Aceroside VIII is a New Natural Selective HDAC6 Inhibitor that Synergistically Enhances the Anticancer Activity of HDAC Inhibitor in HT29 Cells

• Introduction
• Results
• Discussion
• Materials and Methods
• Compounds and chemicals
• Cell culture
• Trypan blue exclusion assay
• Cell viability assay
• Western blot
• Combined drug analysis
• Statistical analysis
• Acknowledgements
• References

Abstract

The identification of new isoform-specific histone deacetylase inhibitors is important for revealing the biological functions of individual histone deacetylase and for determining their potential use as therapeutic agents. Among the 11 zinc-dependent histone deacetylases that have been identified in humans, histone deacetylase 6 is a structurally and functionally unique enzyme. Here, we tested the inhibitory activity of diarylheptanoids isolated from Betula platyphylla against histone deacetylase 6. Aceroside VIII selectively inhibited histone deacetylase 6 catalytic activity and the combined treatment of aceroside VIII or (−)-centrolobol with A452, another selective histone deacetylase 6 inhibitor, led to a synergistic increase in levels of acetylated α-tubulin. Aceroside VIII, paltyphyllone, and (−)-centrolobol synergistically enhanced the induction of apoptosis and growth inhibition by A452. Consistent with these results, A452 in combination with aceroside VIII, paltyphyllone, or (−)-centrolobol was more potent than either drug alone for the induction of apoptosis. Together, these findings indicate that aceroside VIII is a specific histone deacetylase 6 inhibitor and points to a mechanism by which natural histone deacetylase 6-selective inhibitors may enhance the efficacy of other histone deacetylase 6 inhibitors in colon cancer cells.

Introduction

HDAC6 is structurally and functionally unique among the 11 zinc-dependent HDACs in humans [1]. HDAC6 is primarily localized in the cytoplasm and found in the nucleus in only minor amounts. HDAC6 possesses two catalytic domains and a C-terminal ZnF-UBP domain (also known as BUZ) that binds free ubiquitin as well as mono- and polyubiquitinated proteins with high affinity [2], [3], [4]. The known substrates of HDAC6 comprise non-histone cytoplasmic substrates such as tubulin, Hsp90, cortactin, and PRX [5], [6], [7], [8]. By complexing with partner proteins, HDAC6 functions as a distinct regulator of diverse cellular processes, including cell migration and death as well as immune synapse formation, viral infection, degradation of misfolded proteins, and stress granule formation [9]. In addition, HDAC6 influences a number of cellular pathways involved in tumorigenesis. Interestingly, mice lacking HDAC6 develop normally and do not exhibit abnormalities in major organ functions [10], suggesting that HDAC6 inhibition may not cause major side effects in contrast to the inhibition of other HDACs, in particular class I HDACs. Thus, HDAC6 is an attractive target for potential cancer treatment.

HDAC inhibitors have emerged as promising agents for the treatment of various forms of cancer [11], [12], [13]. Two pan-HDACIs, SAHA (vorinostat) and romidepsin (depsipeptide or FK228), have been approved by the US Food and Drug Administration for the treatment of cutaneous T cell lymphoma [14], [15], [16]. In addition, preclinical data with numerous cancer cell lines supports the synergistic effects of HDACIs with various anticancer therapies or other HDACIs [15]. Among existing HDACIs, several HDAC6-selective inhibitors have been previously reported [17], [18], [19], [20], [21]. Tubacin is the first and most extensively studied HDAC6-selective inhibitor [6], [22]; however, it has non-druggable qualities and is thus used primarily as a research tool rather than a potential drug [23]. Another HDAC6-selective inhibitor, ACY-1215, is currently being evaluated in clinical trials only for multiple myeloma, not solid tumors [20]. Therefore, there is a need to develop HDAC6-selective inhibitors that are effective in solid tumors and do not produce adverse effects such as fatigue, nausea, vomiting, diarrhea, thrombocytopenia, and neutropenia due to unselective pan-HDAC inhibitors.

Betula platyphylla (Betulaceae), commonly called birch tree, is widely distributed in Korea, Japan, China, Sahalin, and Siberia [24]. Several reports have demonstrated that extracts of the bark of B. platyphylla have anticancer, anti-arthritis, and hepatoprotective activities [24], [25], [26] and have also been used as folk medicines for the treatment of various inflammatory diseases, including arthritis, nephritis, dermatitis, and bronchitis [24]. Phytochemical studies on B. platyphylla bark have identified terpenoids, diarylheptanoids, and arylbutanoids [26]. In particular, diarylheptanoids have received significant attention due to their various biological activities [27]. Curcumin, one of the most important diarylheptanoids, has been extensively studied for its anticancer properties in various cancer cell lines [28]. In addition, diarylheptanoids isolated from Alnus glutinosa, also a plant belonging to the family Betulaceae, exhibit significant cytotoxic activities against NCI-H460 and NCI-H460/R cancer cell lines [29]. We previously isolated eight diarylheptanoids from B. platyphylla bark and reported their inhibitory effects on antigen-stimulated degranulation in RBL-2HC cells [30].

Here, we report the identification of a natural HDAC6-selective inhibitor. Specifically, we screened the HDAC6 inhibitory effects of natural compounds isolated from B. platyphylla on colon cancer cells. We found that the natural selective-HDAC6 inhibitor aceroside VIII synergistically increased the effectiveness of the HDAC6 inhibitor A452 with respect to the induction of apoptosis.

Results

We first tested the effects of diarylheptanoids isolated from B. platyphylla on HDAC6 in the HT29 human CRC line. Among the tested compounds, aceroside VIII exhibited weak inhibitory activity towards HDAC6 as evidenced by slightly increased levels of acetylated α-tubulin, a known substrate of HDAC6, but not acetylated histone H3 ([Fig. 1 B]). In contrast, paltyphyllone and (−)-centrolobol had no effect on class I HDACs and class II HDAC6 inhibition in HT29 cells. As a positive control for HDAC inhibition, we used the pan-HDAC inhibitor SAHA, which binds to the active site of class I and class II HDACs and also acts as a chelating agent for zinc ions present in the active site of HDACs. SAHA is in clinical development as an anticancer drug [31].

The γ-lactam based HDAC6 inhibitor A452 is selective in various human cancer cells [32]. Thus, we were interested in determining if any of the natural compounds from B. platyphylla could act synergistically with A452 in the inhibition of cancer cells. To this end, we first analyzed the effect of A452 on inhibition in HT29 cells. A452 exhibited concentration-dependent HDAC6 inhibitory activity ranging from 0.2 to 2 µM ([Fig. 1 C]). Next, HT29 cells were treated with aceroside VIII, paltyphyllone, and (−)-centrolobol alone or in combination with A452 (0.1 µM) for 24 h, and the levels of acetylated α-tubulin were analyzed by immunoblotting. Simultaneous treatment with aceroside VIII or centrolobol and A452 resulted in a synergistic increase in the levels of acetylated α-tubulin ([Fig. 1 B]). These results suggested that the novel natural HDAC6-specific inhibitors aceroside VIII and (−)-centrolobol might synergistically enhance the HDAC6 inhibitory activity of A452.

We next examined the effect of aceroside VIII, paltyphyllone, and (−)-centrolobol on cell growth and viability in HT29 CRC cells. Cells were cultured with these compounds (10 µM) for 72 h, and cell growth and viability were measured by the trypan blue exclusion assay and MTT assay, respectively. Treatment of cells with any of the three natural compounds did not significantly alter cell viability compared with vehicle-treated cells, while aceroside VIII and paltyphyllone modestly inhibited cell growth at 72 h ([Fig. 2 A, C]). Because aceroside VIII and (−)-centrolobol synergistically increased the levels of acetylated tubulin when combined with A452, we set out to identify therapeutic combinations of new potent HDAC6-specific inhibitors in CRC cells. To this end, we tested the cell death-inducing effects of three natural compounds in combination with A452 in HT29 cells. Specifically, HT29 cells were treated with either A452 or in combination with three compounds, and cell growth and viability were determined as described above. The combination of 0.1 µM A452 with 10 µM paltyphyllone or (−)-centrolobol led to a significant inhibition of cell growth and an increase in cell death compared with HT29 cells treated with each compound alone. Specifically, the combination of A452 with paltyphyllone or (−)-centrolobol reduced HT29 cell viability by 39 % and 46 % after 72 h, respectively ([Fig. 2 D, F]). In addition, HT29 cell death was markedly enhanced in cells treated with 0.1 µM A452 and 10 µM aceroside VIII (84 %) compared with cells treated with aceroside VIII alone ([Fig. 2 B]). We used the combination index method of Chou and Talalay [33] to determine whether the observed interactions between three natural compounds and A452 in HT29 cells are additive or synergistic. In [Fig. 2 G] to [I], we calculated the values of CI, a quantitative measure of drug interaction. CI for every A452-aceroside VIII, -paltyphyllone, or -(−)-centrolobol combination was lower than 1, suggesting the synergistic effect of the combination. SAHA in combination with three natural compounds produced similar results on cell growth inhibition and cell death compared with A452 cells. Taken together, these results indicate that aceroside VIII, paltyphyllone, and (−)-centrolobol enhance cell death induced by other HDAC6 inhibitors.

To investigate the mechanism of cell death in CRC cells cultured with the three natural compounds described above, we evaluated their effects on PARP and cleavage, which is a marker of apoptosis [34]. Each of the drugs alone as well as A452 in combination with aceroside VIII or (−)-centrolobol resulted in decreased levels of full-length PARP ([Fig. 3]). To further investigate mechanisms by which the combination treatment induced apoptosis in HT29 cells, we next assessed their abilities to activate the proapoptotic molecule caspase-3. Treatment with aceroside VIII or A452 had a minimal effect on the levels of cleaved caspase-3 compared with control-treated cells. Consistent with cell viability results, A452 in combination with aceroside VIII, paltyphyllone, or (−)-centrolobol synergistically increased the levels of active caspase-3. Overall, our results suggest that cell death induced by aceroside VIII, paltyphyllone, and (−)-centrolobol is, in part, dependent on caspase activation.

Discussion

Recent studies suggest that HDACIs including SAHA can interact synergistically with cytotoxic agents such as doxorubicin and etoposide to dramatically increase mitochondrial injury and apoptosis in leukemia and lung cancer cells [35]. To identify a natural compound with HDAC6 inhibitory activity, we screened diarylheptanoids isolated from B. platyphylla. Among the diarylheptanoids tested, only aceroside VIII was found to selectively inhibit HDAC6. In addition, this compound inhibited the growth of HT29 CRC cells. Aceroside VIII has been previously reported to have cognitive-enhancing activity, neuroprotective activity against glutamate-damaged HT22 cells [36], and hepatoprotective effects against D-GalN-damaged primary cultured rat hepatocytes [26]. Together, these results suggest that aceroside VIII may exert several useful biological activities.

There is very limited information of HDACI in combination with other antitumor agents or HDACI against CRC cells. Interestingly, when aceroside VIII, paltyphyllone, or (−)-centrolobol was combined with A452, it further enhanced the anticancer effects of the latter against CRC cells ([Fig. 2]). Our data demonstrated, for the first time, a synergistic effect of selective-HDAC6 inhibitors from two distinct sources, namely, a small chemical (A452) and natural compounds [aceroside VIII, paltyphyllone, and (−)-centrolobol]. In support of our observation, synergistic and additive tumor cell apoptosis has been observed for the combination of pan-HDAC inhibitors with the HDAC6-selective inhibitor tubacin [35]. Increased DNA damage observed in cells treated with combined inhibitors has been attributed to the induction of histone hyperacetylation by HDACIs, resulting in a more open chromatin structure, making the DNA more susceptible to damage as well as providing increased access to transcriptional machinery.

In contrast to pan HDACIs, a selective-HDAC6 inhibitor may possess different mechanisms of action. Namdar et al. were the first to suggest that the HDAC6-selective inhibitor tubacin causes the accumulation of γH2AX, an early indicator of DNA DSB, in transformed cells and also that the accumulation of DNA breaks may be due, at least in part, to an impaired capacity for DNA DSB repair. Secondly, the chaperone protein HSP90 is a target protein of HDAC6 [5], [37], and acetylation of Hsp90 impairs its chaperone function, which may in turn expose its client proteins, such as DNA repair proteins, to degradation, resulting in defective DNA repair and cell death. Along these lines, we found that aceroside VIII, paltyphyllone, and (−)-centrolobol markedly enhanced A452-induced transformed cell apoptosis, as evidenced by decreased levels of full-length PARP and caspase-dependent cell death.

In summary, we identified aceroside VIII as a natural HDAC6-selective inhibitor that potentiates the anticancer drug efficacy of another HDAC6 inhibitor in human cancer cells. These findings suggest that combination therapy with drugs targeting HDAC6 may be a useful strategy for treating HDAC6-sensitive tumors. Further studies are necessary to confirm our findings in patients with colorectal cancer.

Materials and Methods

Compounds and chemicals

Diarylheptanoids were isolated from the bark of B. platyphylla, and their structures were established on the basis of spectral and chemical evidence [30]. The purities of aceroside VIII, paltyphyllone, and (−)-centrolobol were 100 %, 88.28 %, and 97.08 %, respectively. SAHA (purity ≥ 98 %) was purchased from Sigma-Aldrich Chemical Co. A452 (purity 99 %) is a γ-lactam-based HDAC6 inhibitor [32] and was kindly provided by Dr. Gyoonhee Han (Yonsei University, Seoul, Korea).

Cell culture

The human HT29 cancer cell line was purchased from ATCC and cultured in medium (HyClone, Thermo Scientific Pierce) containing 10 % FBS, 100 units/mL penicillin, and 100 µg/mL streptomycin in a humidified atmosphere of 5 % CO₂ and 95 % air at 37 °C.

Trypan blue exclusion assay

To monitor cell growth and viability, cells were seeded in triplicate at 5 × 10⁴ cells/wells in 1 mL of medium in 24-well plates. Cells were treated with the indicated concentrations of drugs 24 h after seeding. Cells were harvested by trypsin at 24 h, 48 h, and 72 h after drug additions, after which cell number and viability were determined by trypan blue exclusion.

Cell viability assay

Cell viability was assessed by the MTT assay. Briefly, 3 × 10⁵ cells were seeded into 96-well plates for 24 h, followed by incubation with various reagents for the indicated time. After adding 20 µL/well of MTT solution, the cells were incubated for another 2 h. Supernatants were then removed, and the formazan crystals were dissolved in 100 µL of DMSO per well. The absorbance at 570 nm was measured for each sample with a 630 nm as a reference using a multimode microplate reader (Tecan). Results are presented as the percent of absorbance relative to control cultures and were generated from three independent experiments performed in triplicate.

Western blot

Cells were rinsed twice with ice-cold PBS and then extracted with NP-40 lysis buffer (0.5 % NP-40, 50 mM Tris-HCl pH 7.4, 120 mM NaCl, 25 mM NaF, 25 mM glycerol phosphate, 1 mM EDTA, 5 mM EGTA) containing a complete protease inhibitor cocktail tablet (Roche). Lysates were collected and centrifuged at 15 000 × g for 15 min at 4 °C. Protein concentrations were measured with a BCA protein assay kit (Thermo Scientific Pierce). Cell lysates containing 10–50 µg of total protein were subjected to SDS-PAGE on 8–12 % slab gels, and proteins were transferred to nitrocellulose membranes. Membranes were blocked for 1 h in PBS containing 0.1 % Tween-20 and 10 % (v/v) horse serum and incubated overnight with primary antibody. Membranes were then washed with 0.1 % Tween-20/PBS and incubated for 1 h with an anti-rabbit/mouse secondary antibody coupled to HRP; bound antibodies were detected with an ECL Western blotting analysis system (Thermo Scientific Pierce).

Combined drug analysis

For combined drug analysis, a constant ratio combination of A452 and three natural compounds was evaluated. Drug dilutions and combinations were made in McCoyʼs medium immediately before use. Following drug addition, the 96-well plates were incubated for 72 h, and the MTT assay was performed to determine cell viability. Drug interaction was determined by the CI method of Chou and Talalay [33]. CI for the combination treatment group was generated using CompuSyn software (ComboSyn, Inc.). CI > 1 implies antagonism, CI = 1 is additive, and CI < 1 implies synergism.

Statistical analysis

All data are presented as the mean ± SEM of three independent experiments. Statistical differences were determined by Studentʼs t-test. Statistically significant results (p < 0.05) are denoted with asterisks (*).

Acknowledgements

We wish to thank Dr. Gyoonhee Han (Yonsei University, Seoul, Korea) for providing A452. This work was supported, in part, by the Yonsei University Global Specialization Project of 2014. This research was also supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2 012 013 998).

Conflict of Interest

The authors declare that they have no competing interest.

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Correspondence

• References

• 1 Verdel A, Curtet S, Brocard MP, Rousseaux S, Lemercier C, Yoshida M, Khochbin S. Active maintenance of mHDA2/mHDAC6 histone-deacetylase in the cytoplasm. Curr Biol 2000; 10: 747-749
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• 2 Boyault C, Gilquin B, Zhang Y, Rybin V, Garman E, Meyer-Klaucke W, Matthias P, Muller CW, Khochbin S. HDAC6-p 97/VCP controlled polyubiquitin chain turnover. Embo J 2006; 25: 3357-3366
  CrossrefPubMedSearch in Google Scholar
• 3 Hook SS, Orian A, Cowley SM, Eisenman RN. Histone deacetylase 6 binds polyubiquitin through its zinc finger (PAZ domain) and copurifies with deubiquitinating enzymes. Proc Natl Acad Sci U S A 2002; 99: 13425-13430
  CrossrefPubMedSearch in Google Scholar
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  CrossrefPubMedSearch in Google Scholar
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