Dataset Information

Combination of HSP90 and autophagy inhibitors promotes hepatocellular carcinoma apoptosis following incomplete thermal ablation.

ABSTRACT: The present study evaluated the effect of combining inhibitors (17?AAG) of heat shock protein 90 (HSP90) and autophagy (3?MA) on apoptosis using an incomplete thermal ablation animal model. A total of 28 orthotopic mice with hepatocellular carcinoma were randomly divided into 4 groups to receive different drug interventions. Following palliative laser ablation, changes in autophagy, apoptosis and Akt/mTOR expression levels were assessed in tumors. Compared with the controls, the 17?AAG?treated mice exhibited significantly decreased expression levels of phosphorylated (p)?Akt and p?mTOR with enhanced autophagy and apoptosis; no marked increases in the expression levels of p?Akt and p?mTOR were observed in the 3?MA?treated mice, with no significant changes in autophagy; however, apoptosis was enhanced. No significant decreases in p?Akt and p?mTOR or any increase in autophagy were observed in the mice receiving a combination of 17?AAG and 3?MA, but they did exhibit a marked increase in apoptosis. Compared with 17?AAG alone, the combination of 17?AAG and 3?MA resulted in a marked increase in apoptosis without enhanced autophagy. In the incomplete ablation model, the effects of autophagy and apoptosis are antagonistic. The combined use of 17?AAG and 3?MA can significantly promote apoptosis and is worthy of further study.

SUBMITTER: Chen F

PROVIDER: S-EPMC7248472 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Combination of HSP90 and autophagy inhibitors promotes hepatocellular carcinoma apoptosis following incomplete thermal ablation.

Chen Fen F Xie Haiyang H Bao Haiwei H Violetta Laurencia L Zheng Shusen S

Molecular medicine reports 20200421 1

The present study evaluated the effect of combining inhibitors (17‑AAG) of heat shock protein 90 (HSP90) and autophagy (3‑MA) on apoptosis using an incomplete thermal ablation animal model. A total of 28 orthotopic mice with hepatocellular carcinoma were randomly divided into 4 groups to receive different drug interventions. Following palliative laser ablation, changes in autophagy, apoptosis and Akt/mTOR expression levels were assessed in tumors. Compared with the controls, the 17‑AAG‑treated m ...[more]

PMID: 32319654

Similar Datasets

Project description:Background & aimsTremelimumab is a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on the surface of activated T lymphocytes. Ablative therapies induce a peripheral immune response which may enhance the effect of anti-CTLA4 treatment in patients with advanced hepatocellular carcinoma (HCC). This study aimed to demonstrate whether tremelimumab could be combined safely and feasibly with ablation.MethodsThirty-two patients with HCC were enrolled: male:female: 28:4; median age: 62 (range 36-76). Patients were given tremelimumab at two dose levels (3.5 and 10mg/kg i.v.) every 4weeks for 6 doses, followed by 3-monthly infusions until off-treatment criteria were met. On day 36, patients underwent subtotal radiofrequency ablation or chemoablation. Staging was performed by contrast-enhanced CT or MRI scan every 8weeks.ResultsNo dose-limiting toxicities were encountered. The most common toxicity was pruritus. Of the 19 evaluable patients, five (26.3%; 95% CI: 9.1-51.2%) achieved a confirmed partial response. Twelve of 14 patients with quantifiable HCV experienced a marked reduction in viral load. Six-week tumor biopsies showed a clear increase in CD8+ T cells in patients showing a clinical benefit only. Six and 12-month probabilities of tumor progression free survival for this refractory HCC population were 57.1% and 33.1% respectively, with median time to tumor progression of 7.4months (95% CI 4.7 to 19.4months). Median overall survival was 12.3months (95% CI 9.3 to 15.4months).ConclusionsTremelimumab in combination with tumor ablation is a potential new treatment for patients with advanced HCC, and leads to the accumulation of intratumoral CD8+ T cells. Positive clinical activity was seen, with a possible surrogate reduction in HCV viral load.Lay summaryStudies have shown that the killing of tumors by direct methods (known as ablation) can result in the immune system being activated or switched on. The immune system could potentially also recognize and kill the cancer that is left behind. There are new drugs available known as immune checkpoint inhibitors which could enhance this effect. Here, we test one of these drugs (tremelimumab) together with ablation.Clinical trial numberClinicalTrials.gov: NCT01853618.

Dataset Information

Combination of HSP90 and autophagy inhibitors promotes hepatocellular carcinoma apoptosis following incomplete thermal ablation.

Publications

Combination of HSP90 and autophagy inhibitors promotes hepatocellular carcinoma apoptosis following incomplete thermal ablation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets