Potential risks of histone deacetylase inhibitors in cancer therapeutics and feasible combination therapeutic strategies

Abstract

Histone deacetylase inhibitors (HDACis), such as trichostatin A (TSA), have been recognized as promising anti-cancer agents due to their capacity to restore epigenetic regulation and reactivate tumor suppressor genes. However, emerging evidence indicates that unintended pro-metastatic effects may offset the therapeutic benefits of HDACis. Chen et al elucidate this paradox, demonstrating that TSA-induced hyperacetylation activates the BRD4/c-Myc/ER-stress axis, thereby promoting epithelial-mesenchymal transition and metastasis in esophageal squamous cell carcinoma (ESCC). Furthermore, they clarify the clinical significance of histone acetylation in the prognostic evaluation of ESCC. Their findings underscore the complexity of epigenetic therapies and highlight the necessity of reevaluating the associated risks and combinatorial therapeutic strategies with HDACi-based treatments. Here, we summarize the potential risks of HDACis therapy and discuss feasible combination therapeutic strategies.

Key Words: Histone deacetylase inhibitors; Trichostatin A; Combination therapeutics; Selective inhibitors; Multidrug resistance

Core Tip: Histone deacetylase inhibitors (HDACis) have been extensively researched for their potential anticancer effects. However, in addition to their role in inhibiting tumor growth, it has also surprisingly facilitated the metastasis of esophageal squamous cell carcinoma. Clinical studies indicate that the effectiveness of HDACis in treating solid tumors often falls short of expectations, and these inhibitors may inherently carry certain risks. In this article, we examine the potential dangers associated with the clinical use of HDACis, including severe adverse effects, off-target toxicities, multidrug resistance, and limited efficiency in solid tumors. Furthermore, future research should focus on combination therapies, the development of selective or dual-target inhibitors to mitigate the adverse effects of HDACis treatments.

INTRODUCTION

Esophageal cancer, particularly esophageal squamous cell carcinoma (ESCC), presents a significant global health challenge[1]. The poor prognosis associated with ESCC primarily stems from late diagnosis, aggressive tumor biology, and limited treatment efficacy[2]. Histone acetylation plays a critical role in gene expression by modifying chromatin structure, and its dysregulation is implicated in cancer development and progression[3,4]. The overactivity of histone deacetylases (HDACs) can result in the silencing of tumor suppressor genes, thereby facilitating uncontrolled cell growth[4,5]. HDAC inhibitors (HDACis) have shown promise in treating various cancers and neurological disorders, particularly in hematological malignancies[6,7]. They play a crucial role in regulating protein acetylation, disrupting epigenetic silencing, restoring the expression of tumor suppressor genes, and inducing apoptosis or autophagy in cancer cells (Figure 1A and B)[8,9]. In certain tumors, increased acetylation inhibits tumor proliferation; however, it may also facilitate epithelial-mesenchymal transition (EMT) and metastasis, causing the failure of HDACis[5,10]. This research highlights the complexity of epigenetic therapies and emphasizes the necessity of optimizing the application of HDACis in ESCC and potentially other cancers.

Figure 1 The dual-edged sword of histone deacetylase inhibitors in cancer therapy. A: Mechanistic basis of histone deacetylase inhibitors (HDACis) antitumor activity. HDACis suppress tumor cell proliferation and promote caspase-dependent apoptosis through stabilization of p53 signaling, induce cell cycle arrest, and suppress NF-κB nuclear translocation; B: Clinical advantages in haematological malignancies [especially T-cell lymphoma (TCL) and multiple myeloma]. The overall response rate (ORR) and disease control rate (DCR) of patients with peripheral TCL receiving tucidinostat monotherapy were 39.06% and 64.45%, and the 5-year survival rate was improved. Furthermore, HDACis in combination with other therapeutic agents lower the conventional chemotherapeutic dose and reduce the damage to the kidneys; C: Treatment-limiting toxicities. HDACis treatment class-related risks, including cardiotoxicity, hematologic toxicity, myelosuppression, and diarrhoea. Cardiotoxicity mainly includes QTc prolongation, reduced left ventricular ejection fraction, isolated cases, and ventricular tachyarrhythmias. Dose-dependent hematologic toxicity manifests as grade 3/4 thrombocytopenia (38% incidence) and neutropenia (42% incidence). Furthermore, HDACi treatment also leads to increased fatigue in patients; D: Challenges in solid tumor management. One of the primary challenges is limited efficacy in solid tumors, such as non-small cell lung cancer (ORR = 9%), breast cancer (progression-free survival = 2.1 months), and hepatocellular carcinoma (DCR = 18%). Another critical challenge is multidrug resistance, which is mediated by ABC transporter upregulation and compensatory HDAC6 overexpression. HDAC: Histone deacetylase; PFS: Progression-free survival; OS: Overall survival.

Chen et al[11] reveal a novel mechanism by which trichostatin A (TSA) promotes the migration of ESCC cells. They demonstrate that TSA upregulates BRD4, which triggers downstream c-Myc overexpression and endoplasmic reticulum (ER) stress[11]. The ER stress signaling pathway is linked to the regulation of EMT-related transcription factors and signaling pathways, thereby contributing to cancer metastasis[12]. This finding suggests that TSA promotes the ESCC metastasis by activating ER stress-induced EMT. Indeed, the regulatory effect of HDACis on EMT is complex, with specific effects varying depending on the type of inhibitor, cancer model, or molecular pathway[13]. Increasing evidence suggests that certain HDACis promote tumor migration and invasion by inducing transcription factors[13,14]. For instance, HDACis downregulate the expression of E-cadherin by modulating the Claudin-1 mRNA stability, thereby facilitating EMT and invasiveness in multiple colon cancer cell lines[15]. Furthermore, Chen et al[11] found that high levels of histone acetylation in clinical ESCC samples were associated with poor prognosis of patients, suggesting that HDACis monotherapy could promote aggressive, metastatic phenotypes in subsets of patients. These findings are consistent with previous reports that HDACis enhance tumor plasticity in other cancers, but also provide unprecedented mechanistic insights into TSA promotes ESCC metastasis.

The dual role of TSA -both tumor suppression and metastasis promotion- is a critical challenge in the field of epigenetic therapy. Given that TSA promotes ESCC metastasis by the BRD4/c-Myc/ER-stress axis in Chen et al's work[11]. Therefore, the combination of BET inhibitors and TSA is a possible therapy strategy in ESCC. In a preclinical study, the combination therapy of TSA and JQ1 (a BET inhibitor) effectively inhibits the progression of non-small cell lung cancer (NSCLC) by suppressing BET and c-Myc expression in cellular and xenograft mouse models[16]. Moreover, directly targeting c-Myc with small-molecule inhibitors or RNA interference can neutralize this central oncogenic node. For example, MYC inhibitor 361 can effectively inhibit tumor growth in mice by enhancing tumor immune cell infiltration and the expression of PD-L1[17]. In addition, ER stress is an adaptive response that promotes cancer cell survival in previous studies[18]. Preclinical studies have shown that the IRE1α inhibitor 4μ8c directly targets IRE1α/XBP1 signaling and promotes survival in mice with ovarian tumors in situ[19]. The authors also found that TSA promotes ESCC metastasis by activating ER stress. Therefore, the combination of ER stress inhibitors with TSA may inhibit ESCC metastasis by mitigating ER stress.

The clinical application of HDACis is associated with potential risks and challenges, including severe adverse effects, off-target toxicities, and limited efficacy against solid tumors (Figure 1C and D)[5]. The primary challenge of HDACis therapy is the occurrence of severe adverse effects and off-target toxicities, which can impact multiple organ systems[20]. Clinical trials report frequent gastrointestinal disturbances, hematological cytopenias (thrombocytopenia, neutropenia), and potential cardiotoxicity and hepatotoxicity, significantly limiting clinical utility[21,22]. Traditional HDACis are almost all pan-HDACis, which exacerbate the occurrence of adverse events in clinical trials[23]. Mechanistically, broad-spectrum HDAC inhibition disrupts both oncogenic and tumor-suppressive pathways. Consequently, insufficient selectivity may be the main reason for the adverse effects and off-target toxicity of HDACis in cancer treatment. Furthermore, the limited efficiency of monotherapy for solid tumors is a critical challenge for HDACi therapy. Studies have shown that HDAC expression varies greatly in different tumor types. For instance, clinical trials have shown that class I HDAC (HDAC1/2/3) is overexpressed in 71% of gastric cancers and 58% of triple-negative breast cancers (TNBC), whereas class IIb subtype (HDAC6/10) shows an environment-dependent tumor suppressor function[24]. Those results suggest that stratifying patients based on HDAC isoforms and the expression levels provides critical insights into their responsiveness to HDACis therapy. Moreover, HDAC isoform expression patterns combined with c-Myc amplification status improve the prediction of therapeutic response[25]. Furthermore, multidrug resistance (MDR) is another critical challenge. Preclinical studies further identify HDACis-mediated MDR by upregulating the expression of ABCB1. For instance, HDACis upregulates P-glycoprotein (P-gp) by increasing the expression of STAT3 in colorectal cancer cells[26]. This upregulation enhances drug efflux from cancer cells and reduces intracellular drug concentration, thereby inducing MDR in cancer cells.

The combination of HDACis with chemotherapy, radiotherapy, targeted therapy, and immunotherapy is expected to improve the therapeutic effect of the drugs on tumors while reducing their toxicity[7]. Therapeutic synergism is manifested through four main molecular mechanisms. First, HDACis enhance chemotherapy sensitization by impairing DNA damage repair (DDR). Preclinical studies have demonstrated that HDACis compromise DDR to potentiate the effects of chemotherapeutic agents. For instance, the HDAC6 inhibitor ACY1215 synergizes with gemcitabine/oxaliplatin in gallbladder cancer by downregulating BRCA1/2[27], while domatinostat overcomes resistance to gemcitabine and taxol in pancreatic cancer stem cells through the induction of oxidative stress[28]. Clinically, a phase II trial showed superior response rates for chidamide combined with chemotherapy compared to monotherapy (51.18% vs 39.06%) in peripheral T-cell lymphoma[29]. The second mechanism involves kinase inhibitor synergism. Ruxolitinib (a JAK inhibitor) with SAHA (an HDACi) co-treatment inhibits the progression of TNBC[30], and HDACi-DNMT conjugates inhibit the proliferation of gastric cancer[31]. The third mechanism is immunomodulation through microenvironment remodeling. The HDAC6 inhibitor ACY241 enhances anti-PD-L1 efficacy in multiple myeloma and solid tumors by activating the AKT/mTOR/p65 pathways[32]. Furthermore, chidamide combined with PD-L1 blockade demonstrates synergistic activity in NSCLC and TNBC[33]. Finally, radiosensitization is another important mechanism. Chidamide amplifies radiotherapy-induced oxidative stress, promoting apoptosis and reducing stemness in squamous lung cancer cell models[34].

To mitigate off-target toxicity, the development of isomer-selective HDACis or dual inhibitors presents a promising strategy for minimizing adverse reactions in future therapeutic approaches[35]. Notably, the dual HDAC1/3 inhibitor showed a significant inhibitory effect on HCT116 cell xenografts[36]. Similarly, HDAC3/6 dual-selective inhibitors demonstrate low micromolar antiproliferative activity against MDA-MB-231 cells[37]. Additionally, personalized medical approaches, such as pharmacogenomic testing to identify patients at elevated risk for adverse reactions, can facilitate the development of tailored treatment protocols[13]. To address the challenge of MDR, combining HDACis with inhibitors of P-gp may enhance the intracellular accumulation of HDACis within cancer cells. Additionally, molecular targeting strategies designed to modulate the expression of ABC transporters can improve the efficacy of HDACis and help overcome resistance mechanisms[38]. For instance, employing small-molecule inhibitors or RNA interference techniques to downregulate P-gp may significantly enhance the therapeutic effects of HDACis in cancer types exhibiting resistance[39]. Collectively, while HDACis therapy presents potential risks due to severe adverse effects and off-target toxicities, employing strategic combination therapies, developing isomer-selective HDACis or dual-target inhibitors, and implementing personalized medical approaches can enhance therapeutic outcomes and minimize adverse effects.

CONCLUSION

In summary, Chen et al[11] reveal a novel mechanism through which TSA enhances the migration of ESCC cells by activating ER stress-induced EMT. The pro-metastatic effects of TSA in ESCC highlight that epigenetic therapies are not universally benign. This study emphasizes the importance of mechanism-based drug design and combination treatment approaches. Furthermore, traditional HDACis exhibit severe adverse effects in clinical applications, including off-target toxicities and limited therapeutic efficacy against solid tumors. This letter offers new insights into the potential risks associated with HDACis and suggests future strategies to enhance their clinical utility, such as the implementation of diverse combination therapies and the development of selective and dual-target inhibitors. Additionally, considering the differential expression levels of specific HDACs across various malignancies, patient stratification is critical for successfully applying HDACis therapies, ultimately improving therapeutic efficacy and minimizing adverse effects.

ACKNOWLEDGEMENTS

We thank the reviewers for their comments that helped to improve the manuscript.