Anticancer Activity of Trichostatin A: History
Please note this is an old version of this entry, which may differ significantly from the current revision.

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.
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-XL, 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-FLIPL 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.

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 p16INK4A gene methylation, correlated with a rise in p16INK4A mRNA and protein expressions. This combination also reactivated p16INK4A 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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