Disturbance of redox status enhances radiosensitivity of hepatocellular carcinoma

Sun, Chuan Zheng; Liu, X.; Liu, Y.; Zhang, H.

doi:10.1016/s0959-8049(17)30342-8

Cited by 11 publications

(11 citation statements)

References 48 publications

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“…In a non-small lung cancer, genetic modulation of NRF2 levels affects radiation sensitivity and NRF2 knockdown potentiates radiation-induced apoptosis 51 , 52 , which is well consistent with our results. Similar findings were also seen in various cancers including prostate 53 , 54 , squamous cell lung cancer 55 , hepatocellular carcinoma 56 and glioblastoma cells 57 . A recent study on squamous cell lung cancer patients revealed that NRF2 status is a predictive marker of local recurrence after radiation therapy 58 .…”

Section: Discussionsupporting

confidence: 75%

Valproic Acid Sensitizes Hepatocellular Carcinoma Cells to Proton Therapy by Suppressing NRF2 Activation

Choi

Shin

et al. 2017

Sci Rep

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Although efficacy of combined histone deacetylase (HDAC) inhibitors and conventional photon radiotherapy is being tested in clinical trials, their combined effect with proton beam radiotherapy has yet to be determined. Here, we compared combined effect of valproic acid (VPA), a class I and II HDAC inhibitor and antiepileptic drug with proton and photon irradiation in hepatocellular carcinoma (HCC) cells in vitro and in vivo. We found that VPA sensitized more Hep3B cells to proton than to photon irradiation. VPA prolonged proton-induced DNA damage and augmented proton-induced apoptosis. In addition, VPA further increased proton-induced production of intracellular reactive oxygen species and suppressed expression of nuclear factor erythroid-2-related factor 2 (NRF2), a key transcription factor regulating antioxidant response. Downregulation of NRF2 by siRNA transfection increased proton-induced apoptotic cell death, supporting NRF2 as a target of VPA in radiosensitization. In Hep3B tumor xenograft models, VPA significantly enhanced proton-induced tumor growth delay with increased apoptosis and decreased NRF2 expression in vivo. Collectively, our study highlights a proton radiosensitizing effect of VPA in HCC cells. As NRF2 is an emerging prognostic marker contributing to radioresistance in HCC, targeting NRF2 pathway may impact clinical outcome of proton beam radiotherapy.

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Section: Discussionsupporting

confidence: 75%

Valproic Acid Sensitizes Hepatocellular Carcinoma Cells to Proton Therapy by Suppressing NRF2 Activation

Choi

Shin

et al. 2017

Sci Rep

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“…This supports elevation of oxidative stress as a potential mechanism underlying cell death triggered by necroptosis. These findings are supported by studies showing that ISLQ treatment induced redox imbalance and increased oxidative stress in HepG2 hepatocellular carcinoma cells [62] and in HeLa cells [63]. Moreover, dietary flavonoids, including ISLQ, have been shown to be metabolized to pro-oxidant radicals [64].…”

Section: Discussionmentioning

confidence: 62%

The dietary flavonoid isoliquiritigenin is a potent cytotoxin for human neuroblastoma cells

et al. 2019

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Neuroblastoma (NB) is the most common extracranial solid tumor of early childhood; it accounts for approximately 8-10% of all childhood cancers and is the most common cancer in children in the first year of life. Patients in the high-risk group have a poor prognosis, with relapses being common and often refractory to drug treatment in those that survive. Moreover, the drug treatment itself can lead to a range of long-term sequelae. Therefore, there is a critical need to identify new therapeutics for NB. Isoliquiritigenin (ISLQ) is a naturally-occurring, dietary chalcone-type flavonoid with a range of biological effects that depend on the cell type and context. ISLQ has potential as an anticancer agent. Here we show that ISLQ has potent cytotoxic effects on SK-N-BE(2) and IMR-32 human NB cells, which carry amplification of the MYCN gene, the main prognostic marker of poor survival in NB. ISLQ was found to increase cellular reactive oxygen species (ROS). The cytotoxic effect of ISLQ was blocked by small molecule inhibitors of oxidative stress-induced cell death, and by the antioxidant N-acetyl-L-cysteine (NAC). Combined treatment of either SK-N-B-E(2) or IMR-32 cells with ISLQ and the anticancer agent cisplatin resulted in loss of cell viability that was greater than that induced by cisplatin alone. This study provides proof-of-principle that ISLQ is a potent cytotoxin for MYCN-amplified human NB cells. This is an important first step in rationalizing the further study of ISLQ as a potential adjunct therapy for high-risk NB.

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“…Detection of apoptosis. Quantification of apoptosis at the single cell level was as described previously by a combination of flow cytometry with classical Annexin V/PI staining using the Annexin V-FITC Apoptosis Detection Kit (Invitrogen) 47.…”

Section: Methodsmentioning

confidence: 99%

Endocytosis-mediated mitochondrial transplantation: Transferring normal human astrocytic mitochondria into glioma cells rescues aerobic respiration and enhances radiosensitivity

et al. 2019

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Emerging evidence indicates that reprogramming of energy metabolism involving disturbances in energy production from a defect in cellular respiration with a shift to glycolysis is a core hallmark of cancer. Alterations in cancer cell energy metabolism are linked to abnormalities in mitochondrial function. Mitochondrial dysfunction of cancer cells includes increased glycolysis, decreased apoptosis, and resistance to radiotherapy. The study was designed for two main points: firstly, to investigate whether exogenous functional mitochondria can transfer into glioma cells and explore the underlying molecular mechanisms from the perspective of endocytosis; secondly, to further verify whether the mitochondrial transplantation is able to rescue aerobic respiration, attenuate the Warburg effect and enhance the radiosensitivity of gliomas. Methods: Mitochondria were isolated from normal human astrocytes (HA) and immediately co-incubated with starved human glioma cells (U87). Confocal microscopy and gene sequencing were performed to evaluate the ability of isolated mitochondria internalization into U87 cells. The interaction between endocytosis and isolated mitochondria transfer were captured by 3D tomographic microscopy and transmission electron microscopy. NAD + , CD38, cADPR and Ca 2+ release were determined by commercial kits, western blot, HLPC-MS and Fluo-3 AM respectively. PCR array expression profiling and Seahorse XF analysis were used to evaluate the effect of mitochondrial transplantation on energy phenotypes of U87 cells. U87 cells and U87 xenografts were both treated with mitochondrial transplantation, radiation, or a combination of mitochondrial transplantation and radiation. Apoptosis in vitro and in vivo were detected by cytochrome C, cleaved caspase 9 and TUNEL staining. Results: We found that mitochondria from HA could be transferred into starved U87 cells by simple co-incubation. Starvation treatment slowed the rate of glycolysis and decreased the transformation of NAD + to NADH in U87 cells. A large amount of accumulated NAD + was released into the extracellular space. CD38 is a member of the NAD + glycohydrolase family that catalyzes the cyclization of extracellular NAD + to intracellular cADPR. cADPR triggered release of Ca 2+ to promote cytoskeleton remodeling and plasma membrane invagination. Thus, endocytosis involving isolated mitochondria internalization was mediated by NAD + -CD38-cADPR-Ca 2+ signaling. Mitochondrial transfer enhanced gene and protein expression related to the tricarboxylic acid (TCA) cycle, increased aerobic respiration, attenuated glycolysis, reactivated the mitochondrial apoptotic pathway, inhibited malignant proliferation of U87 cells. Isolated mitochondria injected into U87...

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Disturbance of redox status enhances radiosensitivity of hepatocellular carcinoma

Cited by 11 publications

References 48 publications

Valproic Acid Sensitizes Hepatocellular Carcinoma Cells to Proton Therapy by Suppressing NRF2 Activation

Valproic Acid Sensitizes Hepatocellular Carcinoma Cells to Proton Therapy by Suppressing NRF2 Activation

The dietary flavonoid isoliquiritigenin is a potent cytotoxin for human neuroblastoma cells

Endocytosis-mediated mitochondrial transplantation: Transferring normal human astrocytic mitochondria into glioma cells rescues aerobic respiration and enhances radiosensitivity

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