Research ArticleExperimental Studies
Open Access

Anti-Tumor and Chemosensitizing Effects of the CDK Inhibitor Dinaciclib on Cholangiocarcinoma In Vitro and In Vivo

PRIN SUNGWAN, SONEXAI KIDOIKHAMMOUAN, UNCHALEE THONSRI, CHARUPONG SAENGBOONMEE, SOPIT WONGKHAM, SEIJI OKADA and WUNCHANA SEUBWAI
In Vivo September 2024, 38 (5) 2284-2293; DOI: https://doi.org/10.21873/invivo.13693

Abstract

Background/Aim: Cholangiocarcinoma (CCA) is a highly aggressive disease. Most of CCA patients are diagnosed in an advanced stage of the disease, when it is unresectable and there is chemoresistance, resulting in poor prognosis. However, effective therapeutic regimens and molecular targets for CCA remain poor. Cyclin-dependent kinases (CDKs) are key regulatory enzymes in cell cycle progression. Aberrant CDK activation is a hallmark of cancer. Dinaciclib is a small molecule inhibitor of multiple CDKs, currently under clinical evaluation for treating advanced malignancies. The efficacy of anti-tumor activity of dinaciclib against chemotherapy resistant CCA cells was examined in vitro and in vivo. Materials and Methods: In this study, the effect of dinaciclib on growth and cell cycle in CCA cell lines were determined using the MTT assay and cell cycle analysis. The anti-tumor activity of dinaciclib was investigated in CCA-inoculated mice. In addition, the chemosensitizing effect of dinaciclib was investigated in gemcitabine-treated CCA cell lines. Results: Dinaciclib significantly suppressed cell proliferation, induced G1/S phase cell cycle arrest and apoptosis of CCA cell lines. It significantly suppressed the growth of CCA cells in xenograft mouse models. We also found that dinaciclib significantly inhibited the growth of gemcitabine-resistant CCA cell lines (KKU-213A-GemR and KKU-100-GemR). Furthermore, dinaciclib significantly enhanced the anti-tumor activity of gemcitabine in CCA cell lines. Conclusion: Dinaciclib has the potential to be an effective therapeutic agent to control tumor cell growth of both parental and gemcitabine-resistant CCA cells.

Key Words:

Cholangiocarcinoma (CCA) is a highly invasive malignancy derived from bile duct epithelial cells. The incidence and mortality rates of CCA are increasing worldwide, particularly in the Greater Mekong sub-region (1, 2). Typically, CCA is diagnosed at an advanced stage, when patients are non-responsive to chemotherapy, leading to poor prognosis due to cancer recurrence and high metastatic rates. Although surgical resection is the best treatment option for CCA therapy (3, 4), complete resection is achieved in less than 5% of cases (5). CCA patients with incomplete resection are recommended for chemotherapy, either using gemcitabine alone or gemcitabine-based regimens (6, 7). Several chemotherapy drugs, such as gemcitabine, 5-Fluorouracil (5-FU), cisplatin, sorafenib, oxaliplatin/cetuximab, and their combination regimens, have been recommended for CCA treatment. However, only a few effective therapeutic regimens are available for CCA. Currently, the combination of gemcitabine and cisplatin is considered the standard treatment for patients with advanced/metastatic CCA. Despite advancements in systemic chemotherapy and molecular mechanisms, the prognosis and survival rates have remained poor over the past decade. Resistance to a wide variety of chemotherapeutic drugs frequently occurs in CCA patients. Additionally, there is currently no molecularly targeted therapy available for CCA. Thus, the identification of novel therapeutic targets for the effective treatment for CCA is still needed. In our previous report, we demonstrated that CDC20, a regulatory protein involved in cell cycle progression, is highly expressed in CCA patient tissues (8).

Cyclin-dependent kinases (CDKs), a group of serine/threonine kinases, play essential roles in regulating cell cycle progression and transcription in response to extracellular and intracellular signals. The levels of CDKs are generally constant and tightly regulated through interactions with cyclins that can stabilize and activate them. The complexes of CDK1-cyclin A/B, CDK2-cyclin E/A, and CDK4/6-cyclin D are required at specific cell cycle phases. Dysregulation of CDKs or CDK-cyclin complexes is a hallmark of cancer and is associated with tumorigenesis and disease progression (9, 10). Increased CDK and cyclin expression has been observed in several types of cancer, and their inhibition has been reported to result in cell cycle arrest and apoptosis. Therefore, modulation of CDKs with therapeutic agents is an attractive treatment strategy. Several compounds or small molecules have been designed to combat dysregulation of the cell cycle by affecting CDK expression and activity (11, 12).

CDC20 and CDKs are pivotal in the regulation of mitosis. CDK activity influences the timing of CDC20 activation and, consequently, the activation of the APC/C. For instance, the CDK1-cyclin B complex, which is active during early mitosis, phosphorylates various substrates, including components of the APC/C and CDC20 itself, thereby regulating the activity of the APC/C-CDC20 complex (13, 14). This phosphorylation is crucial for the correct timing of APC/C activation and ensures that chromosome segregation and mitotic exit occur only after all chromosomes are correctly attached to the spindle apparatus. Moreover, CDK-mediated phosphorylation of CDC20 may also play a role in the spindle assembly checkpoint (SAC), a surveillance mechanism that delays the onset of anaphase until all chromosomes are properly aligned on the mitotic spindle (15). The SAC inhibits the APC/C-CDC20 complex directly, and the interplay between CDK activity and the SAC ensures that cells do not prematurely enter anaphase, thus preventing chromosomal instability and aneuploidy.

Dinaciclib, a pan CDK inhibitor, is a potent selective small molecule against CDK1, CDK2, CDK5 and CDK9 with IC50 values in the low concentration range of 1-4 nM (16). The anti-tumor effect of dinaciclib was elucidated and showed significant benefits both in vitro and in vivo in various cancers (17-19). Compared with flavopiridol, the first pan-CDK inhibitor under clinical trials, dinaciclib exhibited superior activity with greater therapeutic efficacy and safety profiles. Dinaciclib has shown promising anti-tumor activity in preclinical studies against various cell lines with an IC50 at a low concentration (11 nM) and is in early phase clinical trials for hematological and solid malignancies such as chronic lymphocytic leukemia and breast cancer (18, 20). Dinaciclib induced cell cycle arrest and apoptosis in vitro and in a xenografted mouse model of thyroid cancer and triple-negative breast cancer (17, 20). Dinaciclib suppressed cell proliferation and triggered cell arrest and apoptosis of CCA cells through CDK2, CDK5, CDK9, and anti-apoptotic BCL2, BCL-XL protein suppression (21). However, the anti-tumor activity and chemosensitizing effect of dinaciclib against CCA cells are not fully understood. In this study, we aimed to investigate the anti-tumor activity of dinaciclib against CCA cells using in vitro and in vivo models. The possibility of using dinaciclib as a chemosensitizing agent for CCA was also explored.

Materials and Methods

Cell culture. CCA cell lines, including KKU-213A, KKU-100, KKU-452, KKU-055, KKK-D138, KKU-213A-GemR, and KKU-100-GemR (22-25), were cultured as described previously (26). Briefly, CCA cell lines were cultured in DMEM (Gibco; Paisley, Scotland, UK) supplemented with penicillin and streptomycin (100 U/ml) (Gibco) and 10% FBS (Gibco), in a humidified incubator at standard cell culture conditions (37°C, 5% CO2).

Cytotoxicity test and tetrazolium dye methylthiotetrazole (MTT) assay. CCA cell lines were seeded into 96-wells plates at 1,500 cells/well, cultured overnight (16 h) and incubated with various concentrations of dinaciclib (Abcam plc., Cambridge, UK) for 24, 48, and 72 h. The cell viability was assessed using the MTT assay (Molecular probes, Eugene, OR, USA). The MTT reagent was added and incubated for 4h at 37°C. The optical density (OD) of MTT was measured at 570 nm using a microplate reader (iMark; Bio-Rad Laboratories Inc., Hercules, CA, USA).

Cell cycle analysis. KKU-213A and KKK-D138 cells were seeded into 6 wells plates at 1.5×105 cells/well and cultured overnight (16 h). Then, the cells were treated with various concentrations of dinaciclib for 24 h. After incubation, treated cells were trypsinized, washed with PBS, and fixed with 70% ethanol at 4°C for 20 min. After fixation, the cells were incubated with RNase at a final concentration of 0.1 mg/ml at 37°C for 1 h; they were then stained with 50 μg/ml of propidium iodide (PI) for 20 min in the dark. The DNA content and cell cycle stage were investigated using the BD FACSCelesta™ flow cytometer (BD Bioscience, San Jose, CA). Data were analyzed using FlowJo software version 10.4 (Tree Star, San Carlos, CA, USA).

In vivo tumor transplantation and dinaciclib treatment. The in vivo effect of dinaciclib was examined using Balb/c Rag2™/™Jak3™/™ (BRJ) mice that were kindly provided by Prof. Seiji Okada (Kumamoto University, Kumamoto, Japan) (27). Mice were housed and monitored at the Center for Animal Resources and Development (CARD) of Kumamoto University, according to institutional guidelines. Food and water were provided ad libitum. All experiments were approved by the Kumamoto University Animal Ethics Committee (approval no. A2019-041, A2021-053). 1×106 KKU-213A cells were subcutaneously transplanted in each flank side of 8-12-week-old BRJ mice. Three days after transplantation, the mice in the treatment group (n=5) were intraperitoneally injected with dinaciclib, at a concentration of 20 mg/kg of body weight, every day for two weeks, whereas the control group was treated with DMSO under the same scheme. The tumor diameter was measured every 3 days. Tumor volume was calculated using the formula: V=½ (length×width2).

Combination treatment. To investigate the chemosensitizing effect of dinaciclib on gemcitabine, KKU-213A and KKU-100 were treated with dinaciclib at a dose of IC25, IC50, and IC75 for each cell line combined with various concentrations of gemcitabine (IC25, IC50, and IC75) for 72 h. The growth inhibitory effect of the combination treatment on CCA cells was examined using the MTT assay. The combination index (CI) theorem of Chou–Talalay (28) offers a quantitative definition for additive effect (CI=1), synergism (CI <1), and antagonism (CI >1) in drug combinations. All data were analyzed using the COMPUSYN software (ComboSyn Inc., NY, USA).

Statistical analysis. The results were analyzed using an unpaired t-test or One/Two-way ANOVA followed by Bonferroni post-test. All analyses were performed using the SPSS version 16.0 (SPSS IBM Inc., Chicago, IL, USA) and GraphPad Prism 9.0.0 (GraphPad Software Inc., La Jolla, CA, USA). p<0.05 was considered statistically significant.

Results

Dinaciclib suppresses growth of CCA cell lines. Our previous study showed that the CCA cells were more sensitive to dinaciclib than to the standard chemotherapeutic drug gemcitabine (8). In this study, we confirmed the effects of dinaciclib on five CCA cell lines. CCA cell lines were treated with various concentrations of dinaciclib (0-25 nM) for 24, 48, and 72 h. Treatment with dinaciclib significantly suppressed the cell proliferation of all cell lines in a dose-and time-dependent manner (Figure 1), with IC50 in the low nanomolar range (Table I). This data suggests that CCA cells are generally susceptible to the growth inhibitory effect of dinaciclib.

Figure 1.
Figure 1.

Anti-proliferative activity of dinaciclib in five CCA cell lines, including (A) KKU-213A, (B) KKU-100, (C) KKU-055, (D) KKK-D138 and (E) KKU-452. Significance markers indicate differences between incubation times. Data was analyzed using one-way ANOVA followed by Bonferroni correction (*p<0.05, significant difference between 24 and 48 h; +p<0.05, significant difference between 24 and 72 h; ep<0.05, significant difference between 48 and 72 h).

View this table:
Table I.

IC50 of dinaciclib in five cholangiocarcinoma cell lines.

Dinaciclib induced G1/S phase cell cycle arrest and apoptosis in CCA cell lines. Cell cycle analysis using PI staining was used to examine the effect of dinaciclib treatment on cell cycle arrest and apoptosis induction in CCA cells. KKU-213A and KKK-D138 cells were treated with 6.25, 12.5 and 25 nM dinaciclib for 24 h, and analyzed by FACS with PI-stained cells. The accumulation of CCA cells in the G1/S phase of the cell cycle was significantly increased in dinaciclib-treated cells when compared to vehicle (DMSO) treated cells (Figure 2A, C). Furthermore, apoptosis was quantified by measuring the fraction of cells with sub-diploid DNA content (sub-G1). KKU-213A and KKK-D138 cells treated with dinaciclib showed a significant increase in the sub-G1 population when compared to the vehicle-treated controls in a dose-dependent manner (Figure 2B). The sub-G1 DNA content of dinaciclib treated KKU-213A cells gradually increased from 3.41 to 6.25 nM to 8.94 at 12.5 nM, and 24.7 at 25 nM. A similar trend was observed in KKK-D138 cells when treated with these concentrations of dinaciclib. These results suggest that dinaciclib triggered cell cycle arrest at the G1/S phase.

Figure 2.
Figure 2.

Effect of dinaciclib on cell cycle distribution in CCA cell lines. (A) Cell cycle distribution of KKU-213A and KKK-D138 treated with and without various concentrations of dinaciclib (6.25, 12.5, and 25 nM). (B) The sub-G1 population as an indicator of apoptotic cells in KKU-213A and KKK-D138 cell lines after treatment with dinaciclib. (C) The relative cell population percentages in G1, S, and G2 phases for KKU-213A after 18 h of treatment and KKK-D138 cells after 48 h of treatment with dinaciclib. Data was analyzed using one-way ANOVA followed by Bonferroni’ correction (****p<0.0001 and *p<0.05).

Dinaciclib suppresses CCA growth in mice. The growth inhibitory effect of dinaciclib was explored using CCA xenograft mouse models (Figure 3A). KKU-213A was chosen because of their sensitivity to cell growth inhibition by dinaciclib in vitro. We measured the body weight and tumor volume of mice treated with dinaciclib or vehicle control. The treatments were administered daily via intraperitoneal injections at a dosage of 20 mg/kg, three days per week for two weeks, with five mice in each group. The dinaciclib-treated group relative body weight decreased slightly, and no significant difference was noted when compared to the control group. A significant inhibition of tumor weight and volume was observed in dinaciclib-treated mice (Figure 3B, C).

Figure 3.
Figure 3.

Anti-tumor activity of dinaciclib in CCA inoculated mice. (A) Images of tumor nodules from CCA inoculated mice treated with or without dinaciclib. (B) Left panel: Tumor weight (g), and right panel: tumor volumes. A two-sample t-test (independent t-test) was used for statistical analysis of the left panel, while ANOVA followed by Bonferroni’s post hoc test was used for the right panel (****p<0.0001 and **p<0.01).

Dinaciclib inhibited the proliferation of gemcitabine-resistant CCA cell lines. A key challenge in the chemotherapy of CCA is the development of drug resistance. In the present study, two gemcitabine-resistant CCA cell lines (KKU-213A-GemR and KKU-100-GemR) and their parental cell lines (KKU-213A and KKU-100) were treated with various concentrations of dinaciclib. The cell viability of both parental and gemcitabine-resistant CCA cell lines was significantly decreased by dinaciclib treatment in a dose-dependent manner (Figure 4). IC50 of dinaciclib was similar in both parental and gemcitabine-resistant CCA cell lines (Table II).

Figure 4.
Figure 4.

Anti-tumor activity of dinaciclib in parental (KKU-213A and KKU-100) and gemcitabine-resistant CCA cell lines (KKU-213A-GemR and KKU-100-GemR).

View this table:
Table II.

IC50 of dinaciclib in parental and gemcitabine resistant cholangiocarcinoma cell lines.

The chemosensitizing effect of dinaciclib on gemcitabine-treated CCA cell lines. To investigate the chemosensitizing effect of dinaciclib, CCA cells were treated with dinaciclib at a dose of IC25, IC50, and IC75, combined with various concentrations of gemcitabine (IC25, IC50, and IC75) for 72 h. The growth inhibitory effect of the combination treatment on CCA cells was examined using the MTT assay, and the combination index (CI) and the dose reduction index (DRI) values were analyzed. The constructed isobologram of all combinations for KKU-213A and KKU-100 revealed that the CI values of all combination treatments were less than 1 (Figure 5A and Table III), indicating that dinaciclib exhibited synergistic effects with all concentrations of gemcitabine. The cell viability for all combinations was significantly lower than the viability upon treatment with gemcitabine alone (Figure 5B).

Figure 5.
Figure 5.

Chemosensitizing effect of dinaciclib in gemcitabine treated CCA cell lines. (A) Isobolograms for the combination treatment of dinaciclib and gemcitabine on KKU-213A and KKU-100. The diagonal line indicates the theoretical additive effect between the two drugs. Points falling below the line suggest synergism, whereas points above indicate antagonism. (B) The viability (%) of KKU-213A and KKU-100 cells treated with various combinations of gemcitabine and dinaciclib, relative to control (untreated cells). Data was analyzed using one-way ANOVA followed by Bonferroni correction (***p<0.001, **p<0.01 and *p<0.05).

View this table:
Table III.

Combination index (CI) of dinaciclib and gemcitabine.

Discussion

Cholangiocarcinoma (CCA) remains a significant public health problem, due to its late-stage diagnosis, resistance to chemotherapy, and the subsequent poor patient prognosis. Effective therapeutic regimens and molecular targets for CCA are ongoing, and the results of this study provide promising insights into the potential of dinaciclib as a therapeutic agent for all CCA types.

The role of cyclin-dependent kinases (CDKs) in cell cycle progression is well-established, and their aberrant activation has been identified as a hallmark of various cancers, both solid and hematopoietic malignancies, including CCA (29). Therefore, inhibition of the CDKs is considered a treatment strategy for several cancers (30, 31). Dinaciclib, a multi-CDK inhibitor, has shown its potential to treat advanced malignancies in pre-clinical and clinical trials (17, 32, 33). In addition, radiosensitivity in lung and colon cancer cell lines was enhanced by dinaciclib through the inhibition of CDK12, leading to a decrease in BRCA1 expression (34).

The results of our study provide an additional support for the efficacy of dinaciclib against CCA cells in both in vitro and in vivo models. Dinaciclib can inhibit the growth and induce apoptosis of CCA cell lines in a dose and time-dependent manner. The suppression of proliferation, induction of cell cycle arrest, and promotion of apoptosis by dinaciclib were observed in all five CCA cell lines (KKU-213A, KKU-100, KKU-452, KKU-055, and KKK-D138) upon inhibition of cyclin-dependent kinase (CDKs) activity. All these cell lines were established from liver fluke (Opisthorchis viverrini) infection-associated CCA tissues with distinct histological characteristics (22, 24, 35). Similar results were reported in non-Ov-associated CCA cell lines (CHNG6, HuCCT1, and KMCH) (21), which were caused by other factors, such as genetic mutations, chronic biliary diseases, or exposure to toxins (36). Taking all these into account, dinaciclib may be a potential therapeutic agent for both Ov-associated and non-Ov-associated CCA.

In the present study, we demonstrated that dinaciclib could inhibit not only parental CCA cell lines (KKU-213A and KKU-100) but also their gemcitabine-resistant CCA cell lines (KKU-213A-GemR and KKU-100-GemR). Although gemcitabine is a standard chemotherapeutic drug for CCA, resistance to this drug often develops, resulting in treatment failure and disease progression (5, 37). Thus, administration of gemcitabine combined with a chemosensitizing drug can potentially enhance the therapeutic efficacy in patients with CCA (38). In this study, we demonstrated the chemosensitizing effect of dinaciclib on CCA cell lines. Dinaciclib could substantially enhance the anti-tumor efficacy of gemcitabine against two CCA cell lines, KKU-213A and KKU-100. The CI showed a synergistic effect (CI <1) in combination between dinaciclib and gemcitabine.

Conclusion

In conclusion, this study comprehensively investigated the therapeutic potential of dinaciclib in the treatment of CCA. Our results demonstrated that dinaciclib effectively inhibits cell growth, induces G1/S cell cycle arrest, and triggers apoptosis in CCA cell lines. The growth inhibition effect of dinaciclib was also demonstrated in gemcitabine-resistant CCA cell lines and CCA-inoculated mice. Furthermore, the combination of dinaciclib with gemcitabine exhibited a potent synergistic anticancer effect. Taken together, these findings suggest that dinaciclib is a promising treatment option for patients with CCA.

Acknowledgements

We would like to acknowledge Prof. Yukifumi Nawa, for editing this manuscript via the Publication Clinic, KKU, Thailand.

Footnotes

  • Authors’ Contributions

    P.S. performed experiments, data analysis and drafted the manuscript. S.K. performed experiments and data analysis. U.T. drafted the manuscript. C.S. participated in the design of the experiments and supervised the study. S.W. designed the experiments and supervised the study. S.O. and W.S. conceived and supervised the study and revised the manuscript. All Authors participated in the interpretation of the results and review of the manuscript.

  • Funding

    This research was supported by the Fundamental Fund of Khon Kaen University (to Wunchana Seubwai), e-ASIA Joint Research Program from Japan Agency for Medical Research and Development (AMED) (grant number: 20jm0210062h0003 to Seiji Okada), and Japan Student Services Organization (JASSO) scholarship (to Prin Sungwan).

  • Conflicts of Interest

    The Authors declare no conflicts of interest.

  • Received April 17, 2024.
  • Revision received May 19, 2024.
  • Accepted May 29, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Anti-Tumor and Chemosensitizing Effects of the CDK Inhibitor Dinaciclib on Cholangiocarcinoma In Vitro and In Vivo
PRIN SUNGWAN, SONEXAI KIDOIKHAMMOUAN, UNCHALEE THONSRI, CHARUPONG SAENGBOONMEE, SOPIT WONGKHAM, SEIJI OKADA, WUNCHANA SEUBWAI
In Vivo Sep 2024, 38 (5) 2284-2293; DOI: 10.21873/invivo.13693
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