Single-Dose Neoadjuvant AKT Pathway Inhibitor Reduces Growth of Hepatocellular Carcinoma after Laser Thermal Ablation in Small-Animal Model
| Autor: | Jill L. Anderson, Scott M. Thompson, Bruce E. Knudsen, David A. Woodrum, Lewis R. Roberts, Danielle E. Jondal, Kim A. Butters, Matthew R. Callstrom |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Ablation Techniques
Programmed cell death Carcinoma Hepatocellular medicine.medical_treatment Mice Nude Antineoplastic Agents 030218 nuclear medicine & medical imaging Mice Phosphatidylinositol 3-Kinases 03 medical and health sciences 0302 clinical medicine In vivo Carcinoma Medicine Animals Radiology Nuclear Medicine and imaging Protein kinase B PI3K/AKT/mTOR pathway Original Research business.industry TOR Serine-Threonine Kinases Liver Neoplasms Imidazoles medicine.disease Ablation Combined Modality Therapy Neoadjuvant Therapy Disease Models Animal Apoptosis 030220 oncology & carcinogenesis Hepatocellular carcinoma Quinolines Cancer research business Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Radiology |
| Popis: | BACKGROUND: Local recurrence following thermal ablation of hepatocellular carcinoma (HCC) larger than 2–3 cm remains a challenging clinical problem. Prior studies suggest that phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR)–dependent protein kinase B (AKT) signaling mediates HCC cell survival caused by moderate heat stress in vitro, but these findings need in vivo validation. PURPOSE: To test the hypothesis that neoadjuvant inhibition of PI3K/mTOR/AKT signaling reduces HCC tumor growth in vivo after laser ablation and to evaluate the effects of moderate heat stress on molecular signaling and cellular function in HCC cells in vitro. MATERIALS AND METHODS: HCC tumor–bearing mice were randomized to neoadjuvant PI3K/mTOR inhibitor (BEZ235) or control groups followed by an intentional partial laser ablation or sham ablation; there were at least nine mice per group. Postablation tumor growth was monitored up to 7 days. Tumor volumes were compared for drug or ablation groups by using two-way analysis of variance. N1S1 HCC cells pretreated with BEZ235 or control and subjected to moderate heat stress (45°C for 10 minutes) or control (37°C for 10 minutes) were analyzed by using mass spectrometry. Protein interaction networks were derived from protein expression analysis software, and cellular function activation state (Z-score) and fold-change in AKT phosphorylation were calculated. RESULTS: There was a 37%–75% reduction in HCC tumor volume by day 7 after ablation in the BEZ235 plus ablation group (713 mm(3) ± 417) compared with vehicle plus sham (1559 mm(3) ± 552), vehicle plus ablation (1041 mm(3) ± 591), and BEZ235 plus sham (1108 mm(3) ± 523) groups (P < .001, P = .04, and P = .005, respectively). PI3K/mTOR inhibition prevented moderate heat stress–induced AKT signaling (Z-score, −0.2; P < .001) and isoform-specific AKT phosphorylation compared with the vehicle plus heat stress group. PI3K/mTOR inhibition prevented moderate heat stress–induced global effects on HCC molecular signaling and cellular function, including decreased cell survival, growth, and proliferation (Z-score, −0.3 to −3.2; P < .001) and increased apoptosis and cell death (Z-score, 0.4–1.1; P < .001). CONCLUSION: Moderate heat stress induces PI3K/mTOR/AKT–dependent global effects on hepatocellular carcinoma (HCC) cell survival, function, and death. Neoadjuvant PI3K/mTOR/AKT inhibition reduces postablation HCC tumor growth. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by White in this issue. |
| Databáze: | OpenAIRE |
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