title: Nonspecifically enhanced therapeutic effects of vincristine on multidrug-resistant cancers when coencapsulated with quinine in liposomes.
abstract: The use of vincristine (VCR) to treat cancer has been limited by its dose-dependent toxicity and development of drug resistance after repeated administrations. In this study, we investigated the mechanism by which quinine hydrochloride (QN) acts as a sensitizer for VCR. Our experiments used three kinds of multidrug-resistant cancer cells and demonstrated that QN worked by inducing intracellular depletion of adenosine triphosphate, increasing adenosine triphosphatase activity, and decreasing P-glycoprotein expression. Based on these results, we designed and prepared a VCR and QN codelivery liposome (VQL) and investigated the effect of coencapsulated QN on the in vitro cytotoxicity of VCR in cells and three-dimensional multicellular tumor spheroids. The antitumor effects of the formulation were also evaluated in multidrug-resistant tumor-bearing mice. The results of this in vivo study indicated that VQL could reverse VCR resistance. In addition, it reduced tumor volume 5.4-fold when compared with other test groups. The data suggest that VQL could be a promising nanoscaled therapeutic agent to overcome multidrug resistance, and may have important clinical implications for the treatment of cancer.
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of China.
authors.forename: Yuzhen
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Ministry of Education Key Laboratory of Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, People's Republic of China.
authors.forename: Liyan
authors.initials: L
authors.lastname: Qiu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D008081:Liposomes / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D011803:Quinine / Q000737:chemistry / Q000494:pharmacology; D014750:Vincristine / Q000737:chemistry / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D008081:Liposomes; D014750:Vincristine; D011803:Quinine
keywords: P-glycoprotein; combination therapy; liposome; multidrug resistance reversal; quinine; vincristine