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American Journal of Translational Research logoLink to American Journal of Translational Research
. 2018 Mar 15;10(3):696–708.

YM155 enhances docetaxel efficacy in ovarian cancer

Li-Jiao Hou 1,*, Xiao-Xiu Huang 1,*, Li-Na Xu 1, Yan-Yan Zhang 1, Na Zhao 1, Rong-Ying Ou 1, Wen-Feng Li 3, Wen-Ji Zhang 2, Qi-Wei Jiang 2, Yang Yang 2, Meng-Ning Wei 2, Jia-Rong Huang 2, Kun Wang 2, Meng-Ling Yuan 2, Zi-Hao Xing 2, Zhi Shi 2, Xiao-Jian Yan 1
PMCID: PMC5883111  PMID: 29636860

Abstract

YM155 (Sepantronium bromide) is a potent small molecule inhibitor of survivin by suppression of survivin expression and shows the promising anticancer activity in many types of cancers. Docetaxel (Taxotere®) is a member of the taxane drugs used in the treatment of a number of cancers in clinic. Despite the therapeutic efficacy of docetaxel is encouraging, the emergent resistance is an urgent issue. In this study, we investigate the effect of YM155 on docetaxel efficacy in ovarian cancer cells. Our data showed that YM155 actively induced cell growth inhibition, cell cycle arrest and apoptosis with downregualtion of survivin in ovarian cancer cells. Moreover, YM155 increased the intracellular ROS levels, and pretreatment with either NAC or GSH partially reversed the YM155-induced ROS accumulation and apoptosis only in the parental A2780 cells, but not in the resistant A2780/Taxol cells. Furthermore, YM155 enhanced docetaxel efficacy to inhibit the growth and induce apoptosis in ovarian cancer cells. Take together, our results suggested that combination of YM155 and docetaxel may be a feasible strategy for the treatment of ovarian cancer.

Keywords: Ovarian cancer, YM155, docetaxel

Introduction

Docetaxel (Taxotere®) is a member of the taxane drugs, which is a class of diterpenes derived from the genus Taxus (yews) including paclitaxel (Taxol®), baccatin III, etc. Taxanes act as mitotic inhibitors by stabilizing the microtubule polymer to protect it from disassembly, which results in chromosomes unable to form a metaphase spindle configuration, therefore suppressing mitosis progress and inducing cell death [1]. Currently, docetaxel is used in the treatment of a number of cancers including lung, breast, prostate, gastric, ovarian cancer, and so on. Despite the therapeutic efficacy of docetaxel is encouraging in clinic, the emergent resistance is becoming an important issue. Extensive work has attempted to elucidate the molecular mechanisms of docetaxel resistance, and many molecules have been implicated to involve in docetaxel resistance [1]. Overexpression or mutation of the docetaxel target, β-tubulin, is one of the common reasons of docetaxel resistance [2,3]. Overexpressing the ATP-binding cassette (ABC) transporters such as ABCB1 (also named P-glycoprotein, P-gp), ABCC2 and ABCC10 is another cause resulting in docetaxel resistance [4,5]. Additionally, the deficit of apoptotic cell death also contributes to docetaxel resistance, and alteration of apoptotic related genes (survivin, Bcl-2, p53, etc) are always associated with docetaxel sensitivity [6,7]. Therefore, it is urgent to develop new therapeutic strategies to overcome docetaxel resistance or enhance docetaxel sensitivity for the treatment of cancer.

YM155 (Sepantronium bromide) is a potent small molecule inhibitor of survivin by suppression of survivin expression [8]. YM155 directly binds to the C-terminal of RNA binding proteins interleukin enhancer-binding factor-3 (ILF3/NF110) and disrupts it binding to survivin promoter, leading to downregulation of survivin expression [9,10]. The anticancer activity of YM155 has been demonstrated in many types of cancers, such as lung cancer, breast cancer, Hodgkin lymphoma, prostate cancer and Wilms tumor, etc [11-16]. Althouth YM155 can sensitize ovarian cancer cells to cisplatin inducing apoptosis and tumor regression [17], whether YM155 overcomes docetaxel resistance or enhances docetaxel sensitivity in ovarian cancer are still unclear. In this study, we investigate the effect of YM155 on docetaxel efficacy in ovarian cancer cells.

Material and methods

Cell culture and reagents

Human ovarian cancer cell lines A2780, A2780/Taxol, SKOV3, OVCAR3, HO8910, HO8910PM, and ES2 were cultured in Dulbecco’s modified Eagle’s medium (DMEM) containing 10% fetal calf serum (FBS), penicillin (100 U/ml) and streptomycin (100 ng/ml) in a humidified incubator at 37°C. YM155 and docetaxel were ordered from ApexBio and Hengrui Medicine, respectively. N-acetly-L-cysteine (NAC), glutathione (GSH) and dihydroethidium (DHE) were purchased from Sigma-Aldrich. Anti-PARP (9542), Anti-Mcl-1 (4572), Anti-Survivin (2808), Anti-AKT (4691), Anti-pAKT S473 (4060), Anti-pERK T202/Y204 (4370) and Anti-ERK (4695) antibodies were from Cell Signaling Technologies. Anti-β-tublin (KM9003T) antibodies were from Tianjin Sungene Biotech. Anti-p21 (554262), Anti-p27 (610241), and Anti-p53 (554169) antibodies were from BD Biosciences. Anti-Bax (RLT0456) antibodies were from Ruiying Biotech.

Cell viability assay

Cells were firstly seeded into a 96-well plate at a density of 5000 cells per well, and incubated with drugs in three parallel wells for 72 h. Then 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) was added to each well at a final concentration of 0.5 mg/ml. After incubation for 4 h, formazan crystals were dissolved in 100 μl of DMSO, and absorbance at 570 nm was measured by plate reader. The concentrations required to inhibit growth by 50% (IC50) were calculated from survival curves using the Bliss method [18,19]. For drug combination experiments, cells were co-treated with different concentrations of YM155 and docetaxel for 72 h. The data were analyzed by CompuSyn software with the results showed as combination index (CI) values according to the median-effect principle, where CI <1, =1, and >1 indicate synergism, additive effect, and antagonism, respectively [20,21].

Cell cycle assay

Cells were fixed with ice-cold 70% ethanol for 30 min at 4°C and resuspended with 0.5 ml phosphate buffered saline (PBS) containing PI (50 μg/ml), 0.1% Triton X-100, 0.1% sodium citrate, and DNase-free RNase (100 μg/ml), and 0.1% sodium citrate. After 15 min incubation at room temperature in the dark, cells was measured by flow cytometry (FCM) with an excitation wave length of 480 nm through a FL-2 filter (585 nm). Data were analyzed using ModFit LT 3.0 software (Becton Dickinson) [22,23].

Apoptosis assay

Cells were stained with Annexin V-FITC and propidium iodide (PI) in the binding buffer, and detected by FCM after 15 min incubation at room temperature in the dark. Fluorescence was measured at an excitation wave length of 480 nm through FL-1 (530 nm) and FL-2 filters (585 nm). The apoptotic cells were quantified using FlowJO software [24,25].

Reactive oxygen species (ROS) assay

Cells were incubated with DHE (10 μM) for 30 min at 37°C in the dark. Five fields were observed randomly for each well. ROS activation was analyzed by calculating the percentage of positive cells [26,27].

Western blot analysis

Cells were lysed in RIPA buffer (1% NP-40, 0.5% sodium deoxycholate, 0.1% SDS, 10 ng/ml PMSF, 0.03% aprotinin, 1 μM sodium orthovanadate) at 4°C. Lysates were centrifuged for 10 min at 14,000× g. Proteins were separated on 12% SDS-PAGE gels and transferred to polyvinylidene difluoride membranes. Membranes were blocked with 5% BSA and incubated with the indicated primary antibodies. Corresponding horseradish peroxidase-conjugated secondary antibodies were used against each primary antibody. Proteins were detected using the chemiluminescent detection reagents and chemstudio plus imaging system [28,29].

Statistical analysis

All experiments were repeated at least three times. The statistical significance between two groups was determined with Student’s t-test. A probability value of P<0.05 was considered as significant differences.

Result

YM155 and docetaxel suppress the growth of ovarian cancer cells

To investigate the effect of YM155 on docetaxel efficacy in ovarian cancer cells, we first tested the cytotoxicity of YM155 and docetaxel in seven human ovarian cancer cells. As shown in Figure 1, YM155 inhibited the growth of all ovarian cancer cells in a dose-dependent manner with the IC50 values range from 3.73 nM to 321.31 nM. Similarly, the IC50 values of docetaxel in all ovarian cancer cells were range from 2.505 nM to 301.88 nM. Interestingly, the taxol resistant cells A2780/Taxol, which overexpresses ABCB1 gene [30], showed about 87 folds resistance to both YM155 and docetaxel compared with the parental A2780 cells.

Figure 1.

Figure 1

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YM155 inhibits the growth of ovarian cancer cells. A. Chemical structure of YM155. B. Summary of IC50 of YM155 and docetaxel in the indicated ovarian cancer cells is shown. Cells were grown in 96-well plates for 24 h and treated with the indicated concentrations of YM155 or docetaxel for 72 h, and cell survival was determined by MTT assay. C. The representative growth curves of cells treated with YM155 and docetaxel are shown. Data are mean ± SD of three independent experiments.

YM155 induces cell cycle arrest in ovarian cancer cells

To explore whether the growth inhibition of ovarian cancer cells by YM155 is due to cell cycle arrest, cell cycle distribution was assessed after treating A2780 and A2780/Taxol cells with YM155. As shown in Figure 2A and 2B, YM155 dose-dependently induced cell accumulation at S phase and reduction at G0/G1 phase in both cells. To further investigate the molecular mechanism of cell cycle arrest by YM155, the expression of cell cycle related proteins were detected by Western blot. YM155 dose-dependently decreased the protein levels of survivin as expected, but increased the protein levels of p21, p27 and p53 in both cells (Figure 2C).

Figure 2.

Figure 2

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YM155 induces cell cycle arrest in ovarian cancer cells. A2780 (A) and A2780/Taxol (B) cells were treated with YM155 at the indicated concentrations for 48 h. The distribution of cell cycle was detected by FCM with PI staining. The percentages of subG1, G1/G0, S, G2/M phase were calculated using ModFit LT 3.0 software. The protein expression was examined by Western blot after lysing cells, and β-tublin was used as loading control. The representative charts, quantified results and Western blot results (C) of three independent experiments were shown. The statistical significance between two groups was determined with Student’s t-test. *P<0.05 and **P<0.01 vs. corresponding control.

YM155 triggers apoptosis in ovarian cancer cells

To determine whether the growth inhibition of ovarian cancer cells by YM155 was due to apoptosis, cell apoptosis was assessed after treating A2780 and A2780/Taxol cells with YM155. As shown in Figure 3A and 3B, YM155 in the dose dependent manner triggered apoptosis in both cells. To further investigate the molecular mechanism of cell apoptosis by YM155, the expression of apoptosis related proteins were detected by Western blot. YM155 in the dose dependent manner enhanced the protein levels of cleaved PARP, Bax and Mcl-1, but weakened the protein levels of pAKT S473 and pERK T202/Y204 in both cells (Figure 3C).

Figure 3.

Figure 3

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YM155 triggers apoptosis in ovarian cancer cells. A2780 (A) and A2780/Taxol (B) cells were treated with YM155 at the indicated concentrations for 48 h. The apoptosis was detected by FCM Annexin V/PI staining. The proportions of Annexin V+/PI- and Annexin V+/PI+ cells indicated apoptosis. The protein expression was examined by Western blot after lysing cells, and β-tublin was used as loading control. The representative charts, quantified results and Western blot results (C) of three independent experiments were shown. The statistical significance between two groups was determined with Student’s t-test. *P<0.05 and **P<0.01 vs. corresponding control.

Role of ROS in the effect of YM155 on ovarian cancer cells

To examine the effect of YM155 on the intercellular ROS in ovarian cancer cells, A2780 and A2780/Taxol cells were stained with the ROS fluorescent probe DHE after YM155 treatment. As shown in Figure 4, YM155 dose- and time-dependently augmented the fluorescent intensity of DHE in both cells. To further explore the role of ROS in YM155-induced apoptosis in ovarian cancer cells, both A2780 and A2780/Taxol cells were treated with YM155 for 48h with or without antioxidative agents NAC and GSH pretreated for 1 h. As shown in Figure 5A and 5B, NAC or GSH partially reversed YM155-induced ROS accumulation only in A2780 cells, but not in A2780/Taxol cells. Similarly, NAC or GSH partially rescued YM155-induced apoptosis only in A2780 cells, but not in A2780/Taxol cells (Figure 5C and 5D).

Figure 4.

Figure 4

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YM155 increases the intracellular ROS in ovarian cancer cells. A2780 (A) and A2780/Taxol (B) cells were treated with YM155 at the indicated times and concentrations, stained with DHE and photographed under florescent microscope. The representative micrographs and quantified results of three independent experiments are shown. The statistical significance between two groups was determined with Student’s t-test. *P<0.05 and **P<0.01 vs. corresponding control.

Figure 5.

Figure 5

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Effect of ROS inhibition on YM155-induced apoptosis in ovarian cancer cells. A2780 (A, C) and A2780/Taxol (B, D) cells were treated with YM155 (10 nM and 1000 nM, respectively)for 48 h with or without the NAC (10 mM) or GSH (10 mM) pretreatment for 1 h, stained with DHE and photographed under fluorescent microscope. The apoptosis was detected by FCM with Annexin V/PI staining. The proportions of Annexin V+/PI- and Annexin V+/PI+ cells indicated apoptosis. The representative micrographs, charts and quantified results of three independent experiments are shown. The statistical significance between two groups was determined with Student’s t-test. NS: no significance. *P<0.05 and **P<0.01 vs. corresponding group.

YM155 enhances docetaxel efficacy in ovarian cancer cells

To investigate the combined effects of YM155 and docetaxel on ovarian cancer cells, the effects of docetaxel on cell cycle and apoptosis were detected. As shown in Figure 6A and 6B, docetaxel dose-dependently induced cell accumulation at subG1 and G2/M phase and reduction at S and G0/G1 phase in both A2780 and A2780/Taxol cells. Moreover, docetaxel in the dose dependent manner triggered apoptosis in both cells (Figure 6C and 6D). Then cell survival was detected under the different dose combination of YM155 and docetaxel. Compared with YM155 or docetaxel alone treatment in both cells, the survival of ovarian cells was significantly decreased after combined treatment. All CI values of both cells were <1, suggesting that combination treatment was synergistic to inhibit the growth of ovarian cancer cells (Figure 7A and 7B). Furthermore, the combination of YM155 and docetaxel caused more apoptosis than YM155 or docetaxel alone in both cells (Figure 8A and 8B). Additionally, the protein levels of C-PARP, Bax and Mcl-1 were increased more in the co-treatment group than those in YM155 or docetaxel alone group in both cells (Figure 8C). Together, these results suggested that YM155 was able to enhance docetaxel efficacy in ovarian cancer cells.

Figure 6.

Figure 6

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Docetaxel induces cell cycle arrest and apoptosis in ovarian cancer cells. A2780 (A, C) and A2780/Taxol (B, D) cells were treated with docetaxel at the indicated concentrations for 48 h. The distribution of cell cycle was detected by FCM with PI staining. The percentages of subG1, G1/G0, S, G2/M phase were calculated using ModFit LT 3.0 software. The apoptosis were detected by FCM with Annexin V/PI staining. The proportions of Annexin V+/PI- and Annexin V+/PI+ cells indicated apoptosis. The representative charts and quantified results of three independentexperiments were shown. The statistical significance between two groups was determined with Student’s t-test. *P<0.05 and **P<0.01 vs. corresponding control.

Figure 7.

Figure 7

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YM155 enhances docetaxel efficacy to inhibit the growth of ovarian cancer cells. A2780 (A) and A2780/Taxol (B) cells were treated with the indicated concentrations of YM155 and docetaxel for 72 h, and cell survival was detected by MTT assay. The data were analyzed by CompuSyn software with the results shown as growth histogram, dose-effect curve, CI values and normalized isobologram.

Figure 8.

Figure 8

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YM155 enhances docetaxel efficacy to induce apoptosis in ovarian cancer cells. A2780 (A) cells were treated with 1 nM YM155, 3 nM docetaxel alone or combination for 48 h. A2780/Taxol (B) cells were treated with 100 nM YM155, 100 nM docetaxel alone or combination for 48 h. The apoptosis was detected by FCM Annexin V/PI staining. The proportions of Annexin V+/PI- and Annexin V+/PI+ cells indicated the early and late stage of apoptosis. The protein expression was examined by Western blot after lysing cells, and β-tublin was used as loading control. The representative charts, quantified results and Western blot results (C) of three independent experiments were shown. The statistical significance between two groups was determined with Student’s t-test. DTX: Docetaxel. *P<0.05 and **P<0.01 vs. corresponding control.

Discussion

In the current study, our data presented that the ABCB1-overexpressing taxol resistant ovarian cancer cells A2780/Taxol showed about 87 folds resistance to both YM155 and docetaxel compared with the parental A2780 cells. This phenomenon is probably explained by previous studies which have demonstrated that YM155 is a substrate of ABCB1, and overexpressing of ABCB1 can cause YM155 efflux to mediated YM155-specific resistance [31,32]. YM155 significantly induced cell cycle arrest and apoptosis with the increasing intracellular ROS levels in ovarian cancer cells. Suppression of ROS generation partially rescued YM155-induced apoptosis only in the parental A2780 cells, but not in the resistant A2780/Taxol cells, suggesting that ROS might play the diverse roles in YM155-induced apoptosis in the different ovarian cancer cells.

It is valuable to overcome docetaxel resistance or enhance docetaxel sensitivity for the treatment of cancers. Our results showed that YM155 enhanced docetaxel efficacy to inhibit the growth and induce apoptosis in either parental or resistant ovarian cancer cells. Similarly with our data, YM155 has been reported synergistically to enhance the efficacies of microtubule-targeting agents, including paclitaxel, docetaxel and vinorelbine in triple-negative breast cancer cells [33]. YM155 in combination with docetaxel induced more apoptosis and showed greater efficacy than either agent alone in human malignant melanoma models [34]. YM155 also promoted docetaxel-induced apoptosis and tumor regression in human lung cancer xenograft models [35]. Although these preclinical data are encouraging, the clinical results of YM155 and docetaxel combination for the treatment of cancers are not optimistic. A phase II, multicenter, open-label study of YM155 plus docetaxel in patients with stage III (unresectable) or stage IV melanoma has shown that YM155 was generally well tolerated with modest activity when plus docetaxel, but the predetermined primary efficacy endpoint was not achieved [36]. Another phase II, multicenter, open-label, randomized study of YM155 plus docetaxel as first-line treatment in patients with HER2-negative metastatic breast cancer has exhibited that there was no statistically significant differences in the endpoints between combination and docetaxel alone [37]. In a phase I/II study of YM155 combined with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer, this combination exhibited a favorable safety profile but failed to demonstrate an improvement in response rates [38]. Therefore, whether the combination of YM155 and docetaxel improves clinical outcomes in ovarian cancer patients remains to be determined.

In summary, our study provides the evidence that YM155 can enhance docetaxel efficacy in ovarian cancer cells. Combination of YM155 and docetaxel may be a feasible strategy for the treatment of ovarian cancer.

Acknowledgements

This work was supported by funds from the National Natural Science Foundation of China No. 81661148049, No. 81772540 (Z. S.), No. 81503293 (X. J. Y.) and No. 81373075 (R. Y. O), the Guangdong Natural Science Funds for Distinguished Young Scholar No. 2014A030306001 (Z. S.), the Guangdong Special Support Program for Young Talent No. 2015TQ01R350 (Z. S.), the Science and Technology Program of Guangdong No. 2016A050502027 (Z. S.) and the Science and Technology Program of Guangzhou No. 201704030058 (Z. S.).

Disclosure of conflict of interest

None.

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