Sorafenib modulates the radio sensitivity of hepatocellular carcinoma cells in vitro in a schedule-dependent manner

Li, Qiaoqiao; Hu, Yonghong; Xi, Mian; He, Liru; Zhao, Lei; Liu, Mengzhong

doi:10.1186/1471-2407-12-485

Cited by 23 publications

(18 citation statements)

References 22 publications

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“…To investigate the activity of combined sorafenib and radiation against HCC, we tested concurrent and sequential treatment approaches in four HCC cell lines. Using colony formation assays, we found that a sequential approach produced an additive increase in efficacy, while concurrent therapy resulted in radioprotection or no effect when compared to radiation alone, corroborating the results of Li and colleagues [36]. Based on previous work in non-HCC cell lines [29], we hypothesized that this effect of concurrent treatment might be due to sorafenib-mediated reassortment into less radiosensitive phases of the cell cycle and generalized cell cycle slowing.…”

Section: Discussionsupporting

confidence: 86%

“…Several ongoing phase I–II trials employ sorafenib and radiation concurrently, sequentially, or both (Table 1); however, preclinical data examining sorafenib and radiation in HCC that might guide selection of the optimal therapeutic sequence for clinical use is limited to one in vitro study, which did not involve any in vivo experiments [36]. To investigate the activity of combined sorafenib and radiation against HCC, we tested concurrent and sequential treatment approaches in four HCC cell lines.…”

Section: Discussionmentioning

confidence: 99%

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Concurrent versus Sequential Sorafenib Therapy in Combination with Radiation for Hepatocellular Carcinoma

et al. 2013

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Sorafenib (SOR) is the only systemic agent known to improve survival for hepatocellular carcinoma (HCC). However, SOR prolongs survival by less than 3 months and does not alter symptomatic progression. To improve outcomes, several phase I-II trials are currently examining SOR with radiation (RT) for HCC utilizing heterogeneous concurrent and sequential treatment regimens. Our study provides preclinical data characterizing the effects of concurrent versus sequential RT-SOR on HCC cells both in vitro and in vivo. Concurrent and sequential RT-SOR regimens were tested for efficacy among 4 HCC cell lines in vitro by assessment of clonogenic survival, apoptosis, cell cycle distribution, and γ-H2AX foci formation. Results were confirmed in vivo by evaluating tumor growth delay and performing immunofluorescence staining in a hind-flank xenograft model. In vitro, concurrent RT-SOR produced radioprotection in 3 of 4 cell lines, whereas sequential RT-SOR produced decreased colony formation among all 4. Sequential RT-SOR increased apoptosis compared to RT alone, while concurrent RT-SOR did not. Sorafenib induced reassortment into less radiosensitive phases of the cell cycle through G1-S delay and cell cycle slowing. More double-strand breaks (DSBs) persisted 24 h post-irradiation for RT alone versus concurrent RT-SOR. In vivo, sequential RT-SOR produced the greatest tumor growth delay, while concurrent RT-SOR was similar to RT alone. More persistent DSBs were observed in xenografts treated with sequential RT-SOR or RT alone versus concurrent RT-SOR. Sequential RT-SOR additionally produced a greater reduction in xenograft tumor vascularity and mitotic index than either concurrent RT-SOR or RT alone. In conclusion, sequential RT-SOR demonstrates greater efficacy against HCC than concurrent RT-SOR both in vitro and in vivo. These results may have implications for clinical decision-making and prospective trial design.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Concurrent versus Sequential Sorafenib Therapy in Combination with Radiation for Hepatocellular Carcinoma

et al. 2013

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“…Tyrosine kinase inhibitors are crucial in systemic treatment of HCC as they hinder tumor progression and improve overall survival rate [9]. Some studies have concluded that sorafenib also may enhance tumor sensitivity to radiotherapy [10]. Patients with metastases from HCC can benefit from radiotherapy in terms of prolonged survival [11].…”

Section: Discussionmentioning

confidence: 99%

Multidisciplinary Treatment of Advanced Hepatocellular Carcinoma

Yang

Abdrakhimov

Wang

et al. 2020

Case Rep Gastroenterol

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Current strategy for treatment of hepatocellular carcinoma (HCC) based on Barcelona-Clinic Liver Cancer (BCLC) criteria dictates that patients with advanced-stage HCC are to only receive treatment with tyrosine kinase inhibitors. However, they prolong overall survival just by slightly more than 6 months. In this article, we present a patient with HCC diagnosed at an advanced stage who received multidisciplinary treatment consisting of transarterial chemoembolization, hepatic resection, pulmonary resection, radiofrequency ablation, tyrosine kinase inhibitors, and radiotherapy, and has survived for more than 2 years since diagnosis and counting.

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“…These results suggest that inhibition of NF-κB activation and the expression of its downstream proteins by pretreatment of sorafenib may increase TSA-induced apoptosis and cell death. A previous study suggested that the radiosensitivity of HCC cells may be modulated by sorafenib in a schedule-dependent manner (28). Furthermore, concurrent treatment with radiation and sorafenib and pre-treatment of sorafenib were reported to improve the sensitizing enhancement ratio for human SMMC-7721 and SK-HEP-1 HCC cell lines, respectively (29).…”

Section: Discussionmentioning

confidence: 99%

Enhanced cytotoxicity of human hepatocellular carcinoma cells following pretreatment with sorafenib combined with trichostatin A

Chen¹,

Chuang²,

Liao

et al. 2018

Oncol Lett

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Trichostatin A (TSA), a hydroxamate histone deacetylase inhibitor, is a compound that has been identified to induce anticancer activity. The aim of the present study was to investigate whether sorafenib, in combination with TSA, was able to augment the anticancer effects of TSA, identifying an optimum treatment time plan and the potential underlying molecular mechanisms involved in human hepatocellular carcinoma (HCC) in vitro. Huh7/nuclear factor-κB (NF-κB)-luc2 cells were treated with TSA or sorafenib alone, or sorafenib, prior to, in combination with or following TSA treatment. Huh7/NF-κB-luc2 cell viability following TSA treatment was determined using an MTT assay, and NF-κB activity was analyzed. In addition, the expression levels of NF-κB-regulated downstream effector proteins were assayed by western blotting. Inhibitors of mitogen-activated protein kinases (MAPKs), protein kinase B (AKT) and mutant inhibitor of NF-κBα (IκBαM) vectors were used to confirm the function of the NF-κB signal transduction pathways in response to the effects of sorafenib combined with TSA against HCC. The results of the present study indicated that pre-treatment with sorafenib followed by TSA inhibited the cell viability compared with other treatment modalities, and prevented TSA-induced extracellular-signal-regulated kinase (ERK)/NF-κB activity and expression of downstream effector proteins. It was further demonstrated that IκBαM vector sensitized Huh7/NF-κB-luc2 cells to TSA, thus it was possible to reverse TSA-induced NF-κB activity using PD98059, a MAPK/ERK kinase inhibitor. In conclusion, sorafenib pre-treatment may increase the efficacy of subsequent TSA treatment in HCC. Furthermore, sorafenib pre-treatment is hypothesized to sensitize HCC to TSA via the inhibition of the MEK/ERK/NF-κB signal transduction pathway.

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Sorafenib modulates the radio sensitivity of hepatocellular carcinoma cells in vitro in a schedule-dependent manner

Cited by 23 publications

References 22 publications

Concurrent versus Sequential Sorafenib Therapy in Combination with Radiation for Hepatocellular Carcinoma

Concurrent versus Sequential Sorafenib Therapy in Combination with Radiation for Hepatocellular Carcinoma

Multidisciplinary Treatment of Advanced Hepatocellular Carcinoma

Enhanced cytotoxicity of human hepatocellular carcinoma cells following pretreatment with sorafenib combined with trichostatin A

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