title: A chemical strategy to manipulate the intracellular localization of drugs in resistant cancer cells.
abstract: A number of multidrug-resistant (MDR) cancer cells have been shown to have acquired an increased capacity to sequester weakly basic anticancer drugs in their lysosomes relative to drug-sensitive counterparts. In this report we have comparatively evaluated the concentrations of the anticancer agent daunorubicin (DNR) in intracellular compartments of drug-sensitive and MDR HL-60 cell lines, both of which do not express common efflux transporters such as P-glycoprotein at the plasma membrane. Our results suggest that lysosomal sequestration plays a significant role in the emergence of MDR since it effectively limits the drug's ability to interact with target molecules located in the nucleus. Using a series of weakly basic structural isomers with variable basicity, we illustrate that the magnitude of the pKa value correlates with the degree of lysosomal sequestration. Accordingly, a series of structurally modified forms of DNR with reduced basicity were synthesized, and their intracellular distribution was evaluated. Consistent with model compounds, derivatives of DNR with lowered pKa values showed visibly reduced lysosomal sequestration in two separate MDR cell lines. Collectively, this work highlights the importance of understanding the intracellular localization of drugs and proposes a rational strategy to manipulate it.
authors.affiliation: Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas 66047, USA.
authors.forename: Muralikrishna
authors.initials: M
authors.lastname: Duvvuri
authors.forename: Samidha
authors.initials: S
authors.lastname: Konkar
authors.forename: Ryan S
authors.initials: RS
authors.lastname: Funk
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Krise
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Krise
mesh_terms: D002451:Cell Compartmentation / Q000502:physiology; D003630:Daunorubicin / Q000031:analogs & derivatives / Q000378:metabolism*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D018922:HL-60 Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008856:Microscopy, Fluorescence
chemical_list: D003630:Daunorubicin