Synergistic Antitumor Effect of Sorafenib in Combination with ATM Inhibitor in Hepatocellular Carcinoma Cells

Liu, Jianhua; Liu, Yahui; Meng, Lingyu; Ji, Bing; Yang, Daping

doi:10.7150/ijms.19033

Cited by 25 publications

(15 citation statements)

References 20 publications

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“…The dose response curves of Sora in HepG2 and Huh7 cells were similar to those reported previously, with IC 50 values of 5.93–8.51 (mean 7.10) µM in HepG2 and 7.11–17.11 (mean 11.03) µM in Huh7 cells (Fig. 1; Table I) (20,21). It has been reported that the maximum drug concentration of Art in human plasma is 3,260 (1,020–164,000) ng/ml [8.48 (2.65–427.08) µM] and the terminal elimination half-life is 0.25 (0.1–1.8) h (22).…”

Section: Resultssupporting

confidence: 87%

Artesunate and sorafenib: Combinatorial inhibition of liver cancer cell growth

Pian

et al. 2019

Oncol Lett

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An antimalarial medication, artesunate (Art), has exhibited promising anticancer effects with excellent tolerability in various types of cancer, suggesting that it has the potential to be used in combination with sorafenib (Sora) in hepatocellular carcinoma (HCC) treatment. To determine the potency of this combination, the present study attempted to quantitatively measure the dose-effect relationship of each drug alone and in combination in liver cancer cells in vitro using Calcusyn software. Cell growth inhibition was determined using the CyQUANT proliferation assay in two liver cancer cell lines, HepG2 and Huh7. Drug combination and reduction indices and isobologram plots were used to assess drug interactions. Cell apoptosis was evaluated by measurements of the proportion of cells in the sub G0/G1 phase of the cell cycle, and determination of protein expression levels of cleaved poly ADP ribose polymerase and caspase-9. Additionally, a cell migration assay was conducted using Essen ImageLock plates with an IncuCyte Zoom imaging system. The results of the present study revealed that the inhibitory effect of Sora on cell growth was synergistically enhanced by the combination with Art in HepG2 and Huh7 cells. The combination index and dose reduction index were specific to each cell line. Furthermore, combination at a fixed ratio presented mutual enhancement with respect to apoptosis induction and suppression of in vitro liver cancer cell migration. Therefore, considering the low toxicity and well-defined clinical characteristics of Art, combination of Sora and Art may present an attractive therapeutic option in the development of clinical trials for HCC treatment.

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Section: Resultssupporting

confidence: 87%

Artesunate and sorafenib: Combinatorial inhibition of liver cancer cell growth

Pian

et al. 2019

Oncol Lett

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“…CADMN after 72 h of treatment exhibits a significant cytotoxic effect against HepG2 hepatocellular carcinoma cells with IC 50 17.1 ± 0.592 μM, which is comparable to the positive control 5-FU (IC 50 14.6 ± μM). Previous studies have reported the antiproliferative effects of other chemotherapeutic agents such as sorafenib, a targeted therapy for HCC, and revealed that sorafenib inhibits HepG2 cells with an IC 50 between 7.4 and 2 μM [ 28 , 29 ], which is much lower than that of CADMN and 5-FU.…”

Section: Discussionmentioning

confidence: 99%

Antiproliferative and Apoptotic Effects of Cardamonin against Hepatocellular Carcinoma HepG2 Cells

2020

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Liver cancer is the sixth most common cancer in terms of incidence and the fourth in terms of mortality. Hepatocellular carcinoma (HCC) represents almost 90% of primary liver cancer and has become a major health problem globally. Cardamonin (CADMN) is a natural bioactive chalcone found in several edible plants such as cardamom and Alpinia species. Previous studies have shown that CADMN possesses anticancer activities against breast, lung, prostate and colorectal cancer. In the present study, the mechanisms underlying the anti-hepatocellular carcinoma effects of CADMN were investigated against HepG2 cells. The results demonstrated that CADMN has anti-proliferative effects and apoptotic action on HepG2 cells. CADMN showed potent cytotoxicity against HepG2 cells with an IC50 of 17.1 ± 0.592 μM at 72 h. Flow cytometry analysis demonstrated that CADMN arrests HepG2 cells in G1 phase and induces a significant increase in early and late apoptosis in a time-dependent manner. The mechanism by which CADMN induces apoptotic action was via activation of both extrinsic and intrinsic pathways. Moreover, the findings of this study showed the involvement of reactive oxygen species (ROS), which inhibit the NF-κB pathway and further enhance the apoptotic process. Together, our findings further support the potential anticancer activity of CADMN as an alternative therapeutic agent against HCC.

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“…Sorafenib is the only anticancer drug approved by the FDA for advanced HCC (32,33). However, its anticancer efficacy is poor (34). Ubiquitin proteasome system (UPS) participates in a wide variety of biological processes which include cell cycle, cell proliferation, signal transduction, DNA repair and apoptosis (35).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of neddylation modification by MLN4924 sensitizes hepatocellular carcinoma cells to sorafenib

et al. 2019

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Sorafenib remains the standard care for patients with hepatocellular carcinoma (HCC) even though it has low antitumor efficacy. Protein neddylation is abnormally activated in many types of human cancer. However, whether dysregulation of neddylation is involved in HCC progression and whether targeting neddylation sensitizes HCC cells to sorafenib need to be ascertained. In the present study, it was demonstrated that high expression of neddylation components, neural precursor cell expressed, developmentally downregulated 8 (NEDD8) and NEDD8-activating enzyme 1 (NAE1), were associated with poor survival of patients with HCC. Inhibition of neddylation by MLN4924, a small-molecule inhibitor of NAE1, significantly inhibited HCC growth, reduced clonogenic survival, increased apoptosis, and decreased migration capacity. Sorafenib alone exhibited minimal anticancer efficacy. However, a combination of sorafenib with MLN4924 at a low concentration significantly enhanced the inhibition of cell proliferation and migration as well as the induction of apoptosis induced by sorafenib. In vivo HCC xenograft mouse models also showed that MLN4924 increased the antitumor efficacy of sorafenib. Mechanistically, MLN4924 enhanced the antitumor activity of sorafenib in HCC cells via upregulation of cullin-RING E3 ubiquitin ligase (CRL)/Skp1-Cullin1-F box (SCF) E3 ubiquitin ligase substrates p21, p27, Deptor and IκBɑ. Taken together, these findings suggest that combination therapy of MLN4924 with sorafenib appears to present an additive effect with a maximal in the treatment of HCC.

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Synergistic Antitumor Effect of Sorafenib in Combination with ATM Inhibitor in Hepatocellular Carcinoma Cells

Cited by 25 publications

References 20 publications

Artesunate and sorafenib: Combinatorial inhibition of liver cancer cell growth

Artesunate and sorafenib: Combinatorial inhibition of liver cancer cell growth

Antiproliferative and Apoptotic Effects of Cardamonin against Hepatocellular Carcinoma HepG2 Cells

Inhibition of neddylation modification by MLN4924 sensitizes hepatocellular carcinoma cells to sorafenib

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