CHK1 plays a critical role in the anti-leukemic activity of the wee1 inhibitor MK-1775 in acute myeloid leukemia cells
© Qi et al.; licensee BioMed Central Ltd. 2014
Received: 16 May 2014
Accepted: 8 July 2014
Published: 1 August 2014
Acute myeloid leukemia (AML) remains a difficult disease to treat and requires new therapies to improve treatment outcome. Wee1 inhibitors have been used to prevent activation of the G2 cell cycle checkpoint, thus enhancing the antitumor activity of DNA damaging agents. In this study, we investigated MK-1775 in AML cell lines and diagnostic blast samples to identify sensitive subtypes as well as possible mechanisms of resistance.
In vitro MK-1775 cytotoxicities of AML cell lines and diagnostic blasts were measured using MTT assays. The effects of MK-1775 on cell cycle progression and related proteins were determined by propidium iodide (PI) staining and flow cytometry analysis and Western blotting. Drug-induced apoptosis was determined using annexin V/PI staining and flow cytometry analysis.
We found that newly diagnosed and relapsed patient samples were equally sensitive to MK-1775. In addition, patient samples harboring t(15;17) translocation were significantly more sensitive to MK-1775 than non-t(15;17) samples. MK-1775 induced apoptosis in both AML cell lines and diagnostic blast samples, accompanied by decreased phosphorylation of CDK1 and CDK2 on Tyr-15 and increased DNA double-strand breaks (DSBs). Time-course experiments, using AML cell lines, revealed a time-dependent increase in DNA DSBs, activation of CHK1 and subsequent apoptosis following MK-1775 treatment, which could be attenuated by a CDK1/2 inhibitor, Roscovitine. Simultaneous inhibition of CHK1 and Wee1 resulted in synergistic anti-leukemic activity in both AML cell lines and primary patient samples ex vivo.
Our study provides compelling evidence that CHK1 plays a critical role in the anti-leukemic activity of MK-1775 and highlights a possible mechanism of resistance to MK-1775. In addition, our study strongly supports the use of MK-1775 to treat both newly diagnosed and relapsed AML, especially cases with t(15;17) translocation, and supports the development of combination therapies with CHK1 inhibitors.
KeywordsWee1 MK-1775 CHK1 Acute myeloid leukemia
Acute myeloid leukemia (AML) is a challenging disease to treat, with overall survival rates of 65% for children and 25% for adults ,. Resistance to cytarabine (ara-C) and anthracycline [e.g. daunorubicin (DNR)]-based chemotherapy remains a major cause of treatment failure. Therefore, new therapies are greatly needed to treat this disease.
One mechanism of chemotherapy resistance is the induction of G2/M cell cycle arrest, which allows cells to repair and survive DNA damage . Wee1 kinase is a cell cycle checkpoint protein whose primary function is inhibitory phosphorylation of CDK1 and CDK2 on Tyr-15, preventing progression through G2/M and S phase, respectively ,. Inhibitory phosphorylation of CDK1 and CDK2 on Tyr-15 is removed by CDC25 phosphatases ,. CDC25 activity is inhibited when phosphorylated by CHK1, which is in turn controlled primarily by ATR kinase ,. Upon sensing DNA damage or replication stress ATR phosphorylates CHK1, activating it and eventually leading to S and G2 cell cycle arrest, allowing for DNA repair ,.
The first selective and potent Wee1 inhibitor, MK-1775, has been primarily used to target the G2 checkpoint to exert toxicity in cells with impaired p53 function . It has been demonstrated that when combined with DNA damaging agents it is able to abrogate the G2 checkpoint and enhance apoptosis -. In addition, Wee1 inhibition has been shown to induce DNA damage through the induction of replication stress secondary to overactive CDKs and inhibition of DNA repair .
In this study, we used AML cell lines and blast samples obtained either at diagnosis or at relapse to investigate the cytotoxic effects of MK-1775 on AML. Our results suggest that MK-1775 may be equally effective in newly diagnosed and relapsed AML. Additionally, we demonstrate that patient samples harboring t(15;17) translocation are significantly more sensitive to MK-1775 than others. Furthermore, our study suggests that MK-1775 treatment induces DNA damage which activates CHK1, CHK1 phosphorylates CDC25, inhibiting the dephosphorylation of CDK1/2, thus countering the effects of MK-1775. Activation of CHK1 can be overcome by the addition of a CHK1 inhibitor, resulting in synergistic anti-leukemic activity. This demonstrates a potential mechanism of resistance to MK-1775 treatment and highlights the importance of combination therapies.
MK-1775 induces DNA damage and apoptosis in AML cells
Patient characteristics and MK-1775 sensitivity for primary AML patient samples
Blast purity (%)
46, XX, t(8;21)(q22;q22)
46, XX, del(5q), add(12p)
45, X, -Y, t(8;21)(q22;q22)
46, XY, t(15;17)(q22;q21)
46, XY, t(8;21)(q22;q22)
46, XY, t(15;17)(q22;q21)
47, XX, +10, t(16;21)(p11;q22), add(11p)
46, XY, del(9q)
46, XY, t(15;17)(q22;q21)
46, XY, t(11;15;17)(q25;q15;q21)
46, XY, t(15;17)(q22;q21)
46, XX, t(8;21)(q22;q22)
46, XY/44, XY, -17, -19, (11q-?)
46, XY, +2, +8, I(12)(q10)
46, XX, t(15;17)(q22;q21)
46, XY, t(6;9)(p22;q34)
CDK activity is required for MK-1775 anti-leukemic activity
CHK1 inhibitor LY2603618 synergizes with MK-1775 to induce apoptosis in AML cells
Wee1 inhibitors have primarily been used to target the G2 cell cycle checkpoint, which is activated in response to DNA damaging agents, and has shown promising results when combined with standard chemotherapy drugs -. Using single agent treatment we demonstrate that AML patient samples with t(15;17) translocation are more sensitive to MK-1775 than non-t(15;17), suggesting a possible treatment for patients with t(15;17) who do not respond to all-trans retinoic acid and/or arsenic trioxide based therapies. The t(15;17) translocation results in rearrangement of the promyelocytic leukemia (PML) gene and the retinoic acid receptor α(RARα) gene, generating the PML/RARα fusion protein . This fusion protein acts as a strong transcriptional repressor for numerous genes which are involved in proliferation, DNA repair, and cell death ,, and thus may contribute to the elevated MK-1775 sensitivity. We also found that newly diagnosed and relapsed AML patient samples have similar ex vivo MK-1775 sensitivities, as measured by MTT assays. In addition, our studies in a cytarabine resistant cell line further support the preclinical development of MK-1775 for the treatment of relapsed AML.
In our study, we demonstrate that MK-1775 treatment results in increased phosphorylation of CHK1 and H2AX, in agreement with Chaudhuri et al.'s report . Furthermore, increased phosphorylation of both CHK1 and H2AX is dependent on CDK activity. Inhibition of CHK1 in combination with MK-1775 resulted in synergistic anti-leukemic activities in both AML cell lines and primary patient samples. Although combined Wee1 and CHK1 inhibition has been reported in various cancer types -, including AML , our study confirmed the enhanced anti-leukemic activity with a different CHK1 inhibitor, LY2603618, than has been previously reported (MK-8776, PF-00477736, AR458323) and found similar synergistic anti-leukemic activity. Thus, adding further evidence for the clinical efficacy of combined Wee1 and CHK1 inhibition for the treatment of AML.
In summary, our study demonstrates that MK-1775 has potential as an anti-leukemic drug in the treatment of AML. Particularly, our patient sample data supports the investigation of MK-1775 in relapsed AML, as they had similar sensitivities as newly diagnosed cases. In addition, AML cases with t(15;17) translocation were significantly more sensitive to MK-1775 treatment, suggesting a possible role for patients who do not respond to all-trans retinoic acid and/or arsenic trioxide-based therapies. We also demonstrate that MK-1775 in combination with cytarabine results in synergistic anti-leukemic activity in AML cell lines and patient samples (Additional file 1: Figure S4). Lastly, our results highlight CHK1 activation as a potential mechanism of resistance to MK-1775 treatment, thus supports the development of combination therapies.
Materials and methods
MK-1775 (MK), Roscovitine (Rosc), and LY2603618 (LY) were purchased from Selleck Chemicals (Houston, TX, USA). Cytarabine (ara-C) was purchased from Sigma-Aldrich (St. Louis, MO, USA).
The THP-1, MV4-11, U937, HL-60 cell lines were purchased from the American Type Culture Collection (Manassas, VA, USA). The OCI-AML3 cell line was purchased from the German Collection of Microorganisms and Cell Cultures (DSMZ, Braunschweig, Germany). MOLM-13 cells were purchased from AddexBio (San Diego, CA, USA). The CTS cell line was a gift from Dr. A Fuse from the National Institute of Infectious Diseases, Tokyo, Japan. The cell lines were cultured in RPMI 1640 (except OCI-AML3, which was cultured in alpha-MEM) with 10-15% fetal bovine serum (Hyclone, Logan, UT, USA), 2 mM L-glutamine, 100 U/ml penicillin and 100 μg/ml streptomycin. All cells were cultured in a 37°C humidified atmosphere containing 5% CO2/95% air.
AML blast samples obtained either at diagnosis or at relapse were purified by standard Ficoll-Hypaque density centrifugation, then cultured in RPMI 1640 with 20% fetal bovine serum supplemented with ITS solution (Sigma-Aldrich) and 20% supernatant of the 5637 bladder cancer cell line [as a source of granulocyte-macrophage colony-stimulating factor ,].
HL-60 cytarabine resistant cells (designated HL-60/Ara-C) were generated by stepwise selection of HL-60 cells in the presence of cytarabine, until they could be maintained in the presence of 600 nM cytarabine.
Diagnostic blast samples were obtained from the First Hospital of Jilin University. Written informed consent was provided according to the Declaration of Helsinki. This study was approved by the Human Ethics Committee of the First Hospital of Jilin University. Clinical samples were screened for FLT3-ITD, NPM1, C-kit, CEBPA, IDH1, IDH2 and DNMT3A gene mutations. The samples were also screened for the following fusion genes by real-time RT-PCR: PML-RARα, BCR-ABL, AML1-MDS1, MLL-AF10, MLL-AF4, MLL-ELL, SET-CAN, TLS-ERG, NPM-RARα, E2A-PBX1, AML1-EAP, MLL-AF17, MLL-AF6, MLL-ENL, SIL-TAL1, HOX11, PLZF-RARα, TEL-AML1, DEK-CAN, MLL-AF1p, MLL-AF9, NPM-ALK, TEL-ABL, EIP1L1-PDGFRA, AML1-ETO, CBFB-MYH11, E2A-HLF, MLL-AF1q, MLL-AFX, NPM-MLF1, dupMLL, and TEL-PDGFB.
In vitro cytotoxicity assays
In vitro cytotoxicities of the AML cells were measured by using MTT (3-[4,5-dimethyl-thiazol-2-yl]-2,5-diphenyltetrazoliumbromide, Sigma-Aldrich) assays, as previously described ,. Briefly, the cells were treated with variable concentrations of MK-1775 for 72 hours. MTT was added to a final concentration of 1 mM and cells were incubated for 4 hours at 37°C. The cells were lysed overnight using 10% SDS in 10 mM HCL and plates were read at 590 nm using a microplate reader. IC50 values were calculated as drug concentrations necessary to inhibit 50% growth compared to vehicle control treated cells. The cell line IC50 values are presented as mean values ± standard errors from at least three independent experiments. The IC50 values for the patient samples are means of duplicates from one experiment, due to limited sample. Patient samples for the combined drug treatments were chosen based on sample availability.
Western blot analysis
Cells were lysed in the presence of protease and phosphatase inhibitors (Roche Diagnostics, Indianapolis, IN, USA). Whole cell lysates were subjected to SDS-polyacrylamide gel electrophoresis, electrophoretically transferred onto polyvinylidene difluoride (PVDF) membranes (Thermo Fisher Inc., Rockford, IL, USA) and immunoblotted with anti-p-CDK1 (Y15), -CDK1, -p-CDK2 (Y15), -CDK2, -Wee1, -MYT1, -γH2AX, -CHK1, -p-CHK1 (S345), -p-CDC25C (S216) (Cell Signaling Technology, Danvers, MA, USA), or -β-actin (Sigma-Aldrich) antibody, as previously described ,. Immunoreactive proteins were visualized using the Odyssey Infrared Imaging System (Li-Cor, Lincoln, NE, USA), as described by the manufacturer. Western blots were repeated at least three times and one representative blot is shown. Only one patient sample was used for MK-1775 treatment and subsequent Western blot analysis due to the limited amount of sample available. Densitometry measurements were made using Odyssey V3.0 (Li-Cor), normalized to β-actin, and then fold change relative to no drug control was calculated.
AML cells were treated with MK-1775, Roscovitine, LY2603618, or the indicated combinations and subjected to flow cytometry analysis to determine drug-induced apoptosis using an annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) apoptosis Kit (Beckman Coulter; Brea, CA, USA), as previously described ,. Results are expressed as percent of annexin V + cells. Experiments with AML cell lines were performed 3 independent times in triplicates and data presented are from one representative experiment, while patient sample experiments were performed once in triplicates. Data are presented as mean values ± standard errors from one representative experiment. Due to limited sample, only three patient samples were evaluated for MK-1775-induced apoptosis by flow cytometry.
Cell cycle progression
Cells were treated with the indicated drugs for up to 48 h. The cells were harvested and fixed with ice-cold 80% (v/v) ethanol for 24 h. The cells were pelleted, washed with PBS, and resuspended in PBS containing 50 μg/mL propidium iodide (PI), 0.1% Triton X-100 (v/v), and 1 μg/mL DNase-free RNase. DNA content was determined by flow cytometry analysis using a FACScan flow cytometer (Becton Dickinson, San Jose, CA, USA) as previously described . Cell cycle analysis was performed using Multicycle software (Phoenix Flow Systems, Inc., San Diego, CA, USA). Histograms were created using FlowJo v7.6.5 (Tree Star, Ashland, OR, USA).
Differences in cell apoptosis between treated (individually or combined) and untreated cells were compared using the pair-wise two-sample t-test. The p value for the differences between MK-1775 IC50s for the groups of patient samples was calculated using the Mann-Whitney U test. Statistical analyses were performed with GraphPad Prism 5.0.
WQ and CX performed the molecular biology studies. CL, JWT, YW, HL, and YG participated in the design and coordination of the study. CL, JTC, HE, JWT, YW, HL, and YG participated in the data analysis and interpretation. CL, JTC, HE, JWT, YW, HL, and YG helped to draft the manuscript. All authors read and approved the final manuscript.
This study was support by a Start-up Fund from Jilin University, Changchun, China, and grants from the National Natural Science Foundation of China (NSFC 31271477 and 81200363). Mr. JTC is a predoctoral trainee supported by T32 CA009531 from the National Cancer Institute. The funders had no role in study design, data collection, analysis and interpretation, writing of the manuscript, and in the decision to submit the article for publication. The authors would like to thank Dr. Mark Stout for generating the cytarabine resistant HL60 cells.
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