Anticancer Activity of Trichostatin A

Anticancer Activity of Trichostatin A: History

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Contributor:

Tarik Aanniz

Mohammed Merae Alshahrani

Ahmed Abdullah Al Awadh

Learn-Han Lee

Taoufiq Benali

Mohammad S. Mubarak

Trichostatin A (TSA), a natural derivative of dienohydroxamic acid derived from a fungal metabolite, exhibits various biological activities. It exerts antidiabetic activity and reverses high glucose levels caused by the downregulation of brain-derived neurotrophic factor (BDNF) expression in Schwann cells, anti-inflammatory activity by suppressing the expression of various cytokines, and significant antioxidant activity by suppressing oxidative stress through multiple mechanisms. Most importantly, TSA exhibits potent inhibitory activity against different types of cancer through different pathways. The anticancer activity of TSA appeared in many in vitro and in vivo investigations that involved various cell lines and animal models.

Trichostatin A
pharmacological activity
anticancer action

1. Direct Anticancer Mechanisms of TSA

TSA inhibited the growth of different cancer cells via cycle arrest and apoptosis. This compound suppressed the invasion and migration and reduced the radio resistance in many cancer cell lines in a time- and dose-dependent manner. According to the literature, numerous studies investigated the cytotoxicity impact of TSA and the mechanisms by which TSA affects cancer cells. Although the antitumor activity of TSA seems to be strongly linked to its HDAC inhibitory effect, this compound’s antitumor molecular mechanisms are multiple and target different pathways. Table 1 lists the anticancer activity of trichostatin A along with pertinent references.

Table 1. Direct anticancer activity of trichostatin A.

Origin	Used Model	Experimental Approach	Key Results	References
Purchased	RPMI8226 and MM.1S cells	Immunofluorescence Immunoprecipitation Western blot analysis qPCR	Induced cytotoxic effect in multiple myeloma cell lines Induced cell apoptosis Inhibited hedgehog signaling pathway	^[1]
Purchased	YD-10B oral squamous carcinoma cells	MTT assay Cell cycle analysis Western blot analysis DAPI staining	Inhibited cell proliferation Arrested cell cycle progression at the G₂/M phase Induced mitochondrial membrane destruction Induced cyto-c release and proteolytic activation of caspases-3 and -7	^[2]
Purchased	MDA-MB-231 and MCF-7 human breast carcinoma and SK-UT-1B uterine cancer cell lines	Flow cytometry analysis RT-PCP	Induced cyclin D1 downregulation through both ERα-dependent and ERα-independent mechanisms	^[3]
Purchased	MCF-7 cells	Cell proliferation assay Immunoblotting Flow cytometry analysis	Induced Akt dephosphorylation in a PP1-dependent manner, resulting in the activation of GSK3β in MCF-7 cells TSA-induced cytotoxicity was attenuated by the selective inhibition of GSK3β resulting in increased proliferation	^[4]
Not reported	U87 glioblastoma cells	RT-PCP	Reduced proliferation and colony sizes resulting in G₂/M arrest Inhibited tumorsphere formation	^[5]
Not reported	Gastric cancer cells (MKN-45 and SGC-7901 cells)	MTT and BrdU immunofluorescence assays Soft agar assay Flow cytometry analysis Western blot analysis	Suppressed cell proliferation Induced apoptosis by regulating the PI3K/AKT signaling pathway in gastric cancer cells Induced cell cycle arrest at the G₁ phase and apoptosis	^[6]
Not reported	Two leukemic cell lines (CCRF-CEM and HL-60)	Flow cytometry analysis	The IC₅₀ value of CCRF-CEM was 2.65 ± 0.3 μM The IC₅₀ value of HL-60 was 2.35 ± 0.2 μM CCRF-CEM cells were reduced to 56.5%, 45.3%, and 40.2% on the first, third, and sixth days HL-60 cells were reduced to 55.6%, 45.2%, and 36.3% on the first, second, and fourth days	^[7]
Purchased	Human osteosarcoma cells	Confocal microscopy Western blot analysis Flow cytometry analysis	Promoted osteosarcoma cell death Induced autophagy in U2OS cells Inhibited mTOR signaling pathway and enhanced FOXO1 transcriptional activity	^[8]
Not reported	Pancreatic and colon carcinoma cell lines	Western blot analysis Real-time RT- PCR	Increased MDR1 mRNA levels Downregulated the upstream promoter responsible for the active P-glycoprotein expression	^[9]
Purchased	Human colon adenocarcinoma cell lines DLD-1 and SW480	Viability assays Western blot analysis Gene expression microarrays	Reduced cell viability Reversed the upregulation of gene expression levels induced by gain of chromosome 7	^[10]
Purchased	Human pancreatic endocrine tumor cell lines (CM, BON, and QGP-1)	Cell proliferation assay Cell cycle analysis 2-D gel electrophoresis	Inhibited cell growth by arresting the cell cycle in the G₂/M phase and inducing apoptosis	^[11]
Purchased	Lung cancer cells	mRNA extraction and qRT-PCR Colony formation assay Flow cytometry analysis Cell cycle analysis Western blot analysis	Inhibited proliferation, reduced colony formation, and induced cell cycle arrest and apoptosis Reduced the expression of Bcl-2 through the upregulation of miR-15a/16-1	^[12]
Not reported	Human pancreatic cancer cell lines (PANC-1, SW1990, and MIATACA-2 cells)	MTT assay Hoechst 33258 staining Flow cytometry analysis RT-PCR and western blot analyses	Decreased cell viability in a dose-dependent manner in PANC-1 cells Increased apoptosis of PANC-1 cells Increased the expression levels of Bax and caspase-3 Downregulated the expression level of Bcl-2	^[13]
Purchased	Osteosarcoma MG-63 cells	MTT assay TUNEL assay Annexin V staining Flow cytometry analysis	Inhibited cell proliferation Induced apoptosis of MG-63 cells Arrested the cell cycle in G₁/G₂ phase Inhibited the invasiveness of MG-63 cells	^[14]
Purchased	Five human hepatoma cell lines	MTT assay TUNEL assay Semi-Quantitative RT-PCR Chromatin Immunoprecipitation (ChIP) assay	Inhibited cell growth Induced apoptosis Inhibited the gene expression profile in hepatoma cell lines	^[15]
Not reported	Mouse model with L1 neoplastic tumors	Measurement of tumor size and mice body weight Preparation of four formulations for the in vivo study	Reduced neoplastic tumor growth using the semi-solid formulation applied to the skin Impaired the skin barrier function of neoplastic tumors	^[16]
Purchased	A549 cells	DNA fragmentation assay Flow cytometry analysis RNA extraction and RT-PCR Western blot analysis	Inhibited the cell viability Induced the apoptosis of A549 cells Induced the proteolytic activation of caspases-3 and -9 Induced a concomitant degradation of poly(ADP-ribose)-polymerase protein Decreased the levels of COX-2 mPvNA
Purchased	HCT116 human colon cancer cell lines	MTT assay Reporter assay RNA extraction and RT-qPCR Western blot analysis ChIP assay	Induced the endoplasmic reticulum (ER) stress in wild-type (WT) HCT116 cells Induced apoptosis and cell viability depending on p53
Purchased	Trypanosoma cruzi	Flow cytometry analysis Transmission electron microscopy LC-MS/MS	Reduced protozoa proliferation and viability Altered the dynamics of the microtubule cytoskeleton Altered the segregation of kDNA, generating polynuclear cells with atypical morphology	^[17]
Purchased	Human osteosarcoma MG63 cell line Human osteoblastic cell line hFOB 1.19	MTT assay Flow cytometry analysis Western blot analysis	Inhibited the growth of MG63 cells Promoted apoptosis through activation of p53 signaling pathway	^[18]
Not reported	Keloid fibroblasts	MTT viability assay Hoechst staining Flow cytometry analysis RNA extraction and real time RT-PCR Western blot analysis	Inhibited the collagen synthesis and induced apoptosis in keloid fibroblasts	^[19]
Purchased	MCF-7 cells	RQ-PCR analysis Western blot analysis	Reduced the phospholipase C gamma-1 (PLCγ1) transcript and protein levels in MCF-7 cells	^[20]
Purchased	Human pancreatic carcinoma cell lines (BxPC-3, AsPC-1, and CAPAN-1)	Real-time PCR Immunoblotting	Inhibited the incorporation of BrdU into BxPC-3 cells. Inhibited the phosphorylation of ERK 1/2 and AKT in BxPC-3 cells. Induced an activation of the MAP kinase p38 in all three cell lines especially in BxPC-3 cells Increased the mRNA levels of bax in BxPC-3 cells only Increased cell cycle inhibitor protein p21^Waf1 levels in BxPC-3 and AsPC-1 cells	^[21]
Purchased	MCF10A and MCF10A-ras cells	RT-PCR Western blot analysis	Activated apoptosis in MCF10A-ras cells only Activated the FOXO1 via P21 upregulation Induced autophagy in MCF10A and MCF10A-ras cells by blocking the mammalian target of rapamycin signaling pathway	^[22]
Purchased	BGC-823 human gastric cancer cell line, MCF-7 cells, and KYSE-510 human esophageal squamous cell carcinoma (ESCC)	Immunocytochemistry assay RNA isolation and qPCR Western blot analysis Colony forming assay	Induced mesenchymal-like morphological changes in human cancer cells Increased the expression levels of mesenchymal markers and E-cadherin Reduced cancer cell mobility Reduced cancer cell colony formation
Purchased	Human renal cell carcinoma (RCC) caki cell line	Flow cytometry analysis Western blot analysis Measurement of mitochondrial membrane potential Determination of caspase activity	Increased TRAIL-induced apoptotic cell death in Caki cells Elevated TRAIL-induced activation of caspases in Caki cells Enhanced the downregulation of Bcl-2 and truncation of Bid in TRAIL-treated Caki cells	^[23]
Purchased	Molt-4 cell line	MTT assay Flow cytometry analysis Immunocytochemistry Western blot analysis	Inhibited the proliferation of Molt-4 cells (IC₅₀ = 254.32 μg/L after 24 h of exposure) Decreased the percentage of G₀/G₁ cells and arrested cells in G₂/M phase	^[24]
Purchased	Human endothelial cell line (ECV304 cells)	MTT assay Northern blot analysis Western blot analysis Wounded cell migration assay	Increased thrombospondin-1 expression, which reduced ECV 304 cell migration Inhibited tube formation regardless of the presence of exogenous vascular endothelial growth factor	^[25]
Purchased	Human leukemia cell line Molt-4	MTT assay Annexin-V-FITC staining RT-PCR Western blot analysis	Induced Molt-4 apoptosis Upregulated 310 genes and downregulated 313 genes	^[26]
Purchased	Human malignant glioma LNT-229 and LN-308 cell lines NMRI nude mice	Viability and cell growth assays PCR analysis Caspase activity assay Athymic CD1-deficient NMRI nude mice	Induced the upregulation of natural killer group-2 member-D (NKG2D) ligands and immunogenicity in glioblastoma (GBM) cells Suppressed tumor growth of GBM xenografts (in vivo)	^[27]
Purchased	Human dermal lymphatic endothelial cells	BrdU assay Flow cytometry analysis Western blot analysis Semi-quantitative RT-PCR	Decreased lymphangiogenesis by inducing apoptosis and cell cycle arrest via p21-dependent pathways	^[28]
Not reported	C6 glioma cell line	Immunoblot analysis MTT assay Flow cytometry analysis ChIP assay	Decreased cell viability Induced C6 cell apoptosis Induced the p38MAPK and AMPK activation in C6 cells	^[29]
Not reported	Human cervical carcinoma cell (Hela cells)	MTT assay RT-PCR	Inhibited cell viability Induced cell apoptosis Promoted the expression of apoptosis-related genes	^[30]
Not reported	Two human ESCC cell lines, KYSE-150 and KYSE-450	Western blot analysis Transwell migration assay	Promoted cell migration by RelA K310ac-slug-EMT pathway	^[31]
Not reported	Hepatocellular carcinoma (HCC) cell line Huh7	qRT-PCR Western blot and immunoprecipitation	Alleviated the specific subset of HCC, the hepatitis B virus X protein (HBx)-induced HCC in metabolic stress, through promoting sirtuin 3 (SIRT3) transcription	^[32]
Not reported	A549 cells	Flow cytometry analysis	Induced the growth inhibition and morphological changes Inhibited cyclins and cyclin-dependent kinases (CDKs) expression Induced tumor suppressor p53 and Cdk inhibitors such as p21 and p27	^[33]
Purchased	Oral squamous cell carcinoma (OSCC) lines HSC-3 and Ca9.22	Trypan blue staining MTT assay Western blot analysis	Decreased OSCC cell viability and proliferation Enhanced the expression levels of Bim protein Damaged mitochondrial membrane potential and increased cytosolic apoptosis-inducing factor (AIF) in Ca9.22 cells
Purchased	Jurkat leukemia T cell clone E6-1 cells	RQ-PCR Western blot analysis	Induced ZAP-70, LAT, and SLP-76 transcript and protein downregulation in Jurkat leukemia T cells Reduced the half-life of ZAP-70, LAT, and SLP-76 mRNAs	^[34]
Purchased	Keloid fibroblasts	MTT assay RNA extraction and RT-qPCR Flow cytometry analysis Western blot analysis	Inhibited cell proliferation in a time- and dose-dependent manner Induced alterations in the expression of numerous miRNA sequences Downregulated the expression of miR-30a-5p
Not reported	HeLa and bovine aortic endothelial (BAE) cells	Western blot analysis Northern blot analysis MTT assay	Increased thrombospondin-1 (TSP-1) expression at both the mRNA and protein levels through transcriptional activation	^[35]
Purchased	Four retinoblastoma cell lines	RT-PCR Western blot analysis ChIP assay Luciferase activity assay	Induced the expression of TβR-II mRNA Activated the TβR-II promoter Inhibited cell growth	^[36]
Purchased	Human oral SCC cell line SAS, Ca9-22, and HSC	MTT assay Flow cytometry analysis Western blot analysis RT-PCR Confocal laser microscopic analysis	Enhanced the replication of the HSV-1 mutant through the activation of NF-κB Inhibited cell growth by inducing cell cycle arrest at G₁	^[37]
Not reported	HeLa cells	RT-PCR Western blot analysis	Upregulated the expression of p21^WAF1 and p16^INK4A in various cell lines Downregulated the expression of cyclin A Upregulated the expression of gelsolin and fibronectin	^[38]
Not reported	MDA-MB-231 human breast cancer cell	MTT assay	Decreased cell viability (IC₅₀ = 100 ng/mL) Induced apoptosis Induced poly (ADP-ribose) polymerase-1 (PARP-1) cleavage and caspase-3 activation Upregulated the expression of CDK inhibitor p21^(WAF1/CIP1) protein Downregulated the expression of Bcl-2	^[39]
Purchased	Bone marrow cells and calvarial osteoblasts collected from the tibias and femurs of ICR mice	TRAP staining RT-PCR Western blot analysis In vivo experiment	Inhibited osteoclastogenesis and bone resorption by suppressing the induction of c-Fos by RANKL	^[40]
Not reported	HeLa cells	RT-PCR Western blot analysis ChIP assay	Activated p21^WAF1/CIP1 expression through the downregulation of c-myc and the release of the repression of c-myc from the promoter	^[41]
Purchased	Human bladder cancer cell line, BIU-87	MTT assay Flow cytometry analysis RT-PCR DNA fragmentation analysis	Inhibited bladder cancer cell proliferation Induced cell cycle arrest at the G₁ phase Increased apoptotic cell death Increased p21^WAF1 mRNA expression	^[42]
Purchased	Murine pro-B lymphoma FL5.12 cells	MTT assay DNA fragmentation assay Flow cytometry analysis Western blot analysis RT-PCR	Inhibited cellular proliferation Induced apoptosis Induced DNA fragmentation Increased the protein levels of cleaved caspase-3 and PARP Induced apoptotic protein Bim Inhibited PU.1	^[43]
Not reported	RAW264.7 cells	RT-PCR Western blot analysis ChIP assay	Inhibited LPS-induced C/EBPδ, resulting in a positive effect on LPS-induced cox-2 expression in RAW264.7 cells	^[44]
Not reported	Human colon cancer cell lines HCT116, HT29, SW480	Annexin-V staining qRT-PCR Western blot analysis	Altered the expression of cell cycle-associated genes in HCT116 cells Downregulated the gene expression of minichromosome maintenance protein-2 (MCM-2) Increased phosphorylated JNK, which was involved in the downregulation of MCM-2	^[45]
Not reported	ZAP-Grg1 transgenic mouse line (in vivo) A549 cells Human umbilical vein endothelial cells (HUVECs)	Western blot analysis qRT-PCR MTT assay Electric cell-substrate impedance sensing (ECIS) analysis	Inhibited lung tumorigenesis in Grg1 transgenic mice Reduced the expression of ErbB1 and ErbB2 Reduced the expression of VEGF and VEGFR2	^[46]
Purchased	Human ESCC cell lines KYSE-150 and EC9706	Transwell migration assay qRT-PCR Western blot analysis	Promoted esophageal squamous cell carcinoma cell migration and EMT through BRD4/ERK1/2-dependent pathway
Purchased	HeLa and Caski cervical cancer cell lines	MTT assay Flow cytometry analysis qRT-PCR Western blot analysis	Suppressed cervical cancer cell proliferation and induced apoptosis and autophagy through the regulation of the PRMT5/STC1/TRPV6/JNK axis	^[47]
Purchased	MCF-7 cells	Trypan blue staining qRT-PCR Western blot analysis	Reduced CYP19 transcript and protein contents in MCF-7 cells Lowered CYP19 transcript stability and significantly decreased the transcript’s half-life	^[48]
Purchased	EC9706 cells	Annexin V-FITC/PI staining Western blot analysis MTT assay Flow cytometry analysis	Suppressed ESCC cell growth by inhibiting the activation of the PI3K/Akt and ERK1/2 pathways	^[49]
Purchased	SK-MEL-3 melanoma cells	Fluorescence microscopy Flow cytometry analysis	Downregulated critical components of the MAPK/MEK/BRAF oncogenic pathway, initiating a mitotic arrest	^[50]
Purchased	Human ovarian cancer cell lines, COC1 and its DDP-resistant subline, COC1/DDP	RT-PCR Western blot analysis MSP assay ChIP assay	No effect on the reactivation of hMLH1 expression in COC1/DDP cells	^[51]
Purchased	HCT116 and HT29 cells	Annexin V-FITC PI staining Flow cytometry analysis Bax siRNA transfection Western blot analysis	Induced cell cycle arrest and apoptosis in colorectal cancer cells via p53-dependent and -independent pathways	^[52]
Not reported	16 NSCLC cell lines	MTT assay RNA extraction and RT-PCR	Displayed strong antitumor activities in 50% of NSCLC cell lines	^[53]
Purchased	Human pancreatic cancer cell lines	Oligonucleotide array hybridization Western blot analysis qRT-PCR	Altered the expression of pro- and anti-apoptotic genes in pancreatic adenocarcinoma cells	^[54]
Not reported	CD4⁺ T cells isolated from erythrocyte-depleted spleen cell preparations from C57BL/6 mice	RNA extraction and qRT-PCR Flow cytometry analysis Western blot analysis Determination of ROS generation Annexin V-FITC staining	Induced a rapid decline in cytokine expression and accumulation of cells in the G₁ phase of the cell cycle Induced apoptotic cell death Altered the expression of a subset of genes involved in T cell responses	^[55]
Purchased	Human NSCLC lines (Calu-1, NCI-H520, NCI-H23, and NCI-H441)	Flow cytometry analysis Annexin-V staining Immunoprecipitation Western blot analysis	Inhibited cellular growth Induced apoptosis Reduced the percentage of cells in the S phase (10% to 23%) and increased G₁ populations (10% to 40%) Increased the expression of p21 without significant effect on p16, p27, CDK2, and cyclin D1	^[56]
Purchased	Canine mast cell tumor (MCT)	Trypan blue staining Acridine orange/ethidium bromide staining MTT assay Cell cycle analysis	Reduced the viable cell numbers Increased cell death by apoptosis Increased hypodiploid cells Reduced the G₀/G₁ and G₂/M–phases	^[57]
Purchased	A549 cells	MTT assay Cell morphology analysis Wound healing assay Western blot analysis RNA extraction and RT-q-PCR assay Docking methodology	Effectively inhibited radiation-induced EMT by: Altered epithelial and mesenchymal markers Modulated signaling molecules of TGFb1 pathway Inhibited cancer cell migratory potential in A549 cells Effectively bound to Snail, an enhancer of EMT	^[58]
Purchased	HeLa cells	Flow cytometry analysis Immunofluorescence staining RT-PCR	Induced a delay at the G₂/M transition, chromosome missegregation, and multi-nucleation Induced cell death Induced a transcriptional modulation of key regulator genes of the cell cycle (Cyclin B1, Plk1, Survivin, and p21^WAF1/Cip1)	^[59]
Purchased	MCF-7 cells	Western blot analysis qRT-PCR Transfection and luciferase reporter assays	Augmented ESR1 gene repression at the transcriptional level Downregulated ERα protein expression under hypoxic conditions through a proteasome-mediated pathway Inhibited cell proliferation under both normoxia and hypoxia conditions Enhanced hypoxia-induced repression of ESR1 and degradation of ERα	^[60]
Purchased	Human TK6 lymphoblastoid cell line	Cell cycle analysis Annexin V staining Cytogenetic assays Immunoblot analysis	Induced apoptosis and G₁ cell cycle arrest Induced chromosomal breakage Induced DNA breaks Induced aneuploidy	^[61]
Purchased	Human ESCC cells, EC109 and KYSE150	qRT-PCR Immonochemistry Western blot analysis ChIP-qPCR Annexin-V/FITC staining	Significantly induced DNA damage in ESCC cells Induced Rad9 gene expression both at transcriptional and translational levels in EC109 cells alone Enhanced DNA damage and cell death	^[62]
Not reported	Primary hepatocytes Hepatoma cells	Western blot analysis Northern blot analysis LDH release assay Caspase-3 activation assay	Inhibited hepatocyte proliferation No induction of apoptosis in primary hepatocytes Induced apoptosis in hepatoma cells Upregulated the expression of the anti-apoptotic protein Bcl(xL)	^[63]
Not reported	267B1 human prostate epithelial cells	Fluorescence microscopy Agarose gel electrophoresis Flow cytometry analysis	Inhibited cell growth Induced apoptosis Inhibited the levels of IAP family members Activated caspases and NF-κB	^[64]
Purchased	MCF10A and MCF10A-ras cell lines	Ras activation assay MTT assay DAPI staining of nuclei Flow cytometry analysis Western blot analysis	Induced morphological changes, apoptotic cell death and modulation of the cell cycle regulatory proteins in the MCF10A-ras cells Downregulated the expression of cyclin D1 and CDK4 Upregulated the expression of p21^WAF1 and p53 Induced cell cycle arrest at the G₁ phase in MCF10A-ras cells Decreased hyperphosphorylation levels of the Rb protein	^[64]
Not reported	Chronic lymphocytic leukemia (CLL) cells	Flow cytometry analysis ATP assay Immunoblotting qPCR	Acted via a dual anti-HDAC/Wnt mechanism with a high selectivity and efficacy in CLL	^[65]
Purchased	Human SCLC DMS53 cells	Light microscopy Western blot analysis MTT assay	Induced morphological differentiation and inhibition of cell growth via cell cycle arrest and subsequent apoptosis	^[66]
Not reported	Apoptotic-resistant MCF-7TN-R cells derived from MCF-7 cells	Clonogenicity assay microRNA microarray analysis	Altered the microRNA expression profiles in apoptosis-resistant breast cancer cells	^[67]
Purchased	Human gastric epithelial cell line BGC-823	MTT assay Hoechst 33342 staining Western blot analysis RT-qPCR Immunohistochemistry	Inhibited cell proliferation Induced cell apoptosis Inhibited non-metastatic melanoma protein B (GPNMB) expression	^[68]
Purchased	Plasmacytoid dendritic cells (PDC)	Cytokine ELISA RT-PCR Confocal microscopy	Inhibited the production of IFN-I, TRAIL and of the pro-inflammatory cytokines TNF-α and IL-6 by CpG-activated PDC Inhibited the production of IFNα by PDC cultured in vitro in the presence of serum obtained from systemic lupus erythematosus patients	^[69]
Purchased	SW480 cells	AnnexinV-FITC PI staining qRT-PCR MTT assay Flow cytometry analysis	Inhibited cell growth Induced apoptosis IC₅₀ = 1.5 μM Upregulated p21, p27, and p57 genes expression
Not reported	Human hepatocellular carcinoma Hepa 1-6 cells	MTT assay qRT-PCR AnnexinV- FITC and PI staining	Inhibited cellular proliferation Induced apoptosis Increased ERα gene expression quantity	^[70]
Not reported	Hepatocellular carcinoma HCCLM3, MHCC97H, and MHCC97L cell lines	MTT assay Cell apoptosis assay qRT-PCR	Induced apoptosis and inhibited cell growth through both mitochondrial/intrinsic and cytoplasmic/extrinsic apoptotic pathways	^[71]
Purchased	U87 glioblastoma cells and tumorsphere-derived cells	Tumorsphere formation assay Colony formation assay RT-PCR Western blot analysis Cell migration assay Cell cycle analysis	Inhibited proliferation and altered cell cycle in U87 human GBM cells Induced senescence-like alterations in nuclear morphology in U87 cells Increased mRNA levels of C-Myc and reduced Oct4 mRNA in cells Reduced tumorsphere formation and sizes in U87 cell cultures	^[5]
Purchased	B lymphoblastoid cell lines (LCLs), SNU-20 and SNU-1103 Epstein-Barr virus-negative Burkitt’s lymphoma cell line, BJAB	Flow cytometry analysis Trypan blue staining RNase protection assay RT-PCR Western blot analysis Immunofluorescence assay	Enhanced anti-tumor effect for EBV-associated tumors by inducing a cell cycle arrest, apoptosis, and by triggering an EBV lytic cycle	^[72]
Purchased	HeLa and SiHa cells	Western blot analysis RNA extraction and RT-PCR ChIP assay Transfection and luciferase reporter assay Tumorigenicity in mice xenograft model	Suppressed the PMA-induced OPN gene expression Suppressed the PMA-induced c-Jun recruitment to the OPN promoter by inhibiting c-Jun expression Suppressed cervical tumor growth in response to PMA in NOD/SCID mice xenograft model	^[73]
Purchased	SW480 and SW620 cells	Western blot analysis Immunofluorescence analysis Reporter assays ChIP assay	Modulated claudin-1 mRNA stability through the modulation of Hu antigen R and tristetraprolin in colon cancer cells	^[74]
Purchased	Human nasopharyngeal carcinoma (NPC) cell line CNE2 and undifferentiated C666–1	CCK-8 assay RNA extraction and RT-PCR Western blot analysis Flow cytometric analysis Transwell migration assay Scratch wound healing assay	Inhibited cell proliferation and arrested the cell cycle at G₁ phases Reduced PCNA, cyclin D1, cyclin E1, CDK2, p16, and p21 expressions and stimulated CDK6 levels Promoted Vimentin and Snail1 expression Induced the EMT in CNE2 and C666–1 cells	^[75]
Purchased	Human lung adenocarcinoma A549 cells and normal lung epithelial cells	RNA extraction and RT-PCR Immunocytochemical staining Western blot analysis Migration assay Cell cycle assay Fluorescein isothiocyanate (FITC) permeability assay	Increased anguin-1/LSR, decreased CLDN-2, promoted G₁ arrest, and prevented the migration of A549 cells Increased the expression of LSR and CLDN-2 and decreased that of CLDN-1 with or without TGF-β in normal human lung epithelial cells	^[76]
Not reported	Male Kunming mice	Testis weighing and sperm collection Histological processing Immunofluorescence Fluorescence microscopy	Increased genetic recombination frequency of spermatocyte meiosis	^[77]
Purchased	A2780 cells	Histopathology analysis Immunohistochemistry Flow cytometry analysis	Induced morphological cell transformation, with increased cytoplasm Inhibited cell proliferation Reduced mitotic activity Induced epithelial-like differentiation with increased cytokeratin expression	^[78]
Not reported	Human neuroblastoma (NB) cell lines	MTT assay siRNA-mediated silencing Western blot analysis	Induced cell death in neuroblastic-type NB cells by increasing the acetylation of Ku70, a Bax-binding protein CBP, Bax, and Ku70 contribute to therapeutic response to TSA against NB	^[79]
Not reported	Raji cells and normal peripheral blood mononuclear cells	Flow cytometry analysis TUNEL assay Annexin V/PI staining	Inhibited cell proliferation Induced apoptosis Induced accumulation of cells in G₀/G₁ or G₂/M Decreased cell population in the S phase	^[80]
Not reported	MCF-7, MDA-MB-231 and MCF-10A cell lines	MTT assay Colony-forming assay Western blot analysis Annexin V- FITC and PI staining Cytochrome C release assay	Inhibited cell viability and proliferation without affecting MCF-10A cell Induced cell apoptosis which was initiated by G₂-M arrest and depending on mitochondrial ROS produced after reduced mitochondrial respiratory chain activity	^[81]
Purchased	Human rhabdomyosarcoma cell lines RH30 and RD	Annexin V-FITC and PI staining Flow cytometry analysis Immunohistochemical staining RQ-PCR miRNA transfection	Inhibited rhabdomyosarcoma proliferation and induced differentiation through myomir reactivation	^[82]
Purchased	MCF-7 and MB-MDA-231 cells	MTT assay Annexin V- FITC and PI staining Flow cytometry analysis	Induced cell growth inhibition via 15-Lox-1 associated with the elevation of 15-Lox-1 metabolite (13 (S)-HODE) Induced cell cycle arrest Induced apoptosis	^[83]
Not reported	Female wild-type BALB/c mice	Flow cytometry analysis ELISA test Cell differential counting Histopathology analysis	Suppressed murine innate allergic inflammation by blocking group 2 innate lymphoid cell (ILC2) activation	^[84]
Purchased	MCF-7, T47-D, SKBr-3, and MDA-MB-231 cell lines Tumor xenograft model	Flow cytometry analysis Immunoblotting RT-PCR In vivo liposome uptake Immunohistochemistry of tumor sections	Induced a long-term degradation of cyclin A and a proteasome-dependent loss of ERα and cyclin D1, allowed derepression of p21^WAF1/CIP1 and RhoB GTPase Induced G₂/M cell cycle arrest Induced apoptosis Increased ERα mRNA and p21^WAF1/CIP1 protein expression Decreased cyclin A with a G₂/M blockade and cleavage of PARP	^[85]
Purchased	MCF-7, T-47D, ZR-75-1, BT-474, MDA-MB-231, MDA-MB-453, CAL 51, and SK-BR-3 cells	Cell proliferation assay Immunoprecipitation and western blot analysis Histopathology analysis	Inhibited cell proliferation Exerted antitumor activity in vivo when administered daily (500 μg/kg) by s.c. injection for 4 weeks	^[86]
Purchased	Human tongue squamous cell carcinoma SCC-6 cell lines	MTT assay Cell cycle analysis Cell invasion assay Western blot analysis Annexin V-FITC PI staining	Inhibited cellular proliferation Induced apoptosis Blocked the cell cycle at S and G₂/M phase Inhibited cellular invasion Inhibited hypoxia-induced accumulation of HIF-1α protein and VEGF expression under hypoxic conditions	^[87]
Purchased	Fresh tissues of ESCC were obtained from six patients	Western blot analysis Immunohistochemistry Cell Invasion Assay	Inhibited ESCC cell invasion by approximately 75% Decreased MMP-2 and MMP-9 protein levels in ESCC cells	^[88]
Purchased	AGS gastric cancer cells	CCK-8 experiment Flow cytometry analysis RT-PCR Western blot analysis	Inhibited cell proliferation and promoted cell apoptosis, leading to AGS cell cycle arrest in G₀/G₁ and G₂/M phases, especially G₀/ G₁ phase Increased p21, p53, and Bax gene expression levels Decreased Bcl-2, CDK2, and CyclinD1 gene expression levels	^[88]
Purchased	SW480 and PC3 cells	Transwell invasion and migration assay Western blotting analysis qRT-PCR ChIP assay	Induced the reversal process of EMT in SW480 and PC3 cells, resulting in attenuated cell invasion and migration abilities Decreased the expression of transcription factor Slug	^[89]
Not reported	5,637 Urinary bladder cancer cells	MTT assay Cell cycle analysis Annexin V-FITC and PI staining Measurement of mitochondrial membrane potential Western blot analysis	Altered cell morphology and reduced cell viability Induced cell cycle arrest Induced cell death via apoptosis Induced apoptosis via the mitochondrial pathway by promoting MMP dissipation and caspase-9 Suppressed the PI3K-Akt signaling pathway Induced Sp1 downregulation and suppressed survivin expression	^[90]
Purchased	MCF-7 cells	Transwell invasion and migration assay Wound healing assay RT-qPCR Western blot analysis Overexpression of SLUG	Reversed EMT and attenuated the invasive and migratory abilities of MCF-7 breast cancer cells
Not reported	U937 human leukemic cells	Flow cytometry analysis Cell cycle analysis MTT assay	Induced the growth inhibition and morphological changes in a concentration-dependent manner Increased G₁ cell population of the cell cycle of U937 cells Induced the population of apoptotic sub-G₁ cells Inhibited cyclins, PCNA, and Cdks expression Induced Cdk inhibitors such as p16, p21, and p27	^[91]
Purchased	Human endometrial stromal cell line	MTT assay Real-time RT-PCR Western blot analysis	Inhibited cell proliferation Increased PR-α, PR-β, AR, and FasL expression	^[92]
Purchased	HL-60 cells	MTT assay Annexin V-FITC PI staining Flow cytometry analysis lmmunocytochemical assay	Inhibited cell proliferation IC₅₀ = 100 ng/mL, at the 36th Induced apoptosis	^[93]
Not reported	HeLa cells	RNA isolation and RT-qPCR	Negatively regulated the expression of ubiquitin-specific protease 22 (USP22) Interfered with the binding of RNA polymerase II to the USP22 promoter, directly suppressing its transcription TSA-induced apoptosis was attenuated by the overexpression of USP22 in HeLa cells
Not reported	HeLa cells	MTT assay Hoechst 33258 staining Flow cytometry analysis qRT-PCR	Inhibited cell growth Induced apoptosis Decreased the proportion of cells in S phase and increased the proportion of cells in G₀/G₁ and/or G₂/M phases Induced the overexpression of genes related to malignant phenotype, including an increase in p53, p21^Waf1 and p27^Kipl	^[94]
Purchased	MG-63, 786-0, HT1080 and HeLa cells	Western blot analysis Immunoprecipitation RNA isolation and qPCR Tumor xenograft (BALB/c nude mice)	Inhibited the HIF-2α protein expression Inhibited tumor growth and HIF-2α expression in vivo Destabilized HIF-2α in a proteasome dependent manner, which is unrelated to VHL	^[95]
Purchased	HeLa cells	MTT Assay Flow Cytometric Analyses Measurement of the MMP Immunostaining Annexin V-FITC and PI staining	Reduced cell survival Induced an MMP collapse Apoptotic cell death and the MMP collapse induced by TSA were decreased by the co-treatment of cells with CytoD and LatB	^[96]
Purchased	p815 murine mastocytoma cell line	Trypan blue staining Hoechst 33342 staining Western blot analysis Flow cytometry analysis Immunofluorescent staining	Induced apoptosis Reduced cell viability, and many apoptotic manifestations such as generation of DNA fragmentation, activation of caspase-3, cleavage of PARP, and increased of DNA hypoploidy Increased the expression level of Bad Decreased the level of Bcl-2, Bcl-xL, and X-linked inhibitor of apoptosis protein
Purchased	Mature osteoclasts	Flow cytometry analysis RNA extraction and semi-quantitative RT-PCR Western blot analysis In vivo mouse calvarial resorption analyses	Induced osteoclast apoptosis Induced upregulation of p21^WAF1 in osteoclasts Inhibited RANKL-directed bone destruction in vivo	^[97]
Purchased	HeLa cells	MTT assay Western blot analysis Annexin V staining Measurement of MMP Detection of intracellular O₂^•− levels	Inhibited cell growth Induced apoptosis, caspase-3 activation, and the loss of mitochondrial membrane potential Increased O₂^•− level and induced GSH depletion in HeLa cells The administration of Bcl-2 siRNA intensified TSA-induced HeLa cell death	^[98]
Not reported	Prostate cancer cell line DU145	MTT assay Flow cytometry analysis Immunofluorescence staining Western blot analysis	Induced mitotic catastrophe of DU145 cells, including morphological changes, cell cycle arrest at G₀/G₁ phase, and abnormalities of mitosis Increased the multinuclear cells Inhibited survivin protein expression Increased the expression of P21 protein	^[99]
Purchased	Human pancreatic cancer cell line BxPC-3	MTT assay Cell cycle analysis Annexin V staining miRNA microarray analysis Northern blot analysis	Inhibited pancreatic cancer cell viability Arrested cells in G₀/G₁ phase Induced apoptosis, accompanied by differential expression of microRNAs	^[100]
Purchased	AML-12, 3T3-L1, MDCK, Hep-3B, A549, HeLa, and MCF-7 cells	Flow cytometry analysis Immunoblotting	Suppressed TGF-β1-induced apoptosis in normal hepatocytes but not in hepatoma cells Suppressed serum starvation-induced apoptosis in non-cancer cells but not in cancer cells Induced apoptosis in cancer cells but not in non-cancer cells Activated ERK1/2 in non-cancer cells but not cancer cells	^[101]
Not reported	OVCAR-3 cells	MTT assay Western blot analysis Caspase assay kits	Inhibited cell viability Increased the expression of cytochrome c and P53 and the expression of caspases-3, -8, and -9 Enhanced the mitochondria-mediated apoptotic pathways	^[102]
Purchased	HeLa cells	MTT assay Fourier transform infrared spectroscopy (FT-IR) Immunofluorescence Analysis FT-IR spectroscopic measurements and analysis	Inhibited cell proliferation Induced an elevated level of cellular acetylation and conformational/structural changes of proteins in the cells Induced a higher percent of α-helix structure accompanied by an increment of acetylation level in both histones and cytoskeleton proteins	^[103]
Not reported	HeLa and HepG2 cells	Clonogenic assay	Improved radiation resistance by activating Akt/Nrf2-dependent antioxidation pathway in cancer cells	^[104]
Not reported	MCF-7 cells	MTT assay Annexin-V/PI staining Cell cycle analysis RT-PCR	Inhibited cell proliferation Induced apoptosis Downregulated the expression of ERα, myc-c, cyclin-D, and Bcl-2	^[105]
Purchased	SKOV-3 and A549 cells	MTT assay RNA extraction and qRT-PCR Vybrant apoptosis assay kit Flow cytometry analysis	Exerted dose and time dependent cytotoxicity effect on both cells Upregulated klf4 expression Induced apoptosis	^[106]

The mechanisms involved in anticancer effects of TSA are different and related to each type of cancer. These mechanisms are depending to molecular interaction between TSA and main targets of cancer cells.

2. Anticancer Activity of TSA through Sensitization

Considering the role of various anticancer drugs in chemotherapy and the emergence of chemoresistance, the effect of TSA on the chemosensitivity of several anticancer drugs in cancer cells was investigated by numerous research groups. Findings emphasized that TSA is a potent chemo-sensitizer in human cancer cells to improve chemosensitivity towards many drugs including cisplatin, valproic acid, etoposide, tamoxifen, gemcitabine, 5-fluorouracil, oxaliplatin, irinotecan and gefitinib, sunitinib, and TRAIL. It also enhances the radiosensitivity of cancer cells. Moreover, many molecules, such as genistein, quercetin, and glycyrrhetinic acid potentiated TSA’s anticancer activity against different cancer cell lines. Along this line, TSA reestablished cisplatin sensitivity in many cisplatin-resistant cancer cells and augmented cisplatin activity by eliciting cisplatin-induced apoptosis via various mechanisms. In the head and neck squamous cell carcinoma cell line (UT-SCC-77), cisplatin-induced apoptosis was enhanced by TSA pretreatment ^[107]. TSA decreased lysosomal pH, which augmented cathepsin activity resulting in reduced LAMP-2 level, and the potential LMP promotion. Cells lacking LAMP-2 became more sensitive to cisplatin-induced apoptosis. Earlier work indicated that a lower lysosomal pH increases the efficiency of cisplatin-induced apoptosis. It reduces lysosomal pH and elicits lysosomal proteases and sensitized cells to cisplatin ^[107].

In human lung adenocarcinoma cell line A549 and CDDP-resistant derivative (A549/CDDP), Wu and colleagues ^[108] showed that a low concentration of TSA sensitized cisplatin-resistant apoptosis. TSA upregulated pro-apoptotic proteins (death-associated protein kinase (DAPK)) mediating A549/CDDP cell death induced by cisplatin. TSA pretreatment induced elevation of the active form of DAPK in A549/CDDP, which elicited the chemosensitivity of cells to cisplatin. Similarly, co-treatment of human urothelial carcinoma (UC) cell lines (NTUB1 and T24) with TSA and three chemotherapeutic agents (cisplatin, gemcitabine, and doxorubicin) induced synergistic cytotoxicity and significantly potentiated apoptosis. The combination acted by suppressing Raf/MEK/ERK pathway as it is involved in many aspects of tumorigenesis, including cell growth, proliferation, survival, apoptosis, and chemoresistance in UC ^[109]. The activated Raf/MEK/ERK pathway was observed in human bladder UC specimens from patients with chemoresistant status. The co-treatment with TSA increased cleaved caspases-3,-7, and PARP compared with those induced by chemotherapeutic agents alone, and also suppressed the chemotherapy-induced activation of phospho-Bcl2, an anti-apoptosis regulator. The same conclusions were confirmed, in vivo, in a xenograft nude mouse model.

TNF-related apoptosis-inducing ligand (TRAIL) is a potent anti-cancer agent due to its high selectivity in eradicating cancer cells while sparing normal cells. However, different cancer cells showed TRAIL resistance. In this context, numerous studies reported that TSA enhances TRAIL efficacy and re-sensitizes various cancer cells resistant even at high doses of TRAIL. Researchers ^[110] showed that low doses of TSA sensitized MM1S myeloma cells were resistant to TRAIL-induced apoptosis and enhanced TRAIL cytotoxicity through the caspase-independent pathway. It induced apoptosis involving the downregulation of the antiapoptotic Bcl-2 proteins, Bcl-2 and Bcl-X_L, without altering FLIPS expression. The expression of Bcl-2 members (Bim and Bid) was also upregulated while the expression of PUMA (a and b), Bax, and Noxa, was down-regulated. TSA also induced the transcription of TRAIL death receptor DR5. In another study, Kong et al. ^[111] showed that zebularine and TSA with TRAIL (TZT) treatment sensitizes human breast adenocarcinoma cells (MDA-MB-231 and MCF10A) and augments apoptosis as compared with TRAIL alone. Apoptotic features, including morphological changes, apoptotic activity, and the expression of cleaved poly (ADP) ribose polymerase (PARP) protein were more prominent in MDAMB-231 as compared to MCF10A. No changes in cell cycle were recorded in MDA-MB-231 cells under TRAIL and TZT treatments suggesting other mechanisms ^[111]. Similarly, researchers showed that the co-treatment of human TRAIL-resistant ovarian cancer cells (SKOV3 and Hey8), with TSA and TRAIL inhibits cell proliferation and sensitizes them to TRAIL-induced apoptosis through caspase-dependent mitochondrial pathways ^[64]. Moreover, treating SKOV3 cells with TSA and TRAIL significantly accelerated caspase-8 and truncated Bid resulting in the cytosolic accumulation of cytochrome c and the activation of caspases-3 and -9. On the other hand, the cleavage of PARP, an endogenous substrate of caspase-3, and the upregulation of Bax led to a significant loss of Bcl-2 and Bcl-xL. The sensitization was associated with the downregulation of c-FLIP_L via the inhibition of the EGFR pathway, involving caspase-dependent mitochondrial apoptosis as TRAIL alone did not alter the protein level of c-FLIP.

In gastric cancer cell lines (AGS, NCI-N87, SNU-1 and SNU-16), TSA potentiated TRAIL-induced apoptosis in caspase-dependent manner via the inhibition of the ERK/FOXM1 pathway ^[43]. The combination rendered gastric cancer cells more vulnerable to TRAIL-mediated cytotoxicity and suppressed cell viability in TRAIL-resistant cell AGS and SGC-7901. In the absence of TSA, slight activation of caspases-3, -7, -8, -9, and PARP was observed, whereas the cotreatment greatly potentiated these effects in both SGC-7901 cells. TSA also contributed to the upregulation of DR5 and downregulation of antiapoptotic proteins (XIAP, Mcl-1, Bcl-2 and Survivin) that could be regulated by oncogenic transcription factor Forkhead boxM1 (FOXM1). TSA treatment inhibited FOXM1 expression at both the transcription and protein levels. The expression level of FOXM1 showed a negative correlation with TRAIL sensitivity. FOXM1 downregulation could be ascribed to the inactivation of the ERK pathway, which sensitizes cells to TRAIL.

Research findings ^[112] showed that TSA acts as a sensitizer in chemotherapy and enhances the response to chemotherapeutic agents (gemcitabine, 5-fluorouracil, oxaliplatin, irinotecan and gefitinib) in inhibiting ten pancreatic adenocarcinoma cell proliferation. Ten human pancreatic cancer cell lines, seven derived from primary cancer (MiaPaca2, PaCa3, PaCa44, Panc1, PT45P1, PSN1, and PC) and three from metastatic cancers (HPAF II, CFPAC1, and T3M4) were investigated. TSA was the best partner for all drugs except for 5-fluorouracil leading to potent inhibition of cell growth. The combination of TSA and irinotecan exhibited potent growth inhibition (80%) in most cell lines. In a similar fashion, Zhang et al. ^[113] showed that TSA increases the chemosensitivity of anticancer drugs in two human gastric cancer cell lines (OCUM-8 and MKN-74). The combination of TSA with five anticancer drugs, namely 5-fluorouracil (5-FU), paclitaxel (PTX), oxaliplatin (OXA), irinotecan (SN38), and gemcitabine (GEM) caused a synergistic anti-proliferative effect by combining TSA (30 ng/mL) with 5-fluorouracil, paclitaxel, and irinotecan ^[113]. These three anticancer drugs target cancer through different mechanisms and are used clinically. Furthermore, TSA upregulated the expression of p21, p53, DAPK-1, and the DAPK-2 gene in both OCUM-8 and MKN-74 cells which could be involved in the synergistic effect. The expression level of caspase-3 mRNA increased in OCUM-8 but not in MKN-74, suggesting a key role of caspase-3 in chemosensitivity induced by TSA. It was suggested that the bcl-2 family might not contribute to the enhanced chemosensitivity of TSA as no alteration of bcl-2 was observed.

TSA sensitized estrogen receptor (ER) α-negative in formerly antihormone-unresponsive human breast cancer cells (MDA-MB-231, Hs578T and ZR75-1) to tamoxifen treatment possibly by upregulating ER β activity ^[114]. TSA enhanced the ER transcriptional activity as visualized by estrogen response element-regulated reporter and progesterone receptor expression. It seems that the high ER transcriptional activity is mediated by ER β rather than α as TSA induced the expression and nuclear translocation of ER β but not α. Sato et al. ^[115] showed that the combination of TSA-Sunitinib is effective against RCC cells 786-O, ACHN, and Caki-1 RCC cell lines, especially in 786-O, by enhancing apoptosis or growth inhibition through an increase of p21. VEGF protein expression was suppressed by the used combination. Flow cytometry revealed that the apoptotic cell population (sub-G1) was significantly higher in the TSA-Sunitinib combination group compared to the single SU treatment group. In ACHN cells, a cell cycle arrest at the S and G2/M phase was observed in the combined treatment group. Additionally, p21 was significantly increased in both 786-O and ACHN cells.

In renal cell carcinoma (786-O, ACHN, and Caki-1 RCC cells), TSA reduced sunitinib resistance by triggering intracellular metabolome shifts ^[116]. Combined metabolome and transcriptome analysis suggested that TSA affects the energy productive metabolic pathways, such as those involving the TCA cycle and nucleotide metabolism. The combination of sunitinib and TSA increased cell death with PARP cleavage, an early marker of mitochondrial apoptosis. In contrast, the receptor tyrosine kinase signaling (the target of sunitinib) was not altered. The sunitinib resistant-RCC cell (786-O Res) when exposed to the sunitinib-TSA combination showed significant growth inhibition. Cells experiencing irreversible damage underwent apoptosis, causing an accumulation of cells in the sub-G1 population and the accumulation of cleaved PARP, introduced by caspase-3. In hepatoma cells (HepG2), Donia et al. ^[117] showed that TSA enhances responsiveness and induces apoptosis to Taxol. The sensitizing effect of acetylation modification on the responsiveness of hepatoma cells to anticancer therapy is ascribed to its modulatory role on epigenetics via the upregulation of HDAC1 and downregulation of Dnmt1 and 3α gene and drugs metabolizing genes.

Using cervical cancer HeLa cells, researchers showed that TSA synergistically enhances the DNA targeting capacity and apoptosis-inducing efficacy of silver nanoparticles (AgNPs) due to its effect on chromatin condensation and through the activation of the apoptosis effector caspase. Significant ROS generation was observed upon AgNP and TSA treatment corroborating that oxidative stress contributes to the cellular effects of both compounds. A high number of γH2AX foci was detected, suggesting the enhanced formation of double-strand DNA breaks with the combination treatment ^[118]. TSA sensitized the hepatocellular carcinoma cells (HCC) (HepG2 cells) to enhance NK cell-mediated killing by regulating immune-related genes. In this regard, Shin et al. ^[119] observed a significant alternation in the immune-associated genes in TSA-treated HepG2 cells, particularly concerning innate immunity-related genes and antigen recognition-related genes. These findings suggest that TSA induces NK cell-mediated anti-tumor effects in HCC. TSA indirectly increased the killing of HCC cells by increasing NK cell-directed killing and directly by increasing apoptosis. TSA regulated the transcription of numerous innate immunity and tumor antigen recognition-associated genes, such as ULBP1 and RAET1G, in HCC cells. In addition, TSA treatment of HepG2 cells rendered them more susceptible to NK cell-mediated killing while increasing the expression of NKGD2 ligands, including ULBP1/2/3 and MICA/B. TSA also induced the direct killing of HCC cells by stimulating apoptosis. Furthermore, TSA treatment increased nuclear fragmentation and apoptotic bodies in a dose-dependent manner and increased the cleaved (active) caspase-3 in HepG2 and Huh7 cells whereas, PARP, a critical DNA repair protein, was also cleaved by TSA treatment. In vivo, TSA also reduced tumor cell growth in an NK cell-dependent manner in an established HCC tumor xenograft model in BALB/c nude mice ^[119].

The sensitive effects the sensitizing effect of TSA on cancer cells towards drugs used in chemotherapy can be mediated by suppressing the resistance characteristics of tumor cells. In addition, the determination of the sensitizing molecular action of TSA could make it possible to set up the mechanisms of resistance to anticancer drugs.

3. Effect of Other Molecules on Enhancing the Anticancer Activity of TSA

Numerous studies showed that some anticancer drugs enhanced the anticancer efficacy of TSA. Wu et al. ^[120] reported that the addition of genistein enhanced the inhibition of growth of A549 lung cancer cells and increased apoptosis induced by TSA via, at least in part, the up-regulation of the TNF receptor-1 (TNFR-1) death receptor signaling pathway. TSA, in combination with genistein increased TNFR-1 mRNA and protein expression, while TSA alone exhibited no changes. Moreover, the same combination increased the activation of caspases-3 and -10 and p53 protein expression. Genistein enhanced the effect of TSA by increasing the expression of TNFR-1, which activated the caspase cascade and resulted in apoptosis. The silencing of TNFR-1 expression negatively affected the genistein’s effect on TSA’s anticancer efficacy in human lung cancer A549 cells ^[120]. Similarly, TSA-induced apoptosis was synergistically enhanced by quercetin through the mitochondrial pathway in human lung cancer A549 cells ^[121]. The expression level of p53 was potentiated by the treatment with a combination of TSA and quercetin. In parallel, p53 silencing did not completely inhibit the augmenting effect of quercetin on TSA-induced apoptosis, suggesting the contribution of an additional p53-independent pathway. Quercetin synergistically enhanced the TSA-induced acetylation of histones H3 and H4 suggesting that quercetin enhances TSA-induced histone acetylation by p53-independent mechanisms; this may contribute to the enhancing effect of quercetin on apoptosis. The cotreatment with TSA-quercetin increased the expression of many mitochondria-associated pro-apoptosis genes, including Apaf-1, Bax, and caspase-9, and resulted in a marked release of cytochrome c into the cytosol, which demonstrated, at least in part, a mitochondrial pathway mechanism. Moreover, the cotreatment with TSA-quercetin was tested in a xenograft tumor model in nude mice leading to potent inhibition of tumor growth through the upregulation of p53 protein and a higher level of apoptosis ^[121]. In another study, Chan et al. ^[122] showed that quercetin dose-dependently enhanced the antitumor effect of TSA by upregulating the expression of p53. Quercetin prevented TSA-induced muscle wasting, at least in part, through the activation of Forkhead box O1 (FOXO1), the suppression of muscle wasting associated proteins atrophy gene-1 and muscle ring-finger protein-1 expression and increasing the myosin heavy chain level in the gastrocnemius muscles. Moreover, quercetin attenuated TSA-increased oxidative damage and the pro-inflammatory cytokines ^[122]. TSA-induced apoptosis was potentiated by 18β-glycyrrhetinic acid in human epithelial ovarian carcinoma cell lines (NIH-OVCAR-3 and SK-OV-3 cells) as reported by Lee et al. ^[123]. It was suggested that 18β-glycyrrhetinic acid might potentiate the apoptotic effect of TSA against ovarian carcinoma cell lines by increasing the activation of the caspase-8 dependent pathway and the activation of the mitochondria-mediated cell death pathway, leading to the activation of caspases. In fact, TSA induced nuclear damage, decreased Bid and Bcl-2 protein levels, increased Bax levels, caused cytochrome c release, activated caspases-3, -8, and -9, and increased tumor suppressor p53 levels.

4. Anticancer Effect of TSA in Combination with Chemotherapy

In addition to the promising anticancer activity of TSA confirmed by the multiple studies mentioned above, a synergistic effect of this molecule with other compounds was also proven. In 2002, Chen and collaborators were among the first researchers who sought the synergistic activity of TSA and other compounds to tackle colon cancer ^[124]. They conducted an in vitro study combining TSA with butyrate, a fatty acid produced by microbial fermentation of dietary fiber in the intestinal tract, to assess their anticancer effect against the SW620 human colon cancer cell line. This combination induced the expression of DNA damage-induced gene 45α (GADD45α) and GADD45β, belonging to a family of classical tumor suppressor genes ^[125]. These genes also promoted DNA repair and removed methylation markers ^[126]. The same results were obtained by combining TSA with cycloheximide, an antifungal that inhibits protein synthesis in eukaryotic cells. A year later, Rahman et al. ^[127] verified this synergistic effect of TSA with other compounds in mouse (ddY mice) and rats (male Sprague Dawley rats) bone marrow cultures and murine macrophage cell line RAW264 to elucidate their role in osteoclastogenesis ^[127]. TSA and sodium butyrate (NaB) showed several positive results including the inhibition of osteoclast formation, inhibition of osteoclast-specific mRNA expression in RAW264 cells, and reduction of trans-activation of NF-κB-dependent reporter genes. In another study, Min et al. (2004) evaluated the anti-proliferative activity of TSA with HC-toxin in two human breast cancer cell lines, MCF-7 and MDA-MB-468 ^[128]. These authors observed a strong activity against both cell lines and the induction of apoptosis and cell cycle arrest at the G₂/M phase.

Similarly, Jeon and his coworkers assessed the antitumor effect of TSA combined with gemcitabine, a chemotherapy drug against human bladder cancer cell lines (HTB5, HTB9, T24, J82 and UMUC14). These researchers showed that TSA synergistically potentiated the antitumor effect of gemcitabine, triggering cell cycle arrest and apoptosis and inducing repression of NF-κB signaling pathway activation ^[129]. In pancreatic cancer, the combination of TSA with gemcitabine suppressed the proliferation of human pancreatic adenocarcinoma cell lines in vitro and induced cell apoptosis by increasing the expression of the pro-apoptotic BIM gene accompanied by the downregulation of the 5’-nucleotidase UMPH type II gene ^[130]. Moreover, in vivo studies in xenografts of pancreatic adenocarcinoma cells in nude mice showed that this combination reduced tumor mass to 50% ^[130]. Furthermore, Hammer et al. ^[131]. investigated the in vitro and in vivo anticancer effect of the combinatory treatment of TSA with interferon β (IFN-β), a type of immunomodulating molecule known for its strong antitumor action, against human neuroblastoma cells (NB-1691 and NB-1643) and retroperitoneal human neuroblastoma xenografts. Results demonstrated that TSA acted synergistically with IFN-β, inducing a decrease in cell count compared to the controls in human neuroblastoma NB-1691 and NB-1643 cell lines. This effect was accompanied by the upregulation of p21Waf1 expression levels, especially in NB-1691 cells ^[131].

On the other hand, in vivo experiments showed that this combinatory based-therapy significantly restricted tumor growth in the murine model of neuroblastoma. In this respect, combining TSA with another HDAC inhibitor, valproic acid, inhibited the growth of neuroblastoma cells with IC₅₀ values ranging from 69.8 to 129.4 nM ^[132]. This combination induced the expression of CYP1A1, one of the main cytochromes P450 enzymes involved in the metabolism of carcinogens, which consequently potentiated its anticancer effect against UKF-NB-3 and UKF-NB-4 neuroblastoma cell lines ^[132]. In another study, using renal cell carcinoma (RCC) cells (SK-RC-39 and SK-RC-45 lines) and tumor xenograft model, Touma et al. ^[133] demonstrated that TSA and all-trans retinoic acid (ATRA) combinatory therapy might represent an effective strategy for the treatment of advanced RCC. These authors showed that TSA with ATRA suppressed the proliferation of RCC cell lines and tumor growth in a xenograft model through the reactivation of tumor suppressor genes such as the retinoic acid receptor β2 gene (RARβ2) mRNA expression (8 h after treatment). They also observed that TSA and ATRA combination induced apoptosis and partial G0-G1 arrest in RCC SK-RC-39 cell lines ^[133]. Interestingly, focusing on developing a novel therapeutic strategy against ovarian cancer, particularly taxane-resistant ovarian cancer, Jin et al. ^[134] reported the possible mechanism of the synergistic anticancer effect of TSA with a proteasome inhibitor PS-341 in ovarian cancer A2780 cell line and its resistant variant, A2780T cells. The combination of TSA with PS-331 induced cell cycle arrest at the G2/M phase and apoptosis, and inhibited cell proliferation in A2780 and A2780T cells associated with the overexpression of cyclin B1.

The Raf/MEK/ERK pathway has been the subject of intense investigations in the field of chemotherapy due to its multiple effects on cell growth, proliferation, prevention of cell-cycle arrest and apoptosis and the induction of drug resistance in different cell lines ^[135]. Thus, the Raf/MEK/ERK pathway represents an attractive target-based approach for cancer treatment. Addition of TSA to chemotherapeutic agents such as cisplatin, gemcitabine, or doxorubicin-induced synergistic cytotoxicity and concomitantly inhibited chemotherapeutic drug-induced activation of Raf-MEK-ERK signaling pathway in human urothelial carcinoma (UC) cells ^[109]. Activated Raf/MEK/ERK pathway is involved in the chemoresistant mechanism of UC ^[109]. These findings indicate that combining chemotherapeutic agents with TSA is a promising avenue to overcome the chemotherapeutic resistance of urothelial carcinoma cells via the inactivation of the c-Raf/ERK pathway.

TSA can exhibit its anticancer action via different combinatory effects. Indeed, it potential the effects of used drugs in chemotherapy via its direct and/or indirect effects on cancer cell lines. This property should be explored and further investigations testing the combinatory effects of TSA with anticancer drugs in clinical trials.

5. TSA Targets Epigenetic Modifications in Cancer

Recent investigations showed that cancer cells are characterized by epigenetic instability and memory disruption. During cell differentiation and development, memory cells are installed and maintained under epigenom programs. Epigenomic programs involve epigenetic modifications, which design changes in gene expression without any change in the physical structure of DNA. Several enzymes are involved in these epigenetic modifications including DNAT (DNA methyltransferase), which is responsible for DNA methylation, HDAC (histone deacetylase) and HAT (histone acetylase) which are responsible for histone modifications. Current molecular investigations indicated that the disruption of epigenetic marks can lead to cell transformation and tumorigenesis. Certain pharmacological investigations revealed the role of some molecules called epidrugs against cancer. These molecules target epigenetic perturbations and exhibit remarkable anticancer properties. The TSA direct effects on cancer cell lines, its chemosensitizing agent towards chemotherapy, and its synergistic effect with other chemotherapeutic drugs, suggest its potential as an important epidrug molecule against different human cancers.

The micro-RNA (mRNA) was reported as another key in cancer epigenetic modification. Januchowski et al. ^[136] elucidated the role of TSA in Jurkat T leukemia cells clone E6-1 genetics character expression. By employing Western blot and quantitative real-time PCR methods, these researchers found that TSA can suppress the DNMT1 mRNA stability and protein expression in Jurkat T cells ^[136]. TSA increased the mRNA expression of the DKK1 gene in colon cancer cells ^[137]. Human malignant lymphoma CA46 cells were subjected to TSA alone or combined with epigallocatechin-3-gallate (EGCG) ^[120]^[138]. Results revealed that TSA alone inhibited CA46 cell proliferation, and when TSA (15 ng/mL) was combined with EGCG (6 μg/mL), the proliferation of CA46 cells from 24 to 96 h was decreased ^[138]. The co-treatment with TSA and EGCG downregulated p16^INK4A gene methylation, correlated with a rise in p16INK4A mRNA and protein expressions. This combination also reactivated p16^INK4A gene expression partially by lowering promoter methylation and reducing the CA46 cell overgrowth ^[138]. The above-mentioned studies proved the promising chemopreventive properties of TSA alone or in combination with other compounds and could be employed as a potential target in the treatment of hepatocellular carcinoma, breast, ovarian, and colon cancers.

This entry is adapted from the peer-reviewed paper 10.3390/ph15101235

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