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

Yu, Jeong Il; Choi, Changhoon; Shin, Sarah J.; Son, Arang; Lee, Ga-Haeng; Kim, Shin‐Yeong; Park, Hee Chul

doi:10.1038/s41598-017-15165-3

Cited by 37 publications

(40 citation statements)

References 63 publications

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“…The complex was visualized using diaminobenzidine (DAB). The nuclei were lightly stained with Mayer’s hematoxylin [ 37 , 38 ]. We used Image J program to scan the stained slides.…”

Section: Methodsmentioning

confidence: 99%

Effect of a Synbiotic Containing Lactobacillus paracasei and Opuntia humifusa on a Murine Model of Irritable Bowel Syndrome

Seong

Lee

et al. 2020

Nutrients

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The administration of a combination of probiotics and prebiotics is expected to be a promising strategy for improving irritable bowel syndrome (IBS) symptoms. This study aimed to investigate the efficacy of a synbiotic containing Lactobacillus paracasei and Opuntia humifusa extract for symptomatic improvement of IBS in a murine model and to evaluate the mechanism underlying the beneficial effects of this synbiotic. A total of 20 male Wistar rats aged 8 weeks with IBS induced by restraint stress were assigned into four groups and administered L. paracasei as a probiotic and O. humifusa extract as a prebiotic for 4 weeks. The primary outcome was stool consistency at week 4. To evaluate the mechanism underlying the beneficial effects of the synbiotic, fecal microbial analysis was conducted, and the serum corticosterone levels, tumor necrosis factor-α (TNF-α) levels in the colon tissue, and expression of tight junction proteins were investigated. All three treatment groups showed significantly lower scores for stool consistency than the control group at week 4 (all p < 0.001). When compared with the control group, the synbiotic groups showed a significantly greater abundance of L. paracasei in fecal microbial analysis, lower serum corticosterone levels, lower TNF-α levels in the colon tissue, and higher expression of tight junction proteins. This novel synbiotic containing L. paracasei and O. humifusa extract can improve the stool consistency in a murine model of IBS. It may be a promising treatment option for IBS, and human studies are warranted.

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“…The complex was visualized using diaminobenzidine (DAB). The nuclei were lightly stained with Mayer’s hematoxylin [ 37 , 38 ]. We used Image J program to scan the stained slides.…”

Section: Methodsmentioning

confidence: 99%

Effect of a Synbiotic Containing Lactobacillus paracasei and Opuntia humifusa on a Murine Model of Irritable Bowel Syndrome

Seong

Lee

et al. 2020

Nutrients

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“…For proton irradiation, cell plates were positioned in the center of the spread-out Bragg peak (SOBP) measuring 11.2 cm within a field collimated by 18 × 12 cm Brass blocks. Cells were irradiated with graded doses of 230 MeV protons, for which the beam range was 22.8 cm (distal 90%) [35]. The absolute proton beam dose was verified to an accuracy of 1% for proton therapy, in accordance with TRS-398.…”

Section: Irradiation Experimentsmentioning

confidence: 99%

Checkpoint Kinase 1 (CHK1) Inhibition Enhances the Sensitivity of Triple-Negative Breast Cancer Cells to Proton Irradiation via Rad51 Downregulation

Choi

Cho

Park

et al. 2020

IJMS

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Due to a superior dose conformity to the target, proton beam therapy (PBT) continues to rise in popularity. Recently, considerable efforts have been directed toward discovering treatment options for use in combination with PBT. This study aimed to investigate the targeting of checkpoint kinase 1 (CHK1), a critical player regulating the G2/M checkpoint, as a promising strategy to potentiate PBT in human triple-negative breast cancer (TNBC) cells. Protons induced cell-cycle arrest at the G2/M checkpoint more readily in response to increased CHK1 activation than X-rays. A clonogenic survival assay revealed that CHK1 inhibition using PF-477736 or small interfering RNA (siRNA) enhanced the sensitivity toward protons to a greater extent than toward X-rays. Western blotting demonstrated that PF-477736 treatment in the background of proton irradiation increased the pro-apoptotic signaling, which was further supported by flow cytometry using annexin V. Immunofluorescence revealed that proton-induced DNA double-strand breaks (DSBs) were further enhanced by PF-477736, which was linked to the downregulation of Rad51, essential for the homologous recombination repair of DSBs. Direct inactivation of Rad51 resulted in enhanced proton sensitization. Collectively, these data suggest that targeting CHK1 may be a promising approach for improving PBT efficacy in the treatment of TNBC.

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“…In orthotopic and ectopic xenograft models, this combination treatment reduced tumor growth. In addition, combining VPA with the effect of photon radiotherapy prolonged proton-induced DNA damage, augmented proton-induced apoptosis, increased the proton-induced production of intracellular reactive oxygen species, and suppressed the expression of nuclear factor erythroid-2-related factor 2 (NRF2), which is a key transcription factor regulating the antioxidant response [ 83 ].…”

Section: Hdac Inhibitors As Clinical Trail Of Hccmentioning

confidence: 99%

Modification of Epigenetic Histone Acetylation in Hepatocellular Carcinoma

Liu

Wang

Hsu

2018

Cancers

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Cells respond to various environmental factors such as nutrients, food intake, and drugs or toxins by undergoing dynamic epigenetic changes. An imbalance in dynamic epigenetic changes is one of the major causes of disease, oncogenic activities, and immunosuppressive effects. The aryl hydrocarbon receptor (AHR) is a unique cellular chemical sensor present in most organs, and its dysregulation has been demonstrated in multiple stages of tumor progression in humans and experimental models; however, the effects of the pathogenic mechanisms of AHR on epigenetic regulation remain unclear. Apart from proto-oncogene activation, epigenetic repressions of tumor suppressor genes are involved in tumor initiation, procession, and metastasis. Reverse epigenetic repression of the tumor suppressor genes by epigenetic enzyme activity inhibition and epigenetic enzyme level manipulation is a potential path for tumor therapy. Current evidence and our recent work on deacetylation of histones on tumor-suppressive genes suggest that histone deacetylase (HDAC) is involved in tumor formation and progression, and treating hepatocellular carcinoma with HDAC inhibitors can, at least partially, repress tumor proliferation and transformation by recusing the expression of tumor-suppressive genes such as TP53 and RB1.

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

Cited by 37 publications

References 63 publications

Effect of a Synbiotic Containing Lactobacillus paracasei and Opuntia humifusa on a Murine Model of Irritable Bowel Syndrome

Effect of a Synbiotic Containing Lactobacillus paracasei and Opuntia humifusa on a Murine Model of Irritable Bowel Syndrome

Checkpoint Kinase 1 (CHK1) Inhibition Enhances the Sensitivity of Triple-Negative Breast Cancer Cells to Proton Irradiation via Rad51 Downregulation

Modification of Epigenetic Histone Acetylation in Hepatocellular Carcinoma

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