title: Increased ERK activation and cellular drug accumulation in the enhanced             cytotoxicity of folate receptor-targeted liposomal carboplatin.
abstract: Folate receptor-targeted (FRT) liposomes for carboplatin were developed             and evaluated in FR-positive and FR-negative cell lines, KB and A549, respectively,             for their cytotoxic effects. Significant enhancement in carboplatin potency and             intracellular drug accumulation was observed in KB cells when treated with FRT             liposomes, compared to free drug and non-targeted liposomes. No enhancement was             observed in the FR-negative A549 cells. The increase in carboplatin potency was             hypothesized to be associated with an increase in the formation of DNA-platinum             adducts resulted from an increase in cellular accumulation of the drug. Surprisingly,             FRT carboplatin liposomes showed significantly lower levels of DNA-platinum adducts             in comparison to free drug. To elucidate this discrepancy, activation of extracellular             signal-regulated protein kinase (ERK) was probed, which has been suggested as             an alternative mechanism of carboplatin action. FRT liposomes loaded with carboplatin             exhibited the highest level of ERK phosphorylation, and the cytotoxic effect of             FRT carboplatin liposomes could be reversed by the MEK/ERK inhibitors, U0126 and             PD98059. Importantly, empty FRT liposomes could significantly increase ERK phosphorylation             in a concentration-dependent manner without causing toxicity to cells. For the             first time, increased potency of carboplatin delivered by FRT liposomes was found             to be associated with other molecular targets in addition to DNA-platinum adduct             formation. Collectively, the current study suggests a novel mechanism by which             FRT liposomes could sensitize cancer cells to drug treatment via modulation of             ERK-related cell survival signals.
authors.affiliation: Department of Pharmacy, National University of Singapore, Singapore.
authors.forename: Anumita
authors.initials: A
authors.lastname: Chaudhury
authors.forename: Bee Jee
authors.initials: BJ
authors.lastname: Tan
authors.forename: Surajit
authors.initials: S
authors.lastname: Das
authors.forename: Gigi N C
authors.initials: GN
authors.lastname: Chiu
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016190:Carboplatin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D058973:Folate Receptors, GPI-Anchored / Q000378:metabolism*; D006801:Humans; D007624:KB Cells; D008081:Liposomes / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D010766:Phosphorylation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D058973:Folate Receptors, GPI-Anchored; D008081:Liposomes; D016190:Carboplatin; D048049:Extracellular Signal-Regulated MAP Kinases