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LB-100 sensitizes hepatocellular carcinoma cells to the effects of sorafenib during hypoxia by activation of smad3 phosphorylation
Electronic Poster Abstracts
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constructed and treated with sorafenib with or without LB-100. Results: LB-100 enhanced the effects of sorafenib in HCC cells only during hypoxic environments. LB-100 dramatically increased p-Smad3 level, which was responsible for the sensitizatory effect of LB-100. LB-100 down-regulated Bcl-2 expression and enhanced sorafenib-induced apoptosis in HCC cells. PP2A mediated LB-100 induced pSmad3 overexpression. In addition, p38 mitogen-activated protein kinase pathway was activated in hypoxic conditions, and enhanced p-Smad3-dependent Bcl-2 inhibition and consequent apoptosis. Conclusion: LB-100 sensitized HCC cells to sorafenib in hypoxic environments. This effect was mediated by inactivation of PP2A, resulting in enhanced level of p-Smad3. Increased p-Smad3 down-regulated Bcl-2, causing increased apoptosis of HCC cells.
EP01B-009 HCC RECURRENCE FOLLOWING LIVER TRANPLANTATION SHOULD BE AGGRESIVELY TREATED TO INCREASE PATIENT SURVIVAL
[Figures]
EP01B-008 LB-100 SENSITIZES HEPATOCELLULAR CARCINOMA CELLS TO THE EFFECTS OF SORAFENIB DURING HYPOXIA BY ACTIVATION OF SMAD3 PHOSPHORYLATION Q. Fu1, Q. Zhang1, X. Bai1 and T. Liang1,2 1 Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, and 2Collaborative Innovation Center for Cancer Medicine, Zhejiang University, China Introductions: Hepatocellular carcinoma (HCC) is a common cancer with poor prognosis. The multikinase inhibitor sorafenib is the only clinically proved systematic treatment for HCC. However, few patients respond to sorafenib. Hypoxic microenvironments contribute to sorafenib resistance. LB-100, a serine/threonine protein phosphatase 2A (PP2A) inhibitor was previously found to be a chemosensitizer in HCC. We aimed to test whether LB-100 could sensitize HCC to the effects of sorafenib. Methods: Cell viability was evaluated by using Cell Counting Kit-8. Cell apoptosis assay were performed with Annexin V-FITC Detection Kit. Relative protein expression changes were assessed by immunoblotting. PP2A activity was assessed by using a Ser/Thr phosphatase assay kit. HCC xenograft mouse model was
HPB 2016, 18 (S1), e1ee384
G. Sapisochin1, N. Mehta2, I. Scalera3, C. Sposito4, F. Y. Yao2, P. Muiesan3, V. Mazzaferro4 and D. R. Grant1 1 University of Toronto, Canada, 2University of California, San Francisco, United States, 3Liver e University Hospitals Birmingham NHS Foundation Trust, United Kingdom, and 4Istituto Nazionale dei Tumori, Italy Information on prognosis after hepatocellular carcinoma (HCC) recurrence following liver transplantation (LT) is scarce. A recently published prognostic score identified elevated AFP, short time to recurrence, and treatment without curative intent as factors predicting worse survival. We aimed to confirm these prognostic factors following HCC recurrence in a larger, international multicenter study. Between June 2002eDecember 2014, 130 patients from three different institutions diagnosed with HCC recurrence after LT were included. The median time from LT to HCC recurrence was 17.8 (1e121) months and the median follow-up period after HCC recurrence was 11.6 (0.1e 93.7) months. At recurrence 31.5% were treated with curative intent (surgery or ablation), 49.2% received a palliative treatment and 19.4% the best supportive care. The median survival of patients according to treatment received (curative vs. palliative vs. best supportive care) was 21.6 vs. 11.7 vs. 2.5 months respectively, p < 0.001. On univariate analysis, risks factors for death after HCC recurrence were AFP at recurrence 50 ng/mL, early recurrence ( < 12 months from LT), recurrence with either a single mass > 5cm or multiple masses, and not receiving a curative treatment. On multivariable analysis, early recurrence [HR 3.1 (1.8e5.4), p < 0.001] and not receiving a curative intent treatment [HR 2.9 (1.7e5.0), p < 0.001] predicted worse survival. The 5-year survival of those with neither of these risk factors was 32%, compared to 12% in those with 1 risk factor and 0% with 2 risk factors, p < 0.001. HCC recurrence after LT should not be considered a fatal event and aggressive treatments should be offered when possible.
e197
constructed and treated with sorafenib with or without LB-100. Results: LB-100 enhanced the effects of sorafenib in HCC cells only during hypoxic environments. LB-100 dramatically increased p-Smad3 level, which was responsible for the sensitizatory effect of LB-100. LB-100 down-regulated Bcl-2 expression and enhanced sorafenib-induced apoptosis in HCC cells. PP2A mediated LB-100 induced pSmad3 overexpression. In addition, p38 mitogen-activated protein kinase pathway was activated in hypoxic conditions, and enhanced p-Smad3-dependent Bcl-2 inhibition and consequent apoptosis. Conclusion: LB-100 sensitized HCC cells to sorafenib in hypoxic environments. This effect was mediated by inactivation of PP2A, resulting in enhanced level of p-Smad3. Increased p-Smad3 down-regulated Bcl-2, causing increased apoptosis of HCC cells.
EP01B-009 HCC RECURRENCE FOLLOWING LIVER TRANPLANTATION SHOULD BE AGGRESIVELY TREATED TO INCREASE PATIENT SURVIVAL
[Figures]
EP01B-008 LB-100 SENSITIZES HEPATOCELLULAR CARCINOMA CELLS TO THE EFFECTS OF SORAFENIB DURING HYPOXIA BY ACTIVATION OF SMAD3 PHOSPHORYLATION Q. Fu1, Q. Zhang1, X. Bai1 and T. Liang1,2 1 Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, and 2Collaborative Innovation Center for Cancer Medicine, Zhejiang University, China Introductions: Hepatocellular carcinoma (HCC) is a common cancer with poor prognosis. The multikinase inhibitor sorafenib is the only clinically proved systematic treatment for HCC. However, few patients respond to sorafenib. Hypoxic microenvironments contribute to sorafenib resistance. LB-100, a serine/threonine protein phosphatase 2A (PP2A) inhibitor was previously found to be a chemosensitizer in HCC. We aimed to test whether LB-100 could sensitize HCC to the effects of sorafenib. Methods: Cell viability was evaluated by using Cell Counting Kit-8. Cell apoptosis assay were performed with Annexin V-FITC Detection Kit. Relative protein expression changes were assessed by immunoblotting. PP2A activity was assessed by using a Ser/Thr phosphatase assay kit. HCC xenograft mouse model was
HPB 2016, 18 (S1), e1ee384
G. Sapisochin1, N. Mehta2, I. Scalera3, C. Sposito4, F. Y. Yao2, P. Muiesan3, V. Mazzaferro4 and D. R. Grant1 1 University of Toronto, Canada, 2University of California, San Francisco, United States, 3Liver e University Hospitals Birmingham NHS Foundation Trust, United Kingdom, and 4Istituto Nazionale dei Tumori, Italy Information on prognosis after hepatocellular carcinoma (HCC) recurrence following liver transplantation (LT) is scarce. A recently published prognostic score identified elevated AFP, short time to recurrence, and treatment without curative intent as factors predicting worse survival. We aimed to confirm these prognostic factors following HCC recurrence in a larger, international multicenter study. Between June 2002eDecember 2014, 130 patients from three different institutions diagnosed with HCC recurrence after LT were included. The median time from LT to HCC recurrence was 17.8 (1e121) months and the median follow-up period after HCC recurrence was 11.6 (0.1e 93.7) months. At recurrence 31.5% were treated with curative intent (surgery or ablation), 49.2% received a palliative treatment and 19.4% the best supportive care. The median survival of patients according to treatment received (curative vs. palliative vs. best supportive care) was 21.6 vs. 11.7 vs. 2.5 months respectively, p < 0.001. On univariate analysis, risks factors for death after HCC recurrence were AFP at recurrence 50 ng/mL, early recurrence ( < 12 months from LT), recurrence with either a single mass > 5cm or multiple masses, and not receiving a curative treatment. On multivariable analysis, early recurrence [HR 3.1 (1.8e5.4), p < 0.001] and not receiving a curative intent treatment [HR 2.9 (1.7e5.0), p < 0.001] predicted worse survival. The 5-year survival of those with neither of these risk factors was 32%, compared to 12% in those with 1 risk factor and 0% with 2 risk factors, p < 0.001. HCC recurrence after LT should not be considered a fatal event and aggressive treatments should be offered when possible.