title: Radiofrequency ablation combined with liposomal quercetin to increase tumour destruction by modulation of heat shock protein production in a small animal model.
abstract: OBJECTIVE
  To investigate the effect of heat shock protein (HSP) modulation on tumour coagulation by combining radiofrequency (RF) ablation with adjuvant liposomal quercetin and/or doxorubicin in a rat tumour model.
  
  
  METHODS
  Sixty R3230 breast adenocarcinoma tumours/animals were used in this IACUC-approved study. Initially, 60 tumours (n=6, each subgroup) were randomised into five groups: (1) RF alone, (2) intravenous (IV) liposomal quercetin alone (1 mg/kg), (3) IV liposomal quercetin followed 24 h later with RF, (4) RF followed 15 min later by IV liposomal doxorubicin (8 mg/kg), (5) IV liposomal quercetin 24 h before RF followed by IV liposomal doxorubicin 15 min post-ablation. Animals were sacrificed 4 or 24 h post-treatment and gross coagulation diameters were compared. Next, immunohistochemistry staining was performed for Hsp70 and cleaved caspase-3 expression. Comparisons were performed by using Student t-tests or ANOVA.
  
  
  RESULTS
  Combination RF-quercetin significantly increased coagulation size compared with either RF or liposomal quercetin alone (13.1±0.7 mm vs. 8.8±1.2 mm or 2.3±1.3 mm, respectively, P<0.001 for all comparisons). Triple therapy (quercetin-RF-doxorubicin) showed larger coagulation diameter (14.5±1.0 mm) at 24 h than quercetin-RF (P=0.016) or RF-doxorubicin (13.2±1.3 mm, P=0.042). Combination quercetin-RF decreased Hsp70 expression compared with RF alone at both 4 h (percentage of stained cells/hpf 22.4±13.9% vs. 38.8±16.1%, P<0.03) and 24 h (45.2±10.5% vs. 81.1±3.6%, P<0.001). Quercetin-RF increased cleaved caspase-3 expression at both 4 h (percentage of stained cells/hpf 50.7±13.4% vs. 41.9±15.1%, P<0.03) and 24 h (37.4±7.8% vs. 33.2±6.5%, P=0.045); with, triple therapy (quercetin-RF-doxorubicin) resulting in the highest levels of apoptosis (45.1±10.7%) at 24 h. Similar trends were observed for rim thickness.
  
  
  CONCLUSIONS
  Suppression of HSP production using adjuvant liposomal quercetin can increase apoptosis and improve RF ablation-induced tumour destruction. Further increases in tumour coagulation can be seen including an additional anti-tumour adjuvant agent such as liposomal doxorubicin.
authors.affiliation: Minimally Invasive Tumor Therapies Laboratory, Department of Radiology, Beth Israel Deaconess Medical Center/Harvard Medical School, 1 Deaconess Road, Boston, MA 02215, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.forename: Muneeb
authors.initials: M
authors.lastname: Ahmed
authors.forename: Beenish
authors.initials: B
authors.lastname: Tasawwar
authors.forename: Tatyana
authors.initials: T
authors.lastname: Levchenko
authors.forename: Rupa R
authors.initials: RR
authors.lastname: Sawant
authors.forename: Michael
authors.initials: M
authors.lastname: Collins
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
authors.forename: Vladimir
authors.initials: V
authors.lastname: Torchilin
authors.forename: S Nahum
authors.initials: SN
authors.lastname: Goldberg
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D017115:Catheter Ablation / Q000379:methods; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D008081:Liposomes / Q000627:therapeutic use*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000601:surgery*; D011794:Quercetin / Q000008:administration & dosage*; D051381:Rats
chemical_list: D018840:HSP70 Heat-Shock Proteins; D008081:Liposomes; D004317:Doxorubicin; D011794:Quercetin