title: Substituted steroidal compounds containing amino and amido groups reverse multidrug resistance of mouse T-lymphoma and two human prostate cancer cell lines in vitro.
abstract: BACKGROUND
  Resistance to chemotherapy is a main problem in cancer. The search for new effective compounds that can increase sensitivity of resistant cells to existing chemotherapeutics is an urgent need. In previous studies, it has been demonstrated that steroid derivatives showed promising results concerning their capacity to modulate resistance of multidrug-resistant cell lines.
  
  
  METHODS
  Steroid derivatives were studied for their growth-inhibitory effect, cytotoxicity, reversal of multidrug resistance, apoptosis induction, and interaction with doxorubicin on multidrug resistant human ATP-binding cassette, sub-family B, member 1 (ABCB1) gene-transfected mouse T-lymphoma cell line, and human PC-3 and LNCaP prostate cancer cell lines in vitro. The steroidal interaction with P-glycoprotein (ABCB1) was investigated by molecular docking.
  
  
  RESULTS
  Both the activity of steroid derivatives on inhibition of the ABCB1 pump and their interaction with doxorubicin are dependent on the substituent groups of the investigated steroidal structures. Even though the investigated steroid derivatives were found to have limited antiproliferative effect on the three different cancer cell lines, in combination with doxorubicin, most of them acted as good potentiators. The binding energies from molecular docking ranged from -6.43 to -9.88 kcal/mol. The predicted inhibition constants ranged from 0.1 to 10.1 μM. A significant negative correlation was found between binding energy and fluorescence activity ratio (R=-0.5, p=0.015).
  
  
  CONCLUSIONS
  The effective compounds can be candidates of model molecules for possible application in the treatment of multidrug resistant cancer in rational drug design.
authors: Institute of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Szeged, Hungary Department of Traumatology, Faculty of Medicine, University of Szeged, Szeged, Hungary.
authors: Ákos
authors: Á
authors: Csonka
authors: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
authors: Sami
authors: S
authors: Hamdoun
authors: Institute of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Szeged, Hungary.
authors: Gabriella
authors: G
authors: Spengler
authors: Institute of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Szeged, Hungary Unit of Parasitology and Medical Microbiology, Institute of Hygiene and Tropical Medicine, New University of Lisbon, Lisbon, Portugal.
authors: Ana
authors: A
authors: Martins
authors: Department of Organic Chemistry, Faculty of Natural Sciences and Informatics, University of Szeged, Szeged, Hungary.
authors: Irén
authors: I
authors: Vincze
authors: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
authors: Thomas
authors: T
authors: Efferth
authors: Institute of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Szeged, Hungary molnar.jozsef@med.u-szeged.hu.
authors: Joseph
authors: J
authors: Molnár
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage*; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D066298:In Vitro Techniques; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004317:Doxorubicin
keywords: ABCB1 transporter; PC-3 prostate cancer cell line; mouse T-lymphoma; multidrug resistance; steroids