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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front Med    2013, Vol. 7 Issue (4) : 462-476    https://doi.org/10.1007/s11684-013-0270-6
RESEARCH ARTICLE
Combined gemcitabine and CHK1 inhibitor treatment induces apoptosis resistance in cancer stem cell-like cells enriched with tumor spheroids from a non-small cell lung cancer cell line
Douglas D. Fang(), Joan Cao, Jitesh P. Jani, Konstantinos Tsaparikos, Alessandra Blasina, Jill Kornmann, Maruja E. Lira, Jianying Wang, Zuzana Jirout, Justin Bingham, Zhou Zhu, Yin Gu, Gerrit Los, Zdenek Hostomsky, Todd VanArsdale
Oncology Research Unit, Pfizer, Inc., 10777 Science Center Drive, San Diego, CA 92121, USA
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Abstract

Evaluating the effects of novel drugs on appropriate tumor models has become crucial for developing more effective therapies that target highly tumorigenic and drug-resistant cancer stem cell (CSC) populations. In this study, we demonstrate that a subset of cancer cells with CSC properties may be enriched into tumor spheroids under stem cell conditions from a non-small cell lung cancer cell line. Treating these CSC-like cells with gemcitabine alone and a combination of gemcitabine and the novel CHK1 inhibitor PF-00477736 revealed that PF-00477736 enhances the anti-proliferative effect of gemcitabine against both the parental and the CSC-like cell populations. However, the CSC-like cells exhibited resistance to gemcitabine-induced apoptosis. Collectively, the spheroid-forming CSC-like cells may serve as a model system for understanding the mechanism underlying the drug resistance of CSCs and for guiding the development of better therapies that can inhibit tumor growth and eradicate CSCs.

Keywords drug resistance      cancer stem cell      checkpoint kinase 1 (CHK1)      PF-00477736      lung cancer      tumorigenicity     
Corresponding Author(s): Fang Douglas D.,Email:douglasfang@yahoo.com   
Issue Date: 05 December 2013
 Cite this article:   
Douglas D. Fang,Joan Cao,Jitesh P. Jani, et al. Combined gemcitabine and CHK1 inhibitor treatment induces apoptosis resistance in cancer stem cell-like cells enriched with tumor spheroids from a non-small cell lung cancer cell line[J]. Front Med, 2013, 7(4): 462-476.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-013-0270-6
https://academic.hep.com.cn/fmd/EN/Y2013/V7/I4/462
Fig.1  Isolation of CSC-like cells from NCI-H1299 under serum-free culture conditions.(A) Morphology of the monolayer culture of the original NCI-H1299 cells (left panel), non-adherent 3D CSC-like cells (middle panel), and monolayer culture of cells differentiated from CSC-like cells (right panel). (B) Flow cytometric analyses of cell proliferation of the aforementioned cell types using a BrdU assay.
Fig.2  Differentiation and tumorigenesis of CSC-like cells. (A) Detection of expression of the epithelial lineage marker cytokeratin using flow cytometry. A PE-conjugated mouse isotype-matched antibodies (mIgG-PE) were used as the control (top panel). The data shown represent the results of three independent experiments. (B) limiting dilution assays. Solid line, CSC-like cells; dot line, parental cells. Significant differences in tumor volume were observed between the two groups (** <0.01, *** <0.001, ANOVA analysis)
Cell number injectedParental cell groupSpheroid CSC-like group
2 × 1055/55/5
2 × 1043/55/5
2 × 1030/50/5
Tab.1  Tumor incidence after 42 days post-implantation*
Fig.3  (A) spheroid reforming assay of CSC-like cells. CSC-like cells were disaggregated and seeded at various cell densities in stem cell medium in a 96-well cell culture plate, as indicated. Tumor spheroids (cellular aggregates with≥4 cells) were counted after 5 days. (B) The primary tumor cells isolated from CSC-like cell-derived xenografts reformed tumor spheroids under stem cell conditions. (C) The fold increase in the expression levels of representative genes in the -cultured spheroid CSC-like cells and in CSC-derived xenograft tumors compared with their counterparts (i.e., parental cells and parental cell-derived xenograft tumors), respectively.
Fig.4  Expression profile analysis of the cultured cells and derived xenografts. (A) Unsupervised hierarchical clustering dendrogram of genes differentially expressed in cultured CSC-like and parental cells, as well as their derived xenograft tumors, which are coded in colors. (B) Hierarchical clustering diagram of differentially expressed genes among cultured CSC-like cells, parental cells, and their derived xenograft tumors. A comparison of the overexpression of CD59 among cultured CSC-like cells, xenograft tumors, and cultured NCI-H1299 parental cells is shown. The list of genes is shown in Table 2. (C) Principal component analysis (PCA) of the genome-wide mRNA profiles. Each color-coded dot represents one sample in a 3D diagram showing their relative distribution. The data are summarized for the first three components, all of which account for 68% of the total variability. Results shown are from triplicates samples.
IDGene symbolChangeIDGene symbolChange
207347_atERCC6up226499_atNRARPup
212463_atCD59up227529_s_atAKAP12up
219423_x_atTNFRSF25up227530_atAKAP12up
1554452_a_atHIG2up231067_s_atup
1556773_atup211564_s_atPDLIM4up
206300_s_atPTHLHup226863_atFAM110Cup
219410_atTMEM45Aup201110_s_atTHBS1up
218325_s_atDIDO1up205534_atPCDH7up
228564_atLOC375295up202179_atBLMHdown
203372_s_atSOCS2up202245_atLSSdown
203373_atSOCS2up210986_s_atTPM1down
201693_s_atEGR1up210987_x_atTPM1down
205428_s_atCALB2up211984_atCALM1down
1554008_atOSMRup206117_atTPM1down
202949_s_atFHL2up219985_atHS3ST3A1down
204017_atKDELR3up218974_atSOBPdown
219032_x_atOPN3up206343_s_atNRG1down
220179_atDPEP3up202931_x_atBIN1down
1568574_x_atSPP1up210201_x_atBIN1down
213326_atVAMP1up212437_atCENPBdown
201844_s_atRYBPup201628_s_atRRAGAdown
201846_s_atRYBPup206593_s_atMED22down
209380_s_atABCC5up219560_atC22orf29down
205691_atSYNGR3up201929_s_atPKP4down
236915_atup48808_atDHFRdown
227089_atHBP1up1555427_s_atSYNCRIPdown
206385_s_atANK3up200601_atACTN4down
209442_x_atANK3up205471_s_atDACH1down
223631_s_atC19orf33up227511_atSAMD4Bdown
214185_atKHDRBS1up217992_s_atEFHD2down
223008_s_atC9orf5up208939_atSEPHS1down
218686_s_atRHBDF1up208940_atSEPHS1down
221567_atNOL3up214930_atSLITRK5down
225918_atLOC146346up238015_atLOC201725down
224743_atIMPAD1up208784_s_atKLHDC3down
209278_s_atTFPI2up37996_s_atDMPKdown
224801_atNDFIP2up211725_s_atBIDdown
201641_atBST2up203664_s_atPOLR2Ddown
1556166_x_atup209008_x_atKRT8down
232382_s_atPCMTD1up202093_s_atPAF1down
207768_atup202264_s_atTOMM40down
209758_s_atMFAP5up209675_s_atHNRPUL1down
221506_s_atTNPO2up213429_atBICC1down
219884_atLHX6up212131_atLSM14Adown
213045_atMAST3up215356_atECAT8down
205742_atTNNI3up212472_atMICAL2down
227948_atFGD4up204589_atNUAK1down
235948_atFAM80Aup225471_s_atAKT2down
238168_atTM4SF1up201480_s_atSUPT5Hdown
225257_atCCDC97down213600_atSIPA1L3down
226156_atAKT2down215429_s_atZNF428down
205264_atCD3EAPdown203440_atCDH2down
202108_atPEPDdown229116_atCNKSR2down
204493_atBIDdown227320_atFAM101Adown
205740_s_atRBM42down237034_atdown
219275_atPDCD5down225688_s_atPHLDB2down
229587_atSAE2down202626_s_atLYNdown
227674_atZNF585Adown238066_atRBP7down
202685_s_atAXLdown229139_atJPH1down
209583_s_atCD200down224846_atSHKBP1down
206940_s_atPOU4F1down224694_atANTXR1down
202625_atLYNdown201489_atPPIFdown
230552_atLOC284412down1569086_atEML2down
205347_s_atTMSL8down222809_x_atC14orf65down
224209_s_atGDAdown216299_s_atXRCC3down
206170_atADRB2down221335_x_atC19orf61down
218625_atNRN1down235019_atCPMdown
220257_x_atNXF2Bdown235706_atCPMdown
220981_x_atNXF2down243403_x_atCPMdown
223188_atC19orf61down219779_atZFHX4down
228131_atERCC1down224507_s_atMGC12916down
208190_s_atLSRdown241733_atC18orf54down
240389_atTRPM6down213053_atKIAA0841down
208713_atHNRPUL1down225440_atAGPAT3down
218702_atSARS2down227543_atRNASEH2Cdown
232079_s_atPVRL2down225516_atSLC7A2down
234173_s_atNXF2 /// NXF2Bdown228142_atUCRCdown
219690_atTMEM149down235236_atdown
225626_atPAG1down220085_atHELLSdown
213093_atPRKCAdown226279_atPRSS23down
206693_atIL7down228489_atTM4SF18down
214046_atFUT9down230061_atTM4SF18down
Tab.2  Comparison between the changes in gene expression profiles in cancer stem cell-like and in parental cells (≥3 fold)
Fig.5  Expression of stem cell markers CD44 and CD133 combined with EpCAM was determined using flow cytometry.
Fig.6  Comparison between the responses of the CSC-like cells and NCI-H1299 parental cells to drug treatments. (A) Resistance of the CSC-like cells to treatment using standard-of-care compounds. The results of cell viability assay are shown as percentage of viable cells (mean±SD) from triplicate experiments after normalizing with the controls. The IC in both cell types are indicated. (B) The inhibitory effect of gemcitabine alone and gemcitabine combined with the CHK1 inhibitor PF-00477736. The results of cell viability assay are shown as percentage inhibition (mean±SD; triplicates) after treatment with gemcitabine (Gem, 50 nM) alone or combined with PF-00477736 (540 nM). *<0.05, ** <0.01, one-way ANOVA. (C) Western blot analysis of CDK1, pCDK1, pCHK1, and cleaved PARP (clv) proteins in both cancer stem cell-like and parental cells treated with vehicle, gemcitabine, PF-00477736, and with gemcitabine combined with PF-00477736.
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