Valproic Acid: A Promising Therapeutic Agent in Glioma Treatment

Frontiers in Oncology ◽

10.3389/fonc.2021.687362 ◽

2021 ◽

Vol 11 ◽

Author(s):

Wei Han ◽

Wei Guan

Keyword(s):

Valproic Acid ◽

Histone Deacetylase Inhibitors ◽

Therapeutic Agent ◽

Treatment Resistance ◽

Progression Free Survival ◽

Inhibitory Effects ◽

Free Survival ◽

Underlying Mechanisms

Glioma, characterized by infiltrative growth and treatment resistance, is regarded as the most prevalent intracranial malignant tumor. Due to its poor prognosis, accumulating investigation has been performed for improvement of overall survival (OS) and progression-free survival (PFS) in glioma patients. Valproic acid (VPA), one of the most common histone deacetylase inhibitors (HDACIs), has been detected to directly or synergistically exert inhibitory effects on glioma in vitro and in vivo. In this review, we generalize the latest advances of VPA in treating glioma and its underlying mechanisms and clinical implications, providing a clearer profile for clinical application of VPA as a therapeutic agent for glioma.

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EXTH-71. CYTOSTATIC HYPOTHERMIA FOR GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa215.425 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii102-ii103

Author(s):

Syed Faaiz Enam ◽

Jianxi Huang ◽

Cem Kilic ◽

Connor Tribble ◽

Martha Betancur ◽

...

Keyword(s):

Tumor Recurrence ◽

Progression Free Survival ◽

Rodent Model ◽

Behavioral Alterations ◽

Free Survival ◽

Tumor Bearing ◽

Car T ◽

The Brain

Abstract As a cancer therapy, hypothermia has been used at sub-zero temperatures to cryosurgically ablate tumors. However, these temperatures can indiscriminately damage both tumorous and healthy cells. Additionally, strategies designed to kill tumor typically accelerate their evolution and recurrence can be inevitable in cancers such as glioblastoma (GBM). To bypass these limitations, here we studied the use of hypothermia as a cytostatic tool against cancer and deployed it against an aggressive rodent model of GBM. To identify the minimal dosage of ‘cytostatic hypothermia’, we cultured at least 4 GBM lines at 4 continuous or intermittent degrees of hypothermia and evaluated their growth rates through a custom imaging-based assay. This revealed cell-specific sensitivities to hypothermia. Subsequently, we examined the effects of cytostatic hypothermia on these cells by a cursory study of their cell-cycle, energy metabolism, and protein synthesis. Next, we investigated the use of cytostatic hypothermia as an adjuvant to chemotherapy and CAR T immunotherapy. Our studies demonstrated that cytostatic hypothermia did not interfere with Temozolomide in vitro and may have been synergistic against at least 1 GBM line. Interestingly, we also demonstrated that CAR T immunotherapy can function under cytostatic hypothermia. To assess the efficacy of hypothermia in vivo, we report the design of an implantable device to focally administer cytostatic hypothermia in an aggressive rodent model of F98 GBM. Cytostatic hypothermia significantly doubled the median survival of tumor-bearing rats with no obvious signs of distress. The absence of gross behavioral alterations is in concurrence with literature suggesting the brain is naturally resilient to focal hypothermia. Based on these findings, we anticipate that focally administered cytostatic hypothermia alone has the potential to delay tumor recurrence or increase progression-free survival in patients. Additionally, it could also provide more time to evaluate concomitant, curative cytotoxic treatments.

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Deregulation of Exo70 Facilitates Innate and Acquired Cisplatin Resistance in Epithelial Ovarian Cancer by Promoting Cisplatin Efflux

Cancers ◽

10.3390/cancers13143467 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3467

Author(s):

Yujie Zhao ◽

Xiaoting Hong ◽

Xiong Chen ◽

Chun Hu ◽

Weihong Lu ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Cisplatin Resistance ◽

Progression Free Survival ◽

Platinum Resistance ◽

Lysosomal Degradation ◽

Free Survival ◽

Cisplatin Sensitivity

Whilst researches elucidating a diversity of intracellular mechanisms, platinum-resistant epithelial ovarian cancer (EOC) remains a major challenge in the treatment of ovarian cancer. Here we report that Exo70, a key subunit of the exocyst complex, contributes to both innate and acquired cisplatin resistance of EOC. Upregulation of Exo70 is observed in EOC tissues and is related to platinum resistance and progression-free survival of EOC patients. Exo70 suppressed the cisplatin sensitivity of EOC cells through promoting exocytosis-mediated efflux of cisplatin. Moreover, cisplatin-induced autophagy-lysosomal degradation of Exo70 protein by modulating phosphorylation of AMPK and mTOR, thereby reducing the cellular resistance. However, the function was hampered during prolonged cisplatin treatment, which in turn stabilized Exo70 to facilitate the acquired cisplatin resistance of EOC cells. Knockdown of Exo70, or inhibiting exocytosis by Exo70 inhibitor Endosidin2, reversed the cisplatin resistance of EOC cells both in vitro and in vivo. Our results suggest that Exo70 overexpression and excessive stability contribute to innate and acquired cisplatin resistance through the increase in cisplatin efflux, and targeting Exo70 might be an approach to overcome cisplatin resistance in EOC treatment.

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The Antitriple Negative Breast cancer Efficacy of Spatholobus suberectus Dunn on ROS-Induced Noncanonical Inflammasome Pyroptotic Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/5187569 ◽

2021 ◽

Vol 2021 ◽

pp. 1-17

Author(s):

Feng Zhang ◽

Qingqing Liu ◽

Kumar Ganesan ◽

Zeng Kewu ◽

Jiangang Shen ◽

...

Keyword(s):

Breast Cancer ◽

Morphological Analysis ◽

Chinese Society ◽

Relapse Free Survival ◽

Free Survival ◽

Release Assay ◽

Spatholobus Suberectus ◽

Underlying Mechanisms

Breast cancer (BCa) is the leading cause of women’s death worldwide; among them, triple-negative breast cancer (TNBC) is one of the most troublesome subtypes with easy recurrence and great aggressive properties. Spatholobus suberectus Dunn has been used in the clinic of Chinese society for hundreds of years. Shreds of evidence showed that Spatholobus suberectus Dunn has a favorable outcome in the management of cancer. However, the anti-TNBC efficacy of Spatholobus suberectus Dunn percolation extract (SSP) and its underlying mechanisms have not been fully elucidated. Hence, the present study is aimed at evaluating the anti-TNBC potential of SSP both in vitro and in vivo, through the cell viability, morphological analysis of MDA-MB-231, LDH release assay, ROS assay, and the tests of GSH aborted pyroptotic noninflammasome signaling pathway. Survival analysis using the KM Plotter and TNM plot database exhibited the inhibition of transcription levels of caspase-4 and 9 related to low relapse-free survival in patients with BCa. Based on the findings, SSP possesses anti-TNBC efficacy that relies on ROS-induced noncanonical inflammasome pyroptosis in cancer cells. In this study, our preclinical evidence is complementary to the preceding clinic of Chinese society; studies on the active principles of SPP remain underway in our laboratory.

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Abemaciclib, A Selective CDK4/6 Inhibitor, Restricts the Growth of Pediatric Ependymomas

Cancers ◽

10.3390/cancers12123597 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3597

Author(s):

Muh-Lii Liang ◽

Chun-Han Chen ◽

Yun-Ru Liu ◽

Man-Hsu Huang ◽

Yu-Chen Lin ◽

...

Keyword(s):

Survival Rates ◽

Progression Free Survival ◽

Rna Seq ◽

New Agents ◽

Free Survival ◽

Pediatric Ependymoma ◽

Rb Phosphorylation

Pediatric ependymomas are a type of malignant brain tumor that occurs in children. The overall 10-year survival rate has been reported as being 45–75%. Maximal safe surgical resection combined with adjuvant chemoradiation therapy is associated with the highest overall and progression-free survival rates. Despite aggressive treatment, one-third of ependymomas exhibit recurrence within 2 years of initial treatment. Therefore, this study aimed to find new agents to overcome chemoresistance and defer radiotherapy treatment since, in addition, radiation exposure may cause long-term side effects in the developing brains of young children. By using integrated bioinformatics and through experimental validation, we found that at least one of the genes CCND1 and CDK4 is overexpressed in ependymomas. The use of abemaciclib, a highly selective CDK4/6 inhibitor, effectively inhibited cell proliferation and reduced the expression of cell-cycle-related and DNA-repair-related gene expression via the suppression of RB phosphorylation, which was determined through RNA-seq and Western blot analyses. Furthermore, abemaciclib effectively induced cell death in vitro. The efficiency of abemaciclib was validated in vivo using subcutaneously implanted ependymoma tissues from patient-derived xenografts (PDXs) in mouse models. Treatment with abemaciclib showed encouraging results in preclinical pediatric ependymoma models and represents a potential therapeutic strategy for treating challenging tumors in children.

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Valproic Acid and Breast Cancer: State of the Art in 2021

Cancers ◽

10.3390/cancers13143409 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3409

Author(s):

Anna Wawruszak ◽

Marta Halasa ◽

Estera Okon ◽

Wirginia Kukula-Koch ◽

Andrzej Stepulak

Keyword(s):

Breast Cancer ◽

Valproic Acid ◽

Histone Deacetylase Inhibitors ◽

Disease Free Survival ◽

Anticonvulsant Drug ◽

Bipolar Disorders ◽

Multi Drug Resistance ◽

Multiple Signaling

Valproic acid (2-propylpentanoic acid, VPA) is a short-chain fatty acid, a member of the group of histone deacetylase inhibitors (HDIs). VPA has been successfully used in the treatment of epilepsy, bipolar disorders, and schizophrenia for over 50 years. Numerous in vitro and in vivo pre-clinical studies suggest that this well-known anticonvulsant drug significantly inhibits cancer cell proliferation by modulating multiple signaling pathways. Breast cancer (BC) is the most common malignancy affecting women worldwide. Despite significant progress in the treatment of BC, serious adverse effects, high toxicity to normal cells, and the occurrence of multi-drug resistance (MDR) still limit the effective therapy of BC patients. Thus, new agents which improve the effectiveness of currently used methods, decrease the emergence of MDR, and increase disease-free survival are highly needed. This review focuses on in vitro and in vivo experimental data on VPA, applied individually or in combination with other anti-cancer agents, in the treatment of different histological subtypes of BC.

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Multiple novel hepatocellular carcinoma signature genes are commonly controlled by the master pluripotency factor OCT4

Cellular Oncology ◽

10.1007/s13402-019-00487-3 ◽

2019 ◽

Vol 43 (2) ◽

pp. 279-295 ◽

Cited By ~ 3

Author(s):

Chao Ye ◽

Xiaoqian Zhang ◽

Xinyu Chen ◽

Qingyi Cao ◽

Xiaobing Zhang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Progression Free Survival ◽

Mrna Levels ◽

Rna Seq ◽

Promoter Regions ◽

Free Survival ◽

Treatment Regimens ◽

Signature Genes

Abstract Background Worldwide, hepatocellular carcinoma (HCC) is a common solid tumor with a poor prognosis. HCC is often due to hepatitis B virus (HBV) infection. As yet, efficacious HCC treatment regimens for late-stage HCC patients are lacking. Therefore, the identification of more specific and sensitive biomarkers for its early diagnosis and treatment remains an urgent need. Methods Total RNAs from paired HBV-derived HCC tumors and adjacent peritumor tissues (APTs) were subjected to RNA sequencing (RNA-seq), and differentially expressed genes (DEGs) between HCC tumors and APTs were selected and verified. Results We identified 166 DEGs and found that eight top-ranked and verified DEGs (TK1, CTTN, CEP72, TRIP13, FTH1, FLAD1, CHRM2, AMBP) all contained putative OCT4 binding motifs in their promoter regions. TK1, TRIP13 and OCT4 were found to exhibit concurrent higher expression levels in HCC tumors than in APTs. The mRNA levels of TK1, TRIP13 and OCT4 in a cohort of 384 HCC samples from the TCGA database were all found to be negatively correlated with patient overall survival, relapse-free survival and progression-free survival, underscoring the HCC biomarker status of TK1 and TRIP13 on one hand, and implicating their association with OCT4 on the other hand. Furthermore, OCT4 proteins were found to bind to the promoters of both genes in vitro and in vivo. Knocking out OCT4 in HCC-derived cell lines reduced the expression of TK1 and TRIP13 and significantly decreased their tumorigenicity. Conclusions Using RNA-seq, we identified several novel HCC signature genes that may serve as biomarkers for its diagnosis and prognosis. Their common transcriptional regulation by OCT4 suggests key roles in the development of HCC, and indicates that OCT4 may serve as a potential therapeutic target.

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miR-497-5p/SALL4 axis promotes stemness phenotype of choriocarcinoma and forms a feedback loop with DNMT-mediated epigenetic regulation

Cell Death and Disease ◽

10.1038/s41419-021-04315-1 ◽

2021 ◽

Vol 12 (11) ◽

Author(s):

Zheng Peng ◽

Yi Zhang ◽

Dazun Shi ◽

Yanyan Jia ◽

Huirong Shi ◽

...

Keyword(s):

Epigenetic Regulation ◽

Feedback Loop ◽

Progression Free Survival ◽

Dna Methyltransferases ◽

Free Survival ◽

Key Factor ◽

Direct Binding ◽

Transcription Factor 4

AbstractChoriocarcinoma stem-like cells (CSLCs) might be at the origin of choriocarcinoma development associated with drug resistance or relapse. Spalt-like transcription factor 4 (SALL4), which is considered to be a stemness-related gene, can be regulated by miRNAs. In this study, SALL4 result is associated with progression-free survival of choriocarcinoma patients and CSLC’s stemness characteristics. In addition, it could be downregulated by miR-497-5p by direct binding. miR-497-5p silencing by hypermethylation promoted malignant CSLC phenotype in vitro and in vivo. Furthermore, increased DNA methyltransferases (DNMTs) by SALL4 upregulation inhibited miR-497-5p expression via hypermethylation promotion. SALL4 appeared to be a key factor in promoting stemness phenotype of choriocarcinoma. Silencing miR-497-5p and SALL4 promotes choriocarcinoma progression and forms a feedback loop with DNMT-mediated epigenetic regulation, playing a crucial role in stemness maintenance in choriocarcinoma.

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CWHM-1008 Induces Apoptosis and Protective Autophagy through the Akt/mTOR Axis in LUAD Cells

Journal of Oncology ◽

10.1155/2021/5548128 ◽

2021 ◽

Vol 2021 ◽

pp. 1-14

Author(s):

Jiao Zhang ◽

Man-Yuan Li ◽

Xiao Lu ◽

Quan-Xing Liu ◽

Dong Zhou ◽

...

Keyword(s):

Mammalian Target Of Rapamycin ◽

Inhibitory Effects ◽

Autophagy Flux ◽

Anticancer Properties ◽

Underlying Mechanisms ◽

Induced Apoptosis ◽

Related Proteins ◽

Antiparasitic Agents

Recent studies have revealed that antiparasitic agents showed promising inhibitory effects on tumors, raising a possibility that repositioning this class of drugs may shed new light on clinical therapy against tumors. CWHM-1008 is a novel class of antimalarial drug; however, the inhibitory impact of CWHM-1008 on lung adenocarcinoma (LUAD) cells remains unclear. This study aimed to explore the anticancer effect and underlying mechanisms of CWHM-1008 on LUAD cells in vitro and in vivo. Human LUAD cells, H358 and A549, were treated with varying concentrations of CWHM-1008 at different lengths of time. Cell viability, colony formation, cell count, flow cytometry findings, microtubule-associated protein-1 light chain 3-green- (LC3-) GFP/RFP adenovirus infection status, and the expression of apoptosis and autophagy-related proteins were examined. Potential effects of an autophagy inhibitor (LY294002) and constitutively active Akt plasmid (CA-Akt) on CWHM-1008-induced apoptosis were also examined. Our results showed that CWHM-1008 significantly inhibited proliferation, induced apoptosis, and enhanced autophagy flux by blocking the RAC-alpha serine/threonine-protein kinase/the mammalian target of rapamycin (Akt/mTOR) axis in two LUAD cells. In addition, autophagy inhibited by LY294002 or CA-Akt transfection accelerated CWHM-1008-induced apoptosis in those LUAD cells. Moreover, CWHM-1008 significantly inhibited the growth and induced apoptosis of A549 cell in nude mice in vivo. The present findings provide new insights into anticancer properties of CWHM-1008, suggesting that it may be an adjuvant treatment for LUAD treatment, warranting further study.

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