Targeting the correct target in HCC

Berasain, Carmen; Lechel, André

doi:10.1136/gutjnl-2016-313462

Cited by 10 publications

(5 citation statements)

References 11 publications

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“…Hepatocellular carcinoma (HCC) is one of the commonest malignancies in the world and the second leading cause of cancer-related death [1][2][3]. However, the response of advanced HCC to current clinical treatment is poor, mainly because of resistance to chemotherapeutic agents [4]. There-fore, the mechanism of HCC drug resistance and strategies to prevent or reverse the resistance deserves investigation.…”

Section: Introductionmentioning

confidence: 99%

BEZ235 Increases the Sensitivity of Hepatocellular Carcinoma to Sorafenib by Inhibiting PI3K/AKT/mTOR and Inducing Autophagy

Cao

Liu

Zhang

et al. 2021

BioMed Research International

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Acquired resistance of hepatocellular carcinoma (HCC) to sorafenib (SFB) is the main reason for the failure of SFB treatment of the cancer. Abnormal activation of the PI3K/AKT/mTOR pathway is important in the acquired resistance of SFB. Therefore, we investigated whether BEZ235 (BEZ) could reverse acquired sorafenib resistance by targeting the PI3K/mTOR pathway. A sorafenib-resistant HCC cell line Huh7R was established. MTT assay, clone formation assay, flow cytometry, and immunofluorescence were used to analyze the effects of BEZ235 alone or combined with sorafenib on cell proliferation, cell cycle, apoptosis, and autophagy of Huh7 and Huh7R cells. The antitumor effect was evaluated in animal models of Huh7R xenografts in vivo. Western blot was used to detect protein levels of the PI3K/AKT/mTOR pathway and related effector molecules. In vitro results showed that the Huh7R had a stronger proliferation ability and antiapoptosis effect than did Huh7, and sorafenib had no inhibitory effect on Huh7R. SFB + BEZ inhibited the activation of the PI3K/AKT/mTOR pathway caused by sorafenib. Moreover, SFB + BEZ inhibited the proliferation and cloning ability, blocked the cell cycle in the G0/G1 phase, and promoted apoptosis in the two cell lines. The autophagy level in Huh7R cells was higher than in Huh7 cells, and BEZ or SFB + BEZ further promoted autophagy in the two cell lines. In vivo, SFB + BEZ inhibited tumor growth by inducing apoptosis and autophagy. We concluded that BEZ235 enhanced the sensitivity of sorafenib through suppressing the PI3K/AKT/mTOR pathway and inducing autophagy. These observations may provide the experimental basis for sorafenib combined with BEZ235 in trial treatment of HCC.

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Section: Introductionmentioning

confidence: 99%

BEZ235 Increases the Sensitivity of Hepatocellular Carcinoma to Sorafenib by Inhibiting PI3K/AKT/mTOR and Inducing Autophagy

Cao

Liu

Zhang

et al. 2021

BioMed Research International

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“…However, achieving tumor accumulation and intratumoral penetration with nano-sized drug delivery systems poses significant challenges due to their contradictory requirements. [46,55] On one hand, small-sized nanodrugs possess great advantages in extravasating the leaky vasculature and penetrating the heterogeneous tissue of solid tumors, thus being favorable for improving the therapeutic effect. For instance, while the ideal particle size for tumor accumulation is under 100 nm, nanodrugs smaller than 30 nm are necessary for efficient penetration in tumor tissue, notably in poorly permeable hypovascular tumors such as pancreatic cancer and hepatocellular carcinoma.…”

Section: Discussionmentioning

confidence: 99%

Twins‐like nanodrugs synchronously transport in blood and coalesce inside tumors for sensitive ultrasound imaging and triggerable penetrative drug delivery

Cai,

Chen,

Lin

et al. 2024

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Nanodrugs capable of aggregating in the tumor microenvironment (TME) have demonstrated great efficiency in improving the therapeutic outcome. Among various approaches, the strategy utilizing electrostatic interaction as a driving force to achieve intratumor aggregation of nanodrugs has attracted great attention. However, the great difference between the two nanodrugs with varied physicochemical properties makes their synchronous transport in blood circulation and equal‐opportunity tumor uptake impossible, which significantly detracts from the beneficial effects of nanodrug aggregation inside tumors. We herein propose a new strategy to construct a pair of extremely similar nanodrugs, referred to as “twins‐like nanodrugs (TLNs)”, which have identical physicochemical properties including the same morphology, size, and electroneutrality to render them the same blood circulation time and tumor entrance. The 1:1 mixture of TLNs (TLNs‐Mix) intravenously injected into a mouse model efficiently accumulates in tumor sites and then transfers to oppositely charged nanodrugs for electrostatic interaction‐driven coalescence via responding to matrix metalloproteinase‐2 (MMP‐2) enriched in tumor. In addition to enhanced tumor retention, the thus‐formed micron‐sized aggregates show high echo intensity essential for ultrasound imaging as well as ultrasound‐triggered penetrative drug delivery. Owing to their distinctive features, the TLNs‐Mix carrying sonosensitizer, immune adjuvant, and ultrasound contrast agent exert potent sonodynamic immunotherapy against hypovascular hepatoma, demonstrating their great potential in treating solid malignancies.

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“…Moreover, HBx was recently shown to hijack the cellular DDB1-containing E3 ubiquitin ligase to target the Smc complex Smc5/6 for degradation, which, in turn, facilitates HBV replication (Murphy et al, 2016). As a key viral regulatory protein known to play a central role in HBV infection, replication, pathogenesis, and, possibly, carcinogenesis (Murakami, 2001), HBx is essential for maximal HBV replication and development of HCC (Berasain and Lechel, 2017;Keasler et al, 2007). HBV X region mutations were shown to be associated with clinical severity (Yeh et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Type-I-IFN-Stimulated Gene TRIM5γ Inhibits HBV Replication by Promoting HBx Degradation

Tan

Song

et al. 2019

Cell Reports

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To understand the molecular mechanisms that mediate the anti-hepatitis B virus (HBV) effect of interferon (IFN) therapy, we conduct highthroughput bimolecular fluorescence complementation screening to identify potential physical interactions between the HBx protein and 145 IFNstimulated genes (ISGs). Seven HBx-interacting ISGs have consistent and significant inhibitory effects on HBV replication, among which TRIM5g suppresses HBV replication by promoting K48-linked ubiquitination and degradation of the HBx protein on the K95 ubiquitin site. The B-Box domain of TRIM5g under overexpression conditions is sufficient to trigger HBx degradation and is responsible both for interacting with HBx and recruiting TRIM31, which is an ubiquitin ligase that triggers HBx ubiquitination. High expression levels of TRIM5g in IFN-a-treated HBV patients might indicate a better therapeutic effect. Thus, our studies identify a crucial role for TRIM5g and TRIM31 in promoting HBx degradation, which may facilitate the development of therapeutic agents for the treatment of patients with IFN-resistant HBV infection.

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Targeting the correct target in HCC

Cited by 10 publications

References 11 publications

BEZ235 Increases the Sensitivity of Hepatocellular Carcinoma to Sorafenib by Inhibiting PI3K/AKT/mTOR and Inducing Autophagy

BEZ235 Increases the Sensitivity of Hepatocellular Carcinoma to Sorafenib by Inhibiting PI3K/AKT/mTOR and Inducing Autophagy

Twins‐like nanodrugs synchronously transport in blood and coalesce inside tumors for sensitive ultrasound imaging and triggerable penetrative drug delivery

Type-I-IFN-Stimulated Gene TRIM5γ Inhibits HBV Replication by Promoting HBx Degradation

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