title: Synthetic high-density lipoprotein nanoparticles: A novel therapeutic strategy for adrenocortical carcinomas.
abstract: BACKGROUND
  Chemotherapeutic strategies for adrenocortical carcinoma (ACC) carry substantial toxicities. Cholesterol is critical for ACC cell growth and steroidogenesis, and ACC cells overexpress scavenger receptor BI, which uptakes cholesterol from circulating high-density lipoprotein (HDL) cholesterol. We hypothesize that cholesterol-free synthetic-HDL nanoparticles (sHDL) will deplete cholesterol and synergize with chemotherapeutics to achieve enhanced anticancer effects at lesser (less toxic) drug levels.
  
  
  METHODS
  The antiproliferative efficacy of ACC cells for the combinations of sHDL with chemotherapeutics was tested by Cell-Titer Glo. Cortisol levels were measured from the culture media. Effects on steroidogenesis was measured by real-time polymerase chain reaction (RT-PCR). Induction of apoptosis was evaluated by flow cytometry.
  
  
  RESULTS
  Combination Index (CI) for sHDL and either etoposide (E), cisplatin (P), or mitotane (M) demonstrated synergy (CI < 1) for antiproliferation. Alone or in combination with the chemotherapy drugs, sHDL was able to decrease cortisol production by 70-90% compared with P alone or controls (P < .01). RT-PCR indicated inhibition of steroidogenic enzymes for sHDL (P < .01 vs no sHDL). Combination therapy with sHDL increased apoptosis by 30-50% compared with drug or sHDL alone (P < .03), confirmed by a decrease in the mitochondrial potential.
  
  
  CONCLUSIONS
  sHDL can act synergistically and lessen the amount of M/E/P needed for anticancer efficacy in ACC in part owing to cholesterol starvation. This novel treatment strategy warrants further investigation translationally.
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, MI.
authors.forename: Chitra
authors.initials: C
authors.lastname: Subramanian
authors.affiliation: Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI; Biointerfaces Institute, University of Michigan, Ann Arbor, MI.
authors.forename: Rui
authors.initials: R
authors.lastname: Kuai
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, MI.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, MI.
authors.forename: Peter
authors.initials: P
authors.lastname: White
authors.affiliation: Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI; Biointerfaces Institute, University of Michigan, Ann Arbor, MI.
authors.forename: James J
authors.initials: JJ
authors.lastname: Moon
authors.affiliation: Biointerfaces Institute, University of Michigan, Ann Arbor, MI; Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI.
authors.forename: Anna
authors.initials: A
authors.lastname: Schwendeman
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, MI; Department of Pharmacology, University of Michigan, Ann Arbor, MI. Electronic address: cohenmar@med.umich.edu.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Cohen
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D018268:Adrenocortical Carcinoma / Q000188:drug therapy* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D004359:Drug Therapy, Combination; D006801:Humans; D006854:Hydrocortisone / Q000032:analysis; D008075:Lipoproteins, HDL / Q000494:pharmacology*; D053758:Nanoparticles / Q000008:administration & dosage*; D051122:Scavenger Receptors, Class B / Q000096:biosynthesis*
chemical_list: D000970:Antineoplastic Agents; D008075:Lipoproteins, HDL; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D006854:Hydrocortisone