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HDAC inhibitors: a new radiosensitizer for non-small-cell lung cancer

Abstract

For many decades, lung cancer has been the most common cancer and the leading cause of cancer death worldwide. More than 50% of non-small-cell lung cancer patients receive radiotherapy (alone or in combination with chemotherapy or surgery) during their treatment. The intrinsic radiosensitivity of tumors and dose-limiting toxicity restrict the curative potential of radiotherapy. Histone deacetylase inhibitors (HDACis) are an emerging class of agents that target histone deacetylase and represent promising radiosensitizers that affect various biological processes, such as cell growth, apoptosis, DNA repair, and terminal differentiation. Histone deacetylase inhibitors have been found to suppress many important DNA damage responses by downregulating proteins in the homologous recombination and nonhomologous end joining repair pathways in vitro. In this review, we describe the rationale for using HDACis as radiosensitizers and the clinical evidence regarding the use of HDACis for the treatment of non-small-cell lung cancer.

Tumori 2015; 101(3): 257 - 262

Article Type: REVIEW

DOI:10.5301/tj.5000347

Authors

Lucheng Zhu, Kan Wu, Shenglin Ma, Shirong Zhang

Article History

Disclosures

Financial support: Supported by the National Natural Science Foundation of China (grant no. 81272611).
Conflict of interest: None.

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Introduction

For many decades, lung cancer has been the most common cancer and the leading cause of cancer death worldwide (1). Non-small-cell lung carcinoma (NSCLC) and small-cell lung carcinoma are the 2 primary types of lung cancer. In this review, we focus on NSCLC. Surgery, chemotherapy, and radiotherapy are the 3 primary treatment modalities for NSCLC. More than 50% of NSCLC patients receive radiotherapy (alone or in combination with chemotherapy or surgery) during their treatment (2). However, the intrinsic radiosensitivity of tumors and dose-limiting toxicity restrict the curative potential of radiotherapy (3, 4). Therefore, novel approaches are under investigation to selectively augment the effects of radiation on cancer cells while sparing the surrounding tissue.

We describe the rationale for using histone deacetylase inhibitors (HDACis) as radiosensitizers and the clinical evidence supporting the use of HDACis for the treatment of NSCLC. For this purpose, we searched PubMed, Web of Science, Medline, Embase, and Google Scholar databases. The search strategy included both MeSH terms and free-text words to increase the search sensitivity. The following search terms were used: “non-small cell lung cancer(s)/carcinoma(s)/NSCLC” and “HDACi(s)/HDAC inhibitor(s)/histone deacetylase inhibitor(s).”

Function and classification of HDACis

The nucleosome is the fundamental unit of chromatin and is composed of DNA wrapped around an octamer of histones H2A, H2B, H3, and H4 (5). These proteins are subject to several post-translational modifications, including acetylation, methylation, phosphorylation, and ubiquitination. Acetylation, the best studied post-translational protein modification, is regulated by the opposing action of histone deacetylases (HDACs) and histone acetyltransferases (6, 7). The HDACs catalyze the removal of the acetyl group from the lysine residues of histones, leading to local remodeling of chromatin and resulting in the formation of heterochromatin and the transcriptional silencing of genes (8). The HDACs exert parallel effects on nonhistone proteins to regulate gene expression, cell proliferation, cell migration, cell death, and angiogenesis (9, 10).

The 18 HDACs that have been identified in humans are divided into Classes I-IV (11). According to their similarity to analogous yeast proteins, Class I (HDACs 1, 2, 3, and 8), Class II (Class IIA: HDACs 4, 5, 7, and 9; Class IIb: HDACs 6 and 10), and Class IV (HDAC 11) are Zn2+-dependent, whereas Class III requires NAD+ as an essential cofactor (12-14).

The HDACs play key roles in several cell processes, including cell proliferation, differentiation, migration, and death (15, 16). In addition, several types of human tumors have been found to exhibit altered expression of HDACs (9, 17). Therefore, the inhibition of HDACs would be expected to interrupt or block these processes, providing the rationale for the development of HDACis as cancer therapeutics. The HDACis are an emerging class of agents that target HDAC; as such, these promising radiosensitizers are currently under investigation.

The HDACis are also classified based on their chemical properties, such as short-chain fatty acids (sodium butyrate [NaB] and valproic acid [VPA]), hydroxamic acids (vorinostat [SAHA], panobinostat [LBH589], belinostat [PXD101], and trichostatin A [TSA]), cyclic tetrapeptides (apicidin, romidepsin [FK228], and trapoxin A), and benzamides (entinostat [MS-275] and mocetinostat [MGCD0103]) (18, 19).

The HDACis are epigenetic modulators that affect different biological processes such as cell growth, apoptosis, DNA repair, and terminal differentiation (20, 21). The HDACis primarily exert their effects by modifying histone and chromatin structures, thereby modulating gene transcription (22). In addition, HDACis may facilitate chromatin relaxation by shifting the balance toward histone acetylation, thereby increasing the probability of DNA damage (23, 24). The HDACis have been reported to act as radiosensitizers in many human cancer types, including glioma, colorectal carcinoma, cervical cancer, and melanoma (25-28).

DNA response after ionizing radiation

Ionizing radiation (IR) produces a wide variety of DNA lesions, including modifications of bases and sugars, interstrand crosslinks, single-strand breaks (SSBs), and double-strand breaks (DSBs) (29). Among these lesions, DSBs are considered to be the most biologically significant lesions in terms of toxicity. When DSBs occur, a sophisticated and highly regulated signal transduction network referred to as the DNA damage response (DDR) is activated. Based on the cell cycle phase during which the DNA lesions are generated and the types and complexity of these lesions, 2 major distinct mechanisms, homologous recombination (HR) and nonhomologous end joining (NHEJ), are activated to repair DSBs.

Homologous recombination is characterized by the use of a sister chromatid sequence as a template for the high-fidelity repair of DSBs. Homologous recombination contributes to DNA repair during the S and G2 phases of the cell cycle (30). The first step of HR is the initiation of end resection, which requires the Mre11/Rad50/Nbs1 (MRN) complex and CtIP (31, 32). The second step involves the recruitment of RPA to nuclear foci to activate 2 kinases, ataxia telangiectasia and Rad3-related protein (ATR) and ataxia telangiectasia mutated (ATM) (33). The RAD51 proteins replace the RPA proteins, and XRCC3 identifies a homologous sequence on the sister chromatid (34). Breast cancer type 2 susceptibility protein 2 is necessary to recruit RAD51 to IR-induced damaged DNA foci during the HR pathway (35). Subsequently, ATR and ATM phosphorylate breast cancer type 1 susceptibility protein (36, 37). In addition, the activation of Chk1 by ATR and Chk2 by ATM initiates intra-S cell cycle arrest by inhibiting the nuclear export of Cdc25 (38, 39). Breast cancer type 1 susceptibility protein, along with other HR effectors, promotes HR-mediated DSB repair (40). Figure 1 provides a schematic overview of HR and NHEJ DNA repair pathways.

Schematic overview of homologous recombination and nonhomologous end joining DNA repair pathways.

NHEJ is a potentially inaccurate DSB repair pathway that can be activated throughout the cell cycle and serves as the prevailing DNA repair pathway during the G1 and M phases (41). NHEJ is initiated by 53BP1 and RIF1. This pathway begins with the binding of the Ku heterodimer (Ku70/Ku80) to both ends of the DSB. Subsequently, the DNA-Ku complex attracts a DNA-dependent protein kinase catalytic subunit (DNA-PKc) to the DSB. The DNA-PKc processes the DNA ends by recruiting nucleases, including Artemis (42, 43). Finally, ligase IV/XRCC4/XLF completes end ligation (44, 45).

Preclinical studies of HDACis in NSCLC

γH2AX is an established marker of DSBs and is influenced by HDACis. Pretreatment with SAHA upregulated γH2AX following irradiation in A549 cells (46). Both vorinostat and MPT0E028 (a new HDACi) increased γH2AX expression in A549, PC9/IR, and CL97 cells (47). Vorinostat in combination with carboplatin increased γH2AX expression in A549 cells (48). LBH589 prolonged the duration of γH2AX-bound foci in irradiated H23 and H460 cells (49). LAQ824 (Dacinostat, a new HDACi) and irradiation significantly enhanced the level of γH2AX in H23 and H460 cells (50). CBHA enhanced IR-induced γH2AX expression (51). Vorinostat caused a prolongation of the expression of γH2AX (52). Cotreatment with TSA and IR prolonged the expression of γH2AX in A549 cells (53).

Although the p53 protein is important in DDR processes, the results of preclinical trials modulating this protein have been inconsistent. N25 and vorinostat decreased the expression of the p53 gene in H460 cells (54). Vorinostat increased the level of wild-type p53 protein in H520 and H460 cells (55). Romidepsin increased the level of p53 protein in A549 cells (56). Vorinostat and TSA combined with IR increased p53 in A549 and H1299 cells (57). In the study by Denlinger et al (58), NaB did not increase p53 protein expression in A549, H358, or H460 cells.

The HDACis also target the key proteins involved in the HR and NHEJ pathways. A newly developed HDACi, YCW1, markedly downregulated the mRNA expression levels of RAD51 and BRCA2 (59). Vorinostat decreased both phosphorylated and total Cdc expression in H1299 cells (60). Vorinostat decreased the expression of RAD50 and MRE11 (52). LBH589 inhibited Chk1 expression and upregulated its downstream signaling proteins Cdc25A and Cdc25C in A549 and PC9 cells (61). However, TSA did not alter the expression of Cdk2 in Calu-1, H520, H23, or H441 cells (62). In addition, cotreatment with TSA and IR reduced the expression of Ku70, Ku80, and DNA-PKcs in A549 cells (53) (see details in Tab. I).

Studies of histone deacetylase inhibitors on non-small-cell cancer lines in vivo

HDACis Year Lung cancer cell line DNA repair involvement Ref.
↑ = Increase or upregulate; ↓ = decrease or downregulate; γH2AX = H2A histone family member X; BRCA2 = breast cancer type 2 susceptibility protein; Cdc25A/C = subtype A/C of cell cycle protein 25; Cdk1/2 = cyclin-dependent kinase 1/2; DNA-PKcs = DNA-dependent protein kinase catalytic subunits; HDACis = histone deacetylase inhibitors; Ku70/Ku80 = Ku heterodimer; p-Cdc = phosphorylated cell cycle protein; Rad51 = protein encoded by the RAD51 gene; t-Cdc = total cell cycle protein.
N25, YCW1, MPT0E028, TSA, LBH589, LAQ824, CBHA, NaB: acronym or drug code for an HDACi.
Vorinostat 2014 A549 ↑γH2AX (46)
N25, vorinostat 2014 H460 ↓p53 (54)
Romidepsin 2014 A549 ↑p53 (56)
YCW1 2014 A549, H1435 ↓Rad51, ↓BRCA2 (59)
Vorinostat, MPT0E028 2013 A549, PC9/IR, CL97 ↑γH2AX (47)
Vorinostat 2012 H1299 ↓p-Cdc, ↓t-Cdc (60)
Vorinostat, TSA 2011 A549, H1299 ↑p53 (57)
Vorinostat 2010 A549 ↑γH2AX (48)
Vorinostat 2010 A549 Prolonged expression of γH2AX, ↓RAD50, ↓MRE11 (52)
LBH589 2010 A549, PC9 ↓Chk1, ↑Cdc25A, ↑Cdc25C (61)
LBH589 2006 H460, H23 Prolonged expression of γH2AX (49)
LAQ824 2007 H460, H23 ↑γH2AX (50)
Vorinostat 2006 H520, H460 ↑p53 (55)
TSA 2009 A549 ↓Ku70, ↓Ku80, ↓DNA-PKcs, prolonged expression of γH2AX (53)
CBHA 2006 A549 ↑γH2AX (51)
NaB 2004 A549, H358, H460 p53 expression not increased (58)
TSA 2006 Calu-1, H520, H23, H441 Cdk2 expression not altered (62)

Clinical trials of HDACis in NSCLC

Although HDACis have been extensively investigated, there has been little research on the effect of HDACis on NSCLC. No phase III clinical trials have been performed to determine the efficacy of HDACis for NSCLC to date. We describe the current understanding based on the following trials. In 2004, Reid et al (63) administered Pivanex (a type of HDACi, AN-9) to patients with advanced NSCLC. This study demonstrated that Pivanex exerted commensurate effects with minor toxicities. In 2008, Schrump et al (64) did not obtain significant results using romidepsin. In the study by Vansteenkiste et al (65), the endpoint was not reached due to adverse events, which were predominantly caused by a high dose of vorinostat. In their study, Traynor et al (66) concluded that single-agent administration of vorinostat displayed no objective antitumor activity in patients with relapsed NSCLC and suggested that future research should focus on the combination of vorinostat with other antitumor agents. Ramalingam et al (67) administered vorinostat in combination with carboplatin and paclitaxel as a first-line therapy for advanced NSCLC compared to placebo and showed that vorinostat enhanced the efficacy of carboplatin and paclitaxel, including an improvement in response rate despite treatment failure with respect to the median progression-free survival and overall survival. Witta et al (68) found that erlotinib combined with entinostat did not improve the outcome of patients with NSCLC compared to erlotinib monotherapy. Hoang et al (69) showed that vorinostat combined with bortezomib displayed limited antitumor activity as a third-line therapy for NSCLC. Reguart et al (70) found that the combination of erlotinib with vorinostat displayed no meaningful activity in patients with EGFR-mutant NSCLC after TKI progression (see list in Tab. II).

Summary of clinical trials of HDACis on non-small-cell lung cancer

HDACis Combination Type Year First-line therapy Dosage and usage No. Outcome Ref.
AEs = adverse events; EE = entinostat and erlotinib; EP = placebo and erlotinib; HDACis = histone deacetylase inhibitors; mOS = median overall survival; mPFS = median progression-free survival; mTTP = median time to progression; OS = overall survival; PFSR = progression-free survival rate; RR = response rate; SD = stable disease.
Pivanex None Phase II 2004 No 2.34 g/m2 days 1-3 every 21 days until disease progression 47 mOS was 6.2 mo (63)
Romidepsin None Phase II 2008 No 17.8 mg/m2 days 1, 7 every 21 days for 2 cycles 19 9 patients obtained transient SD (64)
Vorinostat None Phase II 2008 No 200, 300, 400 mg twice d 1-14 every 21 days 10 Endpoint not reached due to AEs (65)
Vorinostat None Phase II 2009 No 400 mg daily every 21 days until disease progression 14 8 patients had SD; mTTP was 2.3 mo; mOS was 7.1 mo (66)
Vorinostat Carboplatin and paclitaxel Phase II 2010 Yes 400 mg days 1-14 every 21 days for 6 cycles 94 RR: 34% vs 12.5% (p = 0.02); mPFS: 6.0 mo vs 4.1 mo (p = 0.48); and OS: 13.0 mo vs .7 mo (p = 0.17) for vorinostat or placebo, respectively (67)
Entinostat Erlotinib Phase II 2012 No 10 mg days 1, 15 every 28 days 132 4-m PFSR was comparable between the entinostat and placebo groups (EE: 18%; EP: 20%; p = 0.7) (68)
Vorinostat Bortezomib Phase II 2014 No 400 mg days 1-14 every 21 days 18 5 patients had SD; mPFS was 1.5 mo; 3-m PFSR was 11.1%; mOS was 4.7 mo (69)
Vorinostat Erlotinib Phase I/II 2014 No 400 mg days 1-7 and days 15-21 every 28 days 25 12-week PFSR was 28%; mPFS was 8 wk; OS was 10.3 mo (70)

Conclusion

The HDACis have been found to downregulate many important DNA damage responses by downregulating proteins in the HR and NHEJ pathways in vitro. The HDACis serve as potent radiosensitizers when combined with radiotherapy. Compared to its use for other neoplasms, the use of HDACis for NSCLC has not been adequately studied either in vitro or in vivo. In this review, we report that HDACis regulate proteins involved in the HR and NHEJ pathways, including γH2AX, RAD51, BRAC2, Cdc, Cdk2, Ku70, Ku80, and DNA-PKcs. Clinical trials examining the efficacy of HDACis for patients with NSCLC have not yielded consistent results. However, the combined treatment modality of HDACis and IR has yet to be studied. Further phase II/III trials are required to determine the value of HDACis as radiosensitizers.

Disclosures

Financial support: Supported by the National Natural Science Foundation of China (grant no. 81272611).
Conflict of interest: None.
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Authors

Affiliations

  • Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou - PR China
  • Hangzhou First People’s Hospital, Hangzhou - PR China
  • Zhejiang Chinese Medical University, Hangzhou - PR China

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