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• W3081610886 abstract "Liver cancer is the fastest growing cause of cancer deaths in the United States due to its aggressiveness and lack of effective therapies. The current preclinical study examines valeric acid (pentanoic acid [C5H10O2]), one of the main compounds of valerian root extract, for its therapeutic use in liver cancer treatment. Anticancer efficacy of valeric acid was tested in a series of in vitro assays and orthotopic xenograft mouse models. The molecular target of valeric acid was also predicted, followed by functional confirmation. Valeric acid has a broad spectrum of anticancer activity with specifically high cytotoxicity for liver cancer in cell proliferation, colony formation, wound healing, cell invasion, and 3D spheroid formation assays. Mouse models further demonstrate that systematic administration of lipid-based nanoparticle-encapsulated valeric acid significantly reduces the tumor burden and improves survival rate. Histone deacetylase (HDAC)-inhibiting functions of valeric acid are also revealed by a structural target prediction tool and HDAC activity assay. Further transcriptional profiling and network analyses illustrate that valeric acid affects several cancer-related pathways that may induce apoptosis. In summary, we demonstrate for the first time that valeric acid suppresses liver cancer development by acting as a potential novel HDAC inhibitor, which warrants further investigation on its therapeutic implications. Liver cancer is the fastest growing cause of cancer deaths in the United States due to its aggressiveness and lack of effective therapies. The current preclinical study examines valeric acid (pentanoic acid [C5H10O2]), one of the main compounds of valerian root extract, for its therapeutic use in liver cancer treatment. Anticancer efficacy of valeric acid was tested in a series of in vitro assays and orthotopic xenograft mouse models. The molecular target of valeric acid was also predicted, followed by functional confirmation. Valeric acid has a broad spectrum of anticancer activity with specifically high cytotoxicity for liver cancer in cell proliferation, colony formation, wound healing, cell invasion, and 3D spheroid formation assays. Mouse models further demonstrate that systematic administration of lipid-based nanoparticle-encapsulated valeric acid significantly reduces the tumor burden and improves survival rate. Histone deacetylase (HDAC)-inhibiting functions of valeric acid are also revealed by a structural target prediction tool and HDAC activity assay. Further transcriptional profiling and network analyses illustrate that valeric acid affects several cancer-related pathways that may induce apoptosis. In summary, we demonstrate for the first time that valeric acid suppresses liver cancer development by acting as a potential novel HDAC inhibitor, which warrants further investigation on its therapeutic implications. Hepatocellular carcinoma (HCC) is the dominant type of liver cancer that ranks as the sixth-most common malignant tumors and cancer-caused deaths.1Niino M. Matsuda T. Incidence rates of liver cancer in the world from the Cancer Incidence in Five Continents XI.Jpn. J. Clin. Oncol. 2019; 49: 693-694Crossref PubMed Scopus (0) Google Scholar HCC is the fastest growing cancer type in the United States, and its incidence has tripled during the past 20 years.2Zhou M. Wang H. Zeng X. Yin P. Zhu J. Chen W. Li X. Wang L. Wang L. Liu Y. et al.Mortality, morbidity, and risk factors in China and its provinces, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017.Lancet. 2019; 394: 1145-1158Abstract Full Text Full Text PDF PubMed Scopus (1230) Google Scholar HCC has a high mortality and poor prognosis3Prevention of Infection Related Cancer (PIRCA) Group, Specialized Committee of Cancer Prevention and Control, Chinese Preventive Medicine AssociationNon-communicable & Chronic Disease Control and Prevention Society, Chinese Preventive Medicine AssociationHealth Communication Society, Chinese Preventive Medicine Association[Strategies of primary prevention of liver cancer in China: expert consensus (2018)].Zhonghua Yu Fang Yi Xue Za Zhi. 2019; 53: 36-44PubMed Google Scholar due to its aggressiveness and lack of effective treatments. There is a tremendous unmet need for the development of novel therapeutics for liver cancer. Valerian (Valeriana officinalis), a member of Valerianaceae family, is a perennial herb4Hobbs C. Phu: valerian and other anti-hysterics in European and American medicine (1733-1936).Pharm. Hist. 1990; 32: 132-137PubMed Google Scholar and has been authorized by the US Food and Drug Administration (FDA) as a complementary and alternative medicine (CAM) to treat insomnia and other sleep-related disorders.5Zare A. Khaksar Z. Sobhani Z. Amini M. Analgesic Effect of Valerian Root and Turnip Extracts.World J. Plast. Surg. 2018; 7: 345-350Crossref PubMed Google Scholar Valerian has been found to have anticancer effect for liver cancer,6Kakehashi A. Kato A. Ishii N. Wei M. Morimura K. Fukushima S. Wanibuchi H. Valerian inhibits rat hepatocarcinogenesis by activating GABA(A) receptor-mediated signaling.PLoS ONE. 2014; 9: e113610Crossref PubMed Scopus (15) Google Scholar and its extraction compounds, such as iridoids, Valepotriates, and F3, have been shown as promising antitumor agents in many types of cancer,7Tian S. Wang Z. Wu Z. Wei Y. Yang B. Lou S. Valtrate from Valeriana jatamansi Jones induces apoptosis and inhibits migration of human breast cancer cells in vitro.Nat. Prod. Res. 2019; : 1-4Crossref PubMed Scopus (4) Google Scholar, 8Tan Y.Z. Peng C. Hu C.J. Li H.X. Li W.B. He J.L. Li Y.Z. Zhang H. Zhang R.Q. Wang L.X. Cao Z.X. Iridoids from Valeriana jatamansi induce autophagy-associated cell death via the PDK1/Akt/mTOR pathway in HCT116 human colorectal carcinoma cells.Bioorg. Chem. 2019; 87: 136-141Crossref PubMed Scopus (9) Google Scholar, 9Lin S. Fu P. Chen T. Ye J. Su Y.Q. Yang X.W. Zhang Z.X. Zhang W.D. Minor valepotriates from Valeriana jatamansi and their cytotoxicity against metastatic prostate cancer cells.Planta Med. 2015; 81: 56-61PubMed Google Scholar which warrants further exploration to discover novel active compounds from valerian for cancer treatment.10Li X. Chen T. Lin S. Zhao J. Chen P. Ba Q. Guo H. Liu Y. Li J. Chu R. et al.Valeriana jatamansi constituent IVHD-valtrate as a novel therapeutic agent to human ovarian cancer: in vitro and in vivo activities and mechanisms.Curr. Cancer Drug Targets. 2013; 13: 472-483Crossref PubMed Scopus (24) Google Scholar Valeric acid (VA), or pentanoic acid (C5H10O2), another major active chemical ingredient of valerian, has been reported to have therapeutic effects on diseases, like insomnia and seizures.11Torres-Hernández B.A. Del Valle-Mojica L.M. Ortíz J.G. Valerenic acid and Valeriana officinalis extracts delay onset of Pentylenetetrazole (PTZ)-Induced seizures in adult Danio rerio (Zebrafish).BMC Complement. Altern. Med. 2015; 15: 228Crossref PubMed Scopus (42) Google Scholar Recent evidence has also shown that VA can improve immunity against cancer.12Scott A.M. Wolchok J.D. Old L.J. Antibody therapy of cancer.Nat. Rev. Cancer. 2012; 12: 278-287Crossref PubMed Scopus (1500) Google Scholar In addition, as an organic acid, VA shares a high structural similarity with the known histone deacetylase inhibitor (HDACi) valproic acid (C8H16O2),13Gurvich N. Tsygankova O.M. Meinkoth J.L. Klein P.S. Histone deacetylase is a target of valproic acid-mediated cellular differentiation.Cancer Res. 2004; 64: 1079-1086Crossref PubMed Scopus (377) Google Scholar which is used as a treatment for seizure disorders, and a FDA-approved suberoylanilide hydroxamic acid (SAHA) (C14H20N2O3), which is used to treat T cell lymphoma.14Duvic M. Talpur R. Ni X. Zhang C. Hazarika P. Kelly C. Chiao J.H. Reilly J.F. Ricker J.L. Richon V.M. Frankel S.R. Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL).Blood. 2007; 109: 31-39Crossref PubMed Scopus (930) Google Scholar However, the antitumor activity of VA has not been examined in previous publications. In this study, we aimed to explore the anticancer effect of VA with a focus on liver cancer. In vitro assays, including cell proliferation, migration, invasion, colony formation, and even 3D formation, were performed. Lipid nanoparticles were used as a delivery vehicle for the systemic administration of VA in animal studies. Functional experiments were also carried out to confirm the HDACi role of VA and its global transcriptional impact on cancer-related pathways. We first used the MTS assay to measure cell proliferation to test the anticancer effect of VA in 12 cancer and 2 normal cell lines. Significant anticancer effects with a positive dose-dependent effect relationship were observed in all tested cell lines. Figure S1 shows cell proliferation results of VA at 5 different concentrations (0.5, 1, 2, 4, and 8 mM) for all 14 cell lines from 4 time points (24, 48, 72, and 96 h). The half-maximal inhibitory concentration (IC50) at 72 h was presented in Figure 1A for all cell lines tested. Three liver cancer cell lines were among the group with the lowest IC50 (Farage: 0.89 mM; HepG2: 0.948 mM; Hep3B: 1.439 mM: and SNU-449: 1.612 mM). However, the IC50 for liver normal cell line THLE-3 (3.097) was 1.92, 2.15, and 3.27 times higher than that for liver cancer cells SNU-449, Hep3B, and HepG2, respectively. A similar trend was also observed for breast cancer and normal cell lines, which exhibited an overall higher IC50 when compared to liver cells. Based on these data, we chose to further investigate the anticancer efficacy of VA for liver cancer. We used the VA concentration of 0.85 mM for the rest of in vitro assays because it displayed a low inhibitory effect (<10%) on normal liver cells while maintaining a high inhibitory effect (>30%) on liver cancer cells. We then carried out the colony formation assay to assess the anticancer effect of VA over a relatively long time period of 10 days. Figure 1B showed the images of the assay from 3 liver cancer cell lines. Compared to the negative control (NC) group, VA significantly reduced the number of cell colonies formed with the 67.99% ± 2.51% (p < 0.001) difference in cell colony number for Hep3B, 63.56% ± 2.11% (p < 0.001) for SNU-449, and 69.83% ± 2.71% (p < 0.001) for HepG2 (Figure 1C). The wound healing assay also showed that cells (Hep3B, SNU-449, HepG2) treated with VA had significantly slower healing rates compared to the control groups (Figures 2A–2C). For Hep3B, the average width of wound gaps in the VA group was 87.22% ± 1.91% of its initial width compared to 67.49% ± 2.38% of the NC group (p < 0.001) at 48 h. Similar significant differences were observed for liver cancer cells SNU-449 and HepG2 (Figures 2D–2F). The cell invasion assays showed that the VA-treated cells displayed significantly weaker invasive abilities than the control group (Figures 2G–2I). For Hep3B cell, the average counts of invading cells in the VA group were 156.67 ± 12.04 cells compared to 334 ± 9.2 cells from the control group (p < 0.001). Similar significant differences were observed for liver cancer cells SNU-449 and HepG2 (Figure 2J). To investigate the effect of VA on 3D spheroid formation of liver cancer cells, Hep3B and SNU-449 cells, containing the luciferase reporter gene, were both cultured using a hanging drop method. The dynamic changes of the cross-section of 3D spheroid formation were displayed in Figures 3A and 3B . 3D formation efficiency calculated from the cell cross-section area showed a significantly larger 3D spheroid formed (p < 0.01) in the control group compared to the VA group at all time points measured (24 h, 48 h, 72 h, and 96 h). Inhibition rates were further calculated for both cell lines, which were 13.96% ± 4.57% at 24 h, 35.36% ± 2.31% at 72 h, and 42.97% ± 5.52% at 96 h for SNU-449. A similar trend was observed for Hep3B cells but with relatively lower inhibition rates compared to SNU-449 cells (Figure 3C). Measurements from the luciferase reporter gene assay for the 3D spheroids formed showed similar results, as calculated above using the cross-section area. The inhibition rates of VA raised from 11.42% ± 2.8% to 49.3% ± 3.9% (24 h to 96 h) for Hep3B cells, and cells in the VA group climbed steadily from 18.87% ± 2.8% to 55.07% ± 1.8% (24 h to 96 h) for SNU-449 cells (Figure 3D). We further tested whether VA encapsulated by a cationic lipid nanoparticle (LNP) can increase its efficacy against liver cancer cells using the MTS assay. Figure 4A showed a brief structure of the LNP-encapsulated VA (LV). Figure S2 showed cell proliferation results of LV at 5 different concentrations (0.5, 1, 2, 4, and 8 mM) for all 14 cell lines from 4 time points (24, 48, 72, and 96 h). Our results showed that LV only increased the inhibitory effect for liver cells compared to VA tested in the same concentration at all 4 time points. Examples of these results were presented in Figure 4B using data collected at 72 h for all 14 testing cell lines treated by 2 mM of VA and LV. For Hep3B, the inhibition rate of LV (67.82% ± 6.06%) was over 16% higher than that of VA (51.75% ± 5.06%, p = 0.024). For SNU-449, the inhibition rate of LV was 70.71% ± 4.57% compared to 55.93% ± 3.88% for VA with a 15% increase (p = 0.013). For normal liver cells (THLE-3), the inhibition rate was 33.15% ± 2.04% for LV and 24.86% ± 2.21% for VA (p = 0.009). However, for HepG2 cells, the inhibition rate significantly dropped from 69.46% ± 1.36% to 62.23% ± 0.99% (p = 0.002) after LV encapsulation. 0.85 mM concentration of LV was further used to treat Hep3B, SNU-449, and THLE-3 cells at different time points (24 h, 48 h, 72 h, 96 h) because the same dose of VA was used in all above in vitro assays due to its high inhibitory rate for liver cancer cells and low toxicity on normal liver cells. Figure 4C illustrated that the inhibition rates in Hep3B and SNU-449 were significantly higher (∼>30%) than their own counterparts in THLE-3 (∼<9%) at 48, 72, and 96 h (all p values less than 0.01). Systematic delivery of LV via tail-vein injection was applied in mouse models implanted by 2 liver cancer cell lines Hep3BLuc and SNU-449Luc. Tumor sizes represented by bioluminescence signals from all testing mice were shown in Figures 5A and 5B . The Hep3B tumors treated by LV measured on day 14 (14d) (1.53 ± 0.42) × 107 and 21d (2.05 ± 1.03) × 107 were significantly smaller compared to the control group (14d: (5.22 ± 1.82) × 107, p = 0.007; 21d: (6.93 ± 2.7) × 107, p = 0.015) (Figure 5C). Similar findings were observed in SNU-449 cell line models as well (Figure 5D). The SNU-449 tumors of LV-treated mice (2.0 ± 1.99) × 107] started to show significant difference compared to the NC group (7.4 ± 1.6) × 107, p = 0.047] on 14d of treatment. On 21d, the bioluminescence value of LV group was (1.69 ± 2.24) × 107 compared to (12.06 ± 3.73) × 107 of the control group (p = 0.003). The inhibition rates of LV were further calculated and shown in Figure 5E, which demonstrated a reduction of 70% and 61% for Hep3B tumors and 70% and 86% for SNU-449 tumors on 14d and 21d of treatment, respectively. Significant differences in mice survivorship were also detected between LV-treated and control groups (p = 0.029 for the Hep3B model; p = 0.050 for the SNU-449 model). In the Hep3B model, the first mouse in the NC group died on 24d of the experiment, whereas the first mouse in the LV group died on 42d after starting treatment (Figure 5F). After the 70d, the survival rate was 50% in the LV group compared to 0% in the NC group. In the SNU-449 model, mice in the NC group died on the 27d, 36d, 49d, and 50d postinitiation of treatment, whereas only one mouse succumbed on 39d, and the rest of the mice all survived to the end of 70d in the LV-treated group (Figure 5G), which yielded a 75% survival rate for the LV-treated group and 0% survival rate for the NC group. When survival data from both Hep3B and SNU-449 models were combined (Figure 5H), the Mantel-Cox log rank test generated a highly significant difference between LV-treated and control groups (p = 0.0018). Mouse weight was monitored daily, and we did not find significant difference between treatment and control groups. We observed the redness and desquamation in the tail-injection site in 2 mice, 2 weeks after starting the treatment. The redness and desquamation completely disappeared about 2 weeks after the last treatment. The molecular formula, weight, and 3D structure of VA were illustrated in Figure 6A. The top proteins predicted as VA targets by the SwissTargetPrediction tool were 5 solute carrier family members and 3 HDAC enzymes (HDAC1, HDAC2, and HDAC3) (Figure 6A). The impact of VA on HDAC activity was tested using the HDAC activity assay, and results showed that both VA and LV significantly decreased HDAC activity in all liver cancer cells at 24 h, 48 h, and 72 h after treatment. For example, in the Hep3B experiment, the normalized HDAC activity of the NC group was 0.623 ± 0.156, calculated by optical density (OD) values, and measured higher compared to 0.265 ± 0.025 in the VA-treated group (p < 0.001) and 0.24 ± 0.039 in the LV-treated group (p < 0.001) (Figure 6B). Similar results were observed in experiments using liver cancer cells SNU-449 (Figure 6C) and HepG2 (Figure 6D). Furthermore, LV inhibited HDAC activity (0.168 ± 0.027) significantly more than VA (0.315 ± 0.05) in Hep3B cells (p = 0.021) at 72 h. A similar trend was also detected in SNU-449 and HepG2 experiments. A gene expression array (Affymetrix) was performed to better understand potential anticancer mechanisms of VA in liver cancer. Treatment of VA caused expression changes of 2,003 genes in liver cancer cells (Hep3B); of these, 880 genes were downregulated (<−2-fold, Bonferroni p < 0.05), and 1,123 genes were overexpressed (>2-fold, Bonferroni p < 0.05). Input of these genes into the Ingenuity Pathway Analysis (IPA) tool (Ingenuity Systems; https://digitalinsights.qiagen.com/) generated top networks with functional relevance to “Cell death and survival; gastrointestinal disease; organismal injury and abnormalities.” Figure 7A summarized key features from these networks, which included multiple cancer- and apoptosis-related pathways that are significantly modulated by the VA treatment. For example, the FOXP1/XBP1 pathway was repressed and resulted in the downregulation of oncogene SLC38A1 (Network 2 in Figure 7A). Moreover, MDM2 (a negative regulator of p53) was downregulated, followed by the suppression of the MET/MDM2, which further affected genes downstream of the p21/CDKN1A pathway and downregulated oncogene CCND1 (Network 3). Figure 7B illustrated that expression levels of 5 selected genes were all consistent between the array date and qPCR results, which confirmed that one gene was overexpressed (BAK1), 2 were downregulated (BCL2L1 and E2F3), and 2 did not have significant expression changes (BCL2 and BAX) after VA treatment. The caspase-3 (CASP3) activity was measured to examine and confirm the predicted impact of VA on apoptosis. Figure 7C showed that the CASP3 activity in the VA-treated group was significantly higher compared to all 3 control groups (inhibited apoptosis + VA, NC, and inhibited apoptosis + NC) in all 3 cell lines tested (all p values < 0.001). The CASP3 specific activity (SA) also showed a similar trend: the VA-treated group had significantly higher SA values compared to the control group (p < 0.001) (Figure 7D). The anticancer efficacy of VA, a small compound and a major ingredient of valerian, has been examined in this study. Our results demonstrated for the first time that VA has a broad spectrum of anticancer activity with specifically high cytotoxicity for liver cancer by serving as a novel HDACi. The IC50 data generated from a series of VA concentrations in the cell proliferation assay showed that VA has the strongest tumor-suppressing role for liver cancer cells. More importantly, its anti-cell proliferation activity was less evident for normal liver cells, suggesting that VA could be a promising agent for liver cancer treatment. This anticancer efficacy of VA for liver cancer is further supported by results from other in vitro assays. Compared to the cell proliferation assay, the colony formation assay allows a longer time period (10–14 days) to evaluate cell survival in response to various treatment conditions. As expected, ∼30% inhibition rate was observed in the cell proliferation assay, and approximately a 60% inhibition rate was detected in the colony formation assay when treated with the same dose of VA. Moreover, VA significantly reduced (>50%) migration and cell-cell interaction of liver cancer cells, as observed in the wound healing and Transwell invasion assays. Results from the 3D spheroid formation assay demonstrated more physiologically relevant information about the tumor-suppressing activity of VA and may provide more predictive data for in vivo tests. Before starting animal studies, we first tested lipid nanoparticle as a delivery vehicle for the systemic administration of VA. The LNP used in this study has been modified as a drug carrier specifically targeting liver cancer cells.15Baig B. Halim S.A. Farrukh A. Greish Y. Amin A. Current status of nanomaterial-based treatment for hepatocellular carcinoma.Biomed. Pharmacother. 2019; 116: 108852Crossref PubMed Scopus (52) Google Scholar LNP, at different concentrations (1 mM, 2 mM, 4 mM, 8 mM), showed no impact on cell proliferation as compared to water controls (data not shown), which indicated the safety of this LNP as reported in previous studies.16Hsu S.H. Yu B. Wang X. Lu Y. Schmidt C.R. Lee R.J. Lee L.J. Jacob S.T. Ghoshal K. Cationic lipid nanoparticles for therapeutic delivery of siRNA and miRNA to murine liver tumor.Nanomedicine (Lond.). 2013; 9: 1169-1180Crossref PubMed Scopus (107) Google Scholar More importantly, LV showed a significantly stronger antiproliferative effect than naked VA only for liver cancer Hep3B, SNU-449, and normal liver THLE-3 cells but not for liver cancer HepG2 and other cancer cell lines tested. This is probably due to the different affinities possessed by the LNP to different cell types. Both Hep3B and SNU-449 are HCC and represent the most common type of primary liver cancer. However, HepG2 is considered to be a hepatoblastoma, a rare type of liver cancer in adults but common in children.17López-Terrada D. Cheung S.W. Finegold M.J. Knowles B.B. Hep G2 is a hepatoblastoma-derived cell line.Hum. Pathol. 2009; 40: 1512-1515Crossref PubMed Scopus (203) Google Scholar Our results from the cell proliferation assay also indicate that LV at 1 mM has over a 30% inhibition rate for HCC cells but less than 10% for normal liver cells, which further suggested that LV is a great potential agent for liver cancer treatment because of its HCC-related high cytotoxicity and normal cell-related low toxicity. LV, via tail-vein injection, was used in our animal studies to treat orthotopic xenograft mice, established by injecting tumor cells directly into mouse liver. Compared to HCC subcutaneous models, the orthotopic model closely mimics the development of human HCC by imitating similar collagen distribution and blood supply in tumor growth and the ability to take up LNP more efficiently.18Wisse E. Jacobs F. Topal B. Frederik P. De Geest B. The size of endothelial fenestrae in human liver sinusoids: implications for hepatocyte-directed gene transfer.Gene Ther. 2008; 15: 1193-1199Crossref PubMed Scopus (207) Google Scholar Our results show that mice that received LV treatment experienced a significantly decreased tumor burden (>90% after 21d) but also had a significantly improved survival rate in both Hep3B and SNU-449 models, indicating the high effectiveness and feasibility of LV in HCC treatment. One of the main reasons for high HCC mortality is the cancer’s high metastatic potential.19Lu Y.S. Kashida Y. Kulp S.K. Wang Y.C. Wang D. Hung J.H. Tang M. Lin Z.Z. Chen T.J. Cheng A.L. Chen C.S. Efficacy of a novel histone deacetylase inhibitor in murine models of hepatocellular carcinoma.Hepatology. 2007; 46: 1119-1130Crossref PubMed Scopus (76) Google Scholar Data from the orthotopic HCC model showed that LV may also prevent liver cancer cells from metastasizing. In our animal experiment, LV might not have achieved the maximum therapeutic potential because the blood supply in tumors of the xenograft model is usually insufficient due to the hindrance of angiogenesis by the fibrotic tissues deposited in the surrounding region of implanted tumor cells.18Wisse E. Jacobs F. Topal B. Frederik P. De Geest B. The size of endothelial fenestrae in human liver sinusoids: implications for hepatocyte-directed gene transfer.Gene Ther. 2008; 15: 1193-1199Crossref PubMed Scopus (207) Google Scholar Taken together, results from both in vitro and in vivo assays suggest LV as a new and effective therapeutic agent for liver cancer treatment. Possible molecular mechanisms accounting for the anticancer effect of VA were also investigated by first searching for its predicted protein targets based on chemical structure similarities. Three HDAC enzymes (HDAC1, HDAC2, and HDAC3) are among the top hits of predicted targets, suggesting VA as a potential HDACi. This prediction was confirmed by findings from the HDAC activity assay. HDAC is a hallmark in cancer and plays a crucial role in gene-transcription regulation, controlling the proliferation, cell survival, differentiation, and genetic stability.20Buurman R. Sandbothe M. Schlegelberger B. Skawran B. HDAC inhibition activates the apoptosome via Apaf1 upregulation in hepatocellular carcinoma.Eur. J. Med. Res. 2016; 21: 26Crossref PubMed Scopus (19) Google Scholar Therefore, HDACs are among the most promising therapeutic targets for cancer treatment. So far, there are 4 FDA-approved HDACi that are all used to treat lymphoma and over one dozen HDACi being tested to treat solid tumors in different phases of clinical trials (by 2018).21Suraweera A. O’Byrne K.J. Richard D.J. Combination Therapy With Histone Deacetylase Inhibitors (HDACi) for the Treatment of Cancer: Achieving the Full Therapeutic Potential of HDACi.Front. Oncol. 2018; 8: 92Crossref PubMed Scopus (363) Google Scholar Studies have demonstrated that HDACs strongly suppress cancer cell apoptosis by decreasing the activity of apoptosis-key effector CASP3.22Dong Z. Yang Y. Liu S. Lu J. Huang B. Zhang Y. HDAC inhibitor PAC-320 induces G2/M cell cycle arrest and apoptosis in human prostate cancer.Oncotarget. 2017; 9: 512-523Crossref PubMed Scopus (12) Google Scholar Previous studies have reported that inhibition of HDAC can increase the activity of CASP3 and promote apoptosis,23Hajji N. Wallenborg K. Vlachos P. Nyman U. Hermanson O. Joseph B. Combinatorial action of the HDAC inhibitor trichostatin A and etoposide induces caspase-mediated AIF-dependent apoptotic cell death in non-small cell lung carcinoma cells.Oncogene. 2008; 27: 3134-3144Crossref PubMed Scopus (48) Google Scholar which was exactly what we observed in our study. HDACs are a superfamily with 18 members,24Seto E. Yoshida M. Erasers of histone acetylation: the histone deacetylase enzymes.Cold Spring Harb. Perspect. Biol. 2014; 6: a018713Crossref PubMed Scopus (869) Google Scholar and HDACs have been implicated in multiple types of cancer with different expression levels. For example, HDAC1, -2, and -3 are frequently upregulated in primary human HCC.20Buurman R. Sandbothe M. Schlegelberger B. Skawran B. HDAC inhibition activates the apoptosome via Apaf1 upregulation in hepatocellular carcinoma.Eur. J. Med. Res. 2016; 21: 26Crossref PubMed Scopus (19) Google Scholar HDAC4, -5, -7, and -9 are overexpressed in glioma.25Laws M.T. Bonomi R.E. Kamal S. Gelovani D.J. Llaniguez J. Potukutchi S. Lu X. Mangner T. Gelovani J.G. Molecular imaging HDACs class IIa expression-activity and pharmacologic inhibition in intracerebral glioma models in rats using PET/CT/(MRI) with [18F]TFAHA.Sci. Rep. 2019; 9: 3595Crossref PubMed Scopus (16) Google Scholar In breast cancer, the common overexpressed HDACs have been found to be HDAC1, -2, -6, and -8.26Müller B.M. Jana L. Kasajima A. Lehmann A. Prinzler J. Budczies J. Winzer K.J. Dietel M. Weichert W. Denkert C. Differential expression of histone deacetylases HDAC1, 2 and 3 in human breast cancer--overexpression of HDAC2 and HDAC3 is associated with clinicopathological indicators of disease progression.BMC Cancer. 2013; 13: 215Crossref PubMed Scopus (152) Google Scholar Researchers have reported that HDAC3, a predicted target of VA, was required for the self-renewal of liver cancer stem cells.27Lu X.F. Cao X.Y. Zhu Y.J. Wu Z.R. Zhuang X. Shao M.Y. Xu Q. Zhou Y.J. Ji H.J. Lu Q.R. et al.Histone deacetylase 3 promotes liver regeneration and liver cancer cells proliferation through signal transducer and activator of transcription 3 signaling pathway.Cell Death Dis. 2018; 9: 398Crossref PubMed Scopus (30) Google Scholar These differential expressions of HDAC genes may help explain the high therapeutic effect of VA on HCC cells because all 3 overexpressed HDACs in HCC are targets of VA. Therefore, VA could function as a novel HDACi and an emerging approach for HCC treatment. The global impact of VA on the human transcriptome revealed more cancer-related pathways and networks affected by VA treatment. The intrinsic apoptotic pathway is reported to be the main mechanism for HDACi to induce apoptosis in cancer cells.28Zhang J. Zhong Q. Histone deacetylase inhibitors and cell death.Cell. Mol. Life Sci. 2014; 71: 3885-3901Crossref PubMed Scopus (141) Google Scholar Bcl-2 family members, such as BCL-2, BCL-XL, BAX, BID, and BAK1, are frequently observed to be significantly regulated by HDACi via an intrinsic apoptotic pathway, therefore activate" @default.
• W3081610886 created "2020-09-08" @default.
• W3081610886 creator A5015467939 @default.
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• W3081610886 creator A5019031074 @default.
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• W3081610886 date "2020-12-01" @default.
• W3081610886 modified "2023-10-12" @default.
• W3081610886 title "Valeric Acid Suppresses Liver Cancer Development by Acting as a Novel HDAC Inhibitor" @default.
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