title: Radiofrequency ablation-induced upregulation of hypoxia-inducible factor-1α can be suppressed with adjuvant bortezomib or liposomal chemotherapy.
abstract: OBJECTIVE
  To characterize upregulation of hypoxia-inducible factor (HIF)-1α after radiofrequency (RF) ablation and the influence of an adjuvant HIF-1α inhibitor (bortezomib) and nanodrugs on modulating RF ablation-upregulated hypoxic pathways.
  
  
  METHODS
  Fisher 344 rats (n = 68) were used. First, RF ablation-induced periablational HIF-1α expression was evaluated in normal liver or subcutaneous R3230 tumors (14-16 mm). Next, the effect of varying RF ablation thermal dose (varying tip temperature 50°C-90°C for 2-20 minutes) on HIF-1α expression was studied in R3230 tumors. Third, RF ablation was performed in R3230 tumors without or with an adjuvant HIF-1α inhibitor, bortezomib (single intraperitoneal dose 0.1 mg/kg). Finally, the combination RF ablation and intravenous liposomal chemotherapeutics with known increases in periablational cellular cytotoxicity (doxorubicin, paclitaxel, and quercetin) was assessed for effect on periablational HIF-1α. Outcome measures included immunohistochemistry of HIF-1α and heat shock protein 70 (marker of nonlethal thermal injury).
  
  
  RESULTS
  RF ablation increased periablational HIF-1α in both normal liver and R3230 tumor, peaking at 24-72 hours. Tumor RF ablation had similar HIF-1α rim thickness but significantly greater percent cell positivity compared with hepatic RF ablation (P < .001). HIF-1α after ablation was the same regardless of thermal dose. Bortezomib suppressed HIF-1α (rim thickness, 68.7 µm ± 21.5 vs 210.3 µm ± 85.1 for RF ablation alone; P < .02) and increased ablation size (11.0 mm ± 1.5 vs 7.7 mm ± 0.6 for RF ablation alone; P < .002). Finally, all three nanodrugs suppressed RF ablation-induced HIF-1α (ie, rim thickness and cell positivity; P < .02 for all comparisons), with liposomal doxorubicin suppressing HIF-1α the most (P < .03).
  
  
  CONCLUSIONS
  RF ablation upregulates HIF-1α in normal liver and tumor in a temperature-independent manner. This progrowth, hypoxia pathway can be successfully suppressed with an adjuvant HIF-1α-specific inhibitor, bortezomib, or non-HIF-1α-specific liposomal chemotherapy.
authors.affiliation: Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, 1 Deaconess Road, WCC 308-B, Boston, MA 02215.
authors.forename: Marwan
authors.initials: M
authors.lastname: Moussa
authors.affiliation: Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, 1 Deaconess Road, WCC 308-B, Boston, MA 02215; Division of Image-guided Therapy and Interventional Oncology, Department of Radiology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: S Nahum
authors.initials: SN
authors.lastname: Goldberg
authors.affiliation: Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, 1 Deaconess Road, WCC 308-B, Boston, MA 02215.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Kumar
authors.affiliation: Department of Pharmaceutical Sciences and Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, Massachusetts.
authors.forename: Rupa R
authors.initials: RR
authors.lastname: Sawant
authors.affiliation: Department of Pharmaceutical Sciences and Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, Massachusetts.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Levchenko
authors.affiliation: Department of Pharmaceutical Sciences and Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, Massachusetts.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Torchilin
authors.affiliation: Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, 1 Deaconess Road, WCC 308-B, Boston, MA 02215. Electronic address: mahmed@bidmc.harvard.edu.
authors.forename: Muneeb
authors.initials: M
authors.lastname: Ahmed
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D001943:Breast Neoplasms / Q000601:surgery*; D017115:Catheter Ablation / Q000379:methods*; D017024:Chemotherapy, Adjuvant; D004195:Disease Models, Animal; D005260:Female; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects* / Q000378:metabolism; D008081:Liposomes / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000601:surgery; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008081:Liposomes; D011719:Pyrazines; D000069286:Bortezomib