title: Effect of Cholesterol on Cellular Uptake of Cancer Drugs Pirarubicin and Ellipticine.
abstract: The cell membrane is a major barrier for drug transport. Given that many cancer drugs must passively cross the cell membrane, understanding drug-membrane interactions is crucial. We used fluorescence-activated cell sorting to investigate how cholesterol influences the transport of the cancer drugs ellipticine and pirarubicin across cell membranes. We showed that cholesterol depletion helped pirarubicin cross the membranes of nonsmall cell lung carcinoma and Chinese hamster ovary cells. In contrast, the uptake of ellipticine was not strongly influenced by cholesterol depletion. To study the microscopic origins of these observations, atomistic molecular dynamics simulations were performed. Doxorubicin (similar in structure to pirarubicin) and ellipticine were simulated in model membranes of POPC and POPC with 40 mol % cholesterol. Atomistic free energy calculations for the translocation of a single ellipticine and doxorubicin across the lipid bilayers qualitatively matched the experiment results. The free energy barrier for doxorubicin crossing the bilayer was strongly increased when cholesterol was present, while for ellipticine the barrier remained similar with and without cholesterol. Molecular dynamics simulations showed that the different hydrogen-bonding propensities of the two drugs are likely the major factor for the different behaviors. The qualitative agreement between cell experiments and atomistic computer simulations illustrates the potential to link observed biological phenomena and single molecule mechanisms of actions. Our results suggest that the traditional understanding of drug permeation and the influence of cholesterol on the small molecule transport is naïve and needs to be re-examined.
authors.affiliation: Biological and Pharmaceutical Engineering, Nanjing Technology University , 30 Puzhu Road South, Nanjing, Jiangsu, China , 211816.|Department of Chemical Engineering and Waterloo Institute for Nanotechnology, University of Waterloo , 200 University Avenue West, Waterloo, Ontario, Canada , N2L 3G1.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Chemistry and Biochemistry, University of California , Santa Barbara, California 93106, United States.
authors.forename: W F Drew
authors.initials: WF
authors.lastname: Bennett
authors.affiliation: Biological and Pharmaceutical Engineering, Nanjing Technology University , 30 Puzhu Road South, Nanjing, Jiangsu, China , 211816.
authors.forename: Tao
authors.initials: T
authors.lastname: Zheng
authors.affiliation: Biological and Pharmaceutical Engineering, Nanjing Technology University , 30 Puzhu Road South, Nanjing, Jiangsu, China , 211816.
authors.forename: Ping-Kai
authors.initials: PK
authors.lastname: Ouyang
authors.affiliation: School of Chemistry and Chemical Engineering, South China University of Technology , Guangzhou, P.R. China , 510640.
authors.forename: Xinping
authors.initials: X
authors.lastname: Ouyang
authors.affiliation: School of Chemistry and Chemical Engineering, South China University of Technology , Guangzhou, P.R. China , 510640.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Qiu
authors.affiliation: Department of Chemical Engineering and Waterloo Institute for Nanotechnology, University of Waterloo , 200 University Avenue West, Waterloo, Ontario, Canada , N2L 3G1.
authors.forename: Anqi
authors.initials: A
authors.lastname: Luo
authors.affiliation: Department of Mathematics and Computer Science & Institute for Complex Molecular Systems, Eindhoven University of Technology, MetaForum , 5600 MB Eindhoven, The Netherlands.
authors.forename: Mikko
authors.initials: M
authors.lastname: Karttunen
authors.affiliation: Biological and Pharmaceutical Engineering, Nanjing Technology University , 30 Puzhu Road South, Nanjing, Jiangsu, China , 211816.|Department of Chemical Engineering and Waterloo Institute for Nanotechnology, University of Waterloo , 200 University Avenue West, Waterloo, Ontario, Canada , N2L 3G1.
authors.forename: P
authors.initials: P
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism*; D002478:Cells, Cultured; D002784:Cholesterol / Q000737:chemistry / Q000494:pharmacology*; D003412:Cricetulus; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D004611:Ellipticines / Q000737:chemistry / Q000493:pharmacokinetics*; D005453:Fluorescence; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure
chemical_list: D000970:Antineoplastic Agents; D004611:Ellipticines; C034192:ellipticine; D004317:Doxorubicin; D002784:Cholesterol; C027260:pirarubicin