname: Patel
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida 32307.
authors.forename: Nusrat
authors.initials: N
authors.lastname: Chowdhury
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida 32307.
authors.forename: Ravi
authors.initials: R
authors.lastname: Doddapaneni
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida 32307.
authors.forename: Cedar H A
authors.initials: CHA
authors.lastname: Boakye
authors.affiliation: Department of Regulatory Toxicology, National Institute of Pharmaceutical Education & Research [NIPER], Bala Nagar, Hyderabad, India.
authors.forename: Chandraiah
authors.initials: C
authors.lastname: Godugu
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida 32307. Electronic address: mandip.sachdeva@famu.edu.
authors.forename: Mandip
authors.initials: M
authors.lastname: Singh
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001682:Biological Availability; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000494:pharmacology; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D004148:Dioxolanes / Q000494:pharmacology*; D000077143:Docetaxel; D004357:Drug Synergism; D005260:Female; D006207:Half-Life; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043823:Taxoids / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010881:Piperidones
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D016572:Cyclosporine; D065692:Cytochrome P-450 CYP3A Inhibitors; D004148:Dioxolanes; D000077143:Docetaxel; D043823:Taxoids; C498077:piperlongumine; D010881:Piperidones
keywords: ADME; Caco-2 cells; absorption enhancer; bioavailability; cytochrome P450; drug interactions; efflux pumps; preclinical pharmacokinetics