Investigations on the effects of cobalt-alkyne complexes on leukemia and lymphoma cells: cytotoxicity and cellular uptake

Cobalt-alkyne complexes represent a new class of antiproliferative drugs with high activity on cell lines derived from human solid tumors. These promising results encouraged us to evaluate also their effects against leukemia and lymphoma cells. For this purpose, we selected three cobalt complexes with (2-propyn-1-yl)acetylsalicylate (Co-ASS), 2-propyn-1-ol (Co-Prop) and diphenylacetylene (Co-Diph) ligands and investigated their growth inhibiting properties on the LAMA-84, K-562, SD-1 leukemia and U-937 lymphoma cell lines. The cobalt complexes showed high effects on LAMA-84 cells (IC(50)=7.7-16.8 microM) after 48 and 72 h of incubation, but were inactive (K-562, U-937) or low active (SD-1) on the other cell lines. The proliferation of SD-1 cells was reduced by Co-Prop (IC(50)=18.6 microM) and Co-Diph (IC(50)=7.5 microM) only after a 72 h exposure. The antiproliferative effects did not correlate with the accumulation of the drugs into the tumor cells. The time dependent uptake during 24 h determined by atomic absorption spectroscopy was comparably the same in sensitive LAMA-84 and insensitive K-562 cells.     

Identification of differentially expressed proteins in imatinib mesylate-resistant chronic myelogenous cells

Resistance to imatinib mesylate (also known as Gleevec, Glivec, and STI571) often becomes a barrier to the treatment of chronic myelogenous leukemia (CML). In order to identify markers of the action of imatinib mesylate, we used a mass spectrometry approach to compare protein expression profiles in human leukemia cells (K562) and in imatinib mesylate-resistant human leukemia cells (K562-R) in the presence and absence of imatinib mesylate. We identified 118 differentially regulated proteins in these two leukemia cell-lines, with and without a 1 microM imatinib mesylate challenge. Nine proteins of unknown function were discovered. This is the first comprehensive report regarding differential protein expression in imatinib mesylate-treated CML cells.     

Combination of tyrosine kinase inhibitors and the MCL1 inhibitor S63845 exerts synergistic antitumorigenic effects on CML cells

Tyrosine kinase inhibitor (TKI) treatment has dramatically improved the survival of chronic myeloid leukemia (CML) patients, but measurable residual disease typically persists. To more effectively eradicate leukemia cells, simultaneous targeting of BCR-ABL1 and additional CML-related survival proteins has been proposed. Notably, several highly specific myeloid cell leukemia 1 (MCL1) inhibitors have recently entered clinical trials for various hematologic malignancies, although not for CML, reflecting the insensitivity of CML cell lines to single MCL1 inhibition. Here, we show that combining TKI (imatinib, nilotinib, dasatinib, or asciminib) treatment with the small-molecule MCL1 inhibitor {"type":"entrez-nucleotide","attrs":{"text":"S63845","term_id":"400540","term_text":"S63845"}}S63845 exerted strong synergistic antiviability and proapoptotic effects on CML lines and CD34+ stem/progenitor cells isolated from untreated CML patients in chronic phase. Using wild-type BCR-ABL1-harboring CML lines and their T315I-mutated sublines (generated by CRISPR/Cas9-mediated homologous recombination), we prove that the synergistic proapoptotic effect of the drug combination depended on TKI-mediated BCR-ABL1 inhibition, but not on TKI-related off-target mechanisms. Moreover, we demonstrate that colony formation of CML but not normal hematopoietic stem/progenitor cells became markedly reduced upon combination treatment compared to imatinib monotherapy. Our results suggest that dual targeting of MCL1 and BCR-ABL1 activity may efficiently eradicate residual CML cells without affecting normal hematopoietic stem/progenitors.Subject terms: Cancer stem cells, Targeted therapies, Preclinical research     

Synthesis, in vitro anticancer evaluation, and interference with cell cycle progression of N-phosphoamino acid esters of zidovudine and stavudine

A series of N-diisopropylphosphoryl (DIPP) L-amino acid ester prodrugs of zidovudine (AZT) (3a-3e) and stavudine (d4T) (4a-4e) has been prepared. The activity of these compounds against MCF-7 cells (human pleural effusion breast adenocarcinoma cell line) and K562 cells (human chronic myeloid leukemia (CML) cell line) was evaluated. In difference from that of AZT amino acid phosphoramidates, the alophatic amino acid esters of AZT were found to be more cytotoxic than the aromatic analogues toward MCF-7 cell. Two DIPP-L-amino acid esters of d4T 4b (CC50 = 83 microM) and 4c (CC50 = 182 microM) were found to be more cytotoxic than the parent drug toward K562 cells. MCF-7 and K562 cell cycle disturbance was investigated showing detectable blockade in the S phase when exposed to biologically active AZT, 3a, 3b, 3c, 4b and 4c, indicating that they inhibit cell growth by blocking cell cycle progression. Together with previous reports, present findings suggest that anti-breast cancer activity of AZT may be due to hamper DNA synthesis.     

Bortezomib and sphingosine kinase inhibitor interact synergistically to induces apoptosis in BCR/ABl cells sensitive and resistant to STI571 through down-regulation Mcl-1

Interactions between the proteasome inhibitor, bortezomib, and the sphingosine kinase (SPK1) inhibitor, SKI, were examined in BCR/ABL human leukemia cells. Coexposure of K562 or chronic myeloid leukemia (CML) cells from patients to subtoxic concentrations of SKI (10 μM) and bortezomib (100 nM) resulted in a synergistic increase in caspase-3 cleavage and apoptosis. These events were associated with the downregulation of BCR–ABL and Mcl-1, and a marked reduction in SPK1 expression. In imatinib mesylate-resistant K562 cells that displayed decreased BCR–ABL expression, bortezomib/SKI treatment markedly increased apoptosis and inhibited colony-formation in association with the downregulation of Mcl-1. Finally, the bortezomib/SKI regimen also potently induced the downregulation of BCR/ABL and Mcl-1 in human leukemia cells. Collectively, these findings suggest that combining SKI and bortezomib may represent a novel strategy in leukemia, including apoptosis-resistant BCR–ABL⁺ hematologic malignancies.     

Imatinib (STI571) inhibits DNA repair in human leukemia oncogenic tyrosine kinase-expressing cells

BCR/ABL oncogene, as a result of chromosome aberration t(9;22), is the pathogenic principle of almost 95% of human chronic myeloid leukemia (CML). Imatinib (STI571) is a highly selective inhibitor of BCR/ABL oncogenic tyrosine kinase used in leukemia treatment. It has been suggested that BCR/ABL may contribute to the resistance of leukemic cells to drug and radiation through stimulation of DNA repair in these cells. To evaluate further the influence of STI571 on DNA repair we studied the efficacy of this process in BCR/ABL-positive and -negative cells using single cell electrophoresis (comet assay). In our experiments, K562 human chronic myeloid leukemia cells expressing BCR/ABL and CCRF-CEM human acute lymphoblastic leukemia cells without BCR/ABL expression were employed. The cells were exposed for 1 h at 37 degrees C to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) at 5 microM, mitomycin C (MMC) at 50 microM or to gamma-radiation at 15 Gy with or without a 24 h preincubation at 1 microM of STI571. The MTT cells survival after 4 days of culture showed that STI571 enhanced the cytotoxity of the examined compounds in the K562 line. Further it was found, that the inhibitor decreased the efficacy of DNA repair challenged by each agent, but only in the K562 expressing BCR/ABL. Due to the variety of DNA damage induced by the employed agents in this study we can speculate, that BCR/ABL may stimulate multiple pathways of DNA repair. These results extend our previous studies performed on BCR/ABL-transformed mouse cells onto human cells. It is shown that BCR/ABL stimulated DNA repair in human leukemia cells. In conclusion we report that STI571 was found to inhibit DNA repair and abrogate BCR/ABL-positive human leukemia cells therapeutic resistance.     

Overexpression of Hes1 is involved in sensitization of K562 cells to Imatinib

Tyrosine kinase inhibitor (TKI)-based therapy has created promising results among much chronic myeloid leukemia (CML) patients. Imatinib as a relatively specific inhibitor of Bcr-Abl is at present one of the undisputed therapeutic agent for newlydiagnosed patients with CML. However, the occurrence of imatinib-resistance enlightens the urgent need to identify other therapeutic agents against CML. Juglone (5-hydroxy-2-methyl-1, 4-naphthoquinone) exerts cytotoxic effects against various human cancer cell lines. However, the mechanisms through which Juglone induces anticancer effects in CML especially in comparison with imatinib treatment remain unknown. Our results revealed that Juglone-inhibited K562 cells growth through inducing apoptosis. Based on our Western blot analyses, Juglone significantly reduced p-Akt levels and increased the expression level of Forkhead box O1 (FoxO1) and FoxO3a proteins. Moreover, hairy/enhancer of split-1 (Hes1) protein, overexpressed under the influence of Juglone, is apparently involved in Juglone-induced apoptosis among K562 cells. Conversely, treatment with imatinib attenuated Hes1 protein expression. Considering the different functional mechanism of Juglone compared with imatinib, it seems that Juglone treatment could be a useful alternative strategy for the treatment of patients with imatinib-resistance.     

Specificity of arachidonic acid-induced inhibition of growth and activation of c-jun kinases and p38 mitogen-activated protein kinase in hematopoietic cells

We demonstrated that arachidonic acid inhibits growth and induces apoptosis in the bcr-abl transformed leukemia cell line, H7.bcr-abl A54 and in human chronic myeloid leukemia hematopoietic cells. This investigation was undertaken to determine the cell-type specificity of this response. We compared the effect of arachidonic acid on H7.bcr-abl A54 cells to Jurkat (human acute T-cell leukemia), U937 (human histiocytic lymphoma) and RPMI 7666 (human normal B-lymphoblasts) cells. Arachidonic acid (100 microM, 72 h) inhibited growth of H7.bcr-abl A54, Jurkat and U937 cells by 82.2, 67.5 and 20%, respectively, but had no effect on RPMI 7666 cells. These effects were investigated in relationship to the activation of p38 mitogen activated protein kinase (p38 MAPK) and c-jun amino-terminal kinase (JNK) by arachidonic acid in these cell lines. Results from these studies suggest that signaling and proliferative responses to arachidonic acid are cell-type specific. Leukemia cells appear to be more sensitive to the antiproliferative effect of arachidonic acid than normal cells.     

慢性粒细胞白血病耐药机制及治疗策略

慢性粒细胞白血病是一类造血干细胞的恶性克隆性疾病,ph染色体是其特征性细胞遗传学标志,即t(9;22)(q34;ql1),存在BCR/ABL融合基因,现阶段造血干细胞移植是当前最有希望治愈CML的疗法,但受年龄、配型等限制,易发生移植物抗宿主病;复发率较高;传统的化疗、干扰素治疗也有副作用,因此,通过信号传导抑制剂抑制BCR-ABL酪氨酸激酶活性,从而阻止一系列信号传导来治疗CML是一个比较好的治疗方法,伊马替尼是一种酪氨酸激酶抑制剂是治疗慢性粒细胞白血病的靶向治疗药物,治疗疗效显著,但是并不能根治慢性粒细胞白血病,需要长期服药,一些患者出现耐药,导致治疗无效或复发。因此,寻求新的治疗方案至关重要。本文就慢性粒细胞白血病的耐药机制及治疗策略做一综述。     

Design and synthesis of 3-substituted benzamide derivatives as Bcr-Abl kinase inhibitors

A series of 3-substituted benzamide derivatives structurally related to STI-571 (imatinib mesylate), a Bcr-Abl tyrosine kinase inhibitor used to treat chronic myeloid leukemia (CML), was prepared and evaluated for antiproliferative activity against the Bcr-Abl-positive leukemia cell line K562. About ten 3-halogenated and 3-trifluoromethylated benzamide derivatives were identified as highly potent Bcr-Abl kinase inhibitors. One of these, NS-187 (9b), is a promising new candidate Bcr-Abl inhibitor for the therapy of STI-571-resistant chronic myeloid leukemia.     

Response to treatment with imatinib mesylate in previously treated chronic-phase chronic myeloid leukemia patients in a hospital in Brazil

We analyzed the results of treatment with imatinib mesylate in 70 patients with chronic-phase chronic myeloid leukemia who had previously been treated (with second-line or higher imatinib), many of them in a late chronic phase. The median follow-up period was 60.5 months (range 3-100 months). Our objective was to assess the efficacy and safety of treatment. The mean dose was 400 mg per day. The hematologic response rate was 92.1% at six months, while the cumulative rates of major and complete cytogenetic responses were 73.6 and 66.3%, respectively. Molecular response rate improved slowly and steadily over time, reaching 65.8% at 60 months, remaining stable for up to 96 months. The five-year progression-free survival and overall survival were 84 and 89%, respectively. Cytogenetic response by 12 months significantly correlated with overall survival (P = 0.0007) and progression-free survival (P = 0.0280). Sokal risk score did not differ significantly between subgroups. The medication was well tolerated, with only 16% of patients showing hematologic toxicity grades 3 and 4. At the end of the assessment, 57% of the patients were still on imatinib mesylate; most of those who discontinued treatment (17/30) did so because of unsatisfactory response. Treatment with imatinib mesylate in previously treated chronic-phase chronic myeloid leukemia induced durable responses in a high proportion of patients and was related to satisfactory long-term and event-free survival.     

Ursodeoxycholyl lysophosphatidylethanolamide inhibits cholestasis- and hypoxia-induced apoptosis by upregulating antiapoptosis proteins

An increase of toxic bile acids such as glycochenodeoxycholic acid occurs during warm ischemia reperfusion causing cholestasis and damage in hepatocytes and intrahepatic biliary epithelial cells. We aim to test antiapoptosis effects of ursodeoxycholyl lysophosphatidylethanolamide under cholestatic induction by glycochenodeoxycholic acid treatment of mouse hepatocytes and hypoxia induction by cobalt chloride treatment of intrahepatic biliary epithelial cancer Mz-ChA-1cell line. Such treatments caused marked increases in apoptosis as evidenced by activation of caspase 3, caspase 8 and poly (ADP-ribose) polymerase-1. Co-treatment with ursodeoxycholyl lysophosphatidylethanolamide significantly inhibited these increases. Interestingly, ursodeoxycholyl lysophosphatidylethanolamide was able to increase expression of antiapoptotic cellular FLICE-inhibitory protein in both cell types. Ursodeoxycholyl lysophosphatidylethanolamide also prevented the decreases of myeloid cell leukemia sequence-1 protein in both experimental systems, and this protection was due to ursodeoxycholyl lysophosphatidylethanolamide’s ability to inhibit ubiquitination-mediated degradation of myeloid cell leukemia sequence-1, and to increase the phosphorylation of GSK-3β. In addition, ursodeoxycholyl lysophosphatidylethanolamide was able to prevent the decreased expression of another antiapoptotic cellular inhibitor of apoptosis 2 in cobalt chloride-treated Mz-ChA-1 cells. Hence, ursodeoxycholyl lysophosphatidylethanolamide mediated cytoprotection against apoptosis during toxic bile-acid and ischemic stresses by a mechanism involving accumulation of cellular FLICE-inhibitory protein, myeloid cell leukemia sequence-1 and cellular inhibitor of apoptosis 2 proteins. Ursodeoxycholyl lysophosphatidylethanolamide may thus be used as an agent to prevent hepatic ischemia reperfusion.     

Dual PPARα/γ Ligand TZD18 Either Alone or in Combination with Imatinib Inhibits Proliferation and Induces Apoptosis of Human CML Cell Lines

Despite progress in the treatment of early-stage chronic myeloid leukemia (CML), the accelerated and blastic phases of CML still remain a therapeutic challenge. Persistence of BCR-ABL-positive (bcr-abl+) cells or secondary resistance during imatinib therapy frequently occurs. In this study, we investigated the activity of a novel dual ligand specific for peroxisome proliferator-activated receptor α and γ (PPARα/γ) against CML blast crisis cell lines. Exposure of these cell lines (K562, KU812 and KCL22) to TZD18 resulted in a growth inhibition in a dose- and time-dependent manner. This effect may not be mediated through PPARγ and/or PPARα activation, since antagonists of PPARg and/or PPARa could not reverse this inhibition. Western blotting analysis showed that expression of the cyclin dependent kinase inhibitor (CDKI) p27kip1 was enhanced, whereas levels of cyclin E, cyclin D2 and cyclin dependent kinase 2 (CDK-2) were decreased when these cells were treated with TZD18. Most interestingly, TZD18 synergistically enhanced the antiproliferative and pro-apoptotic effects of imatinib. Overall, our findings strongly suggest that TZD18, either alone or in combination with imatinib may be beneficial for the treatment of CML in myeloid blast crisis.     

Comparison between molecularly defined and conventional therapeutics in a conditional BCR-ABL cell culture model

Accumulating knowledge about the molecular mechanisms causing human diseases can support the development of targeted therapies such as imatinib, a BCR-ABL-specific tyrosine kinase inhibitor to treat chronic myeloid leukemia (CML). Here, we use lentivirus-mediated RNA interference (RNAi) targeting BCR-ABL and the downstream signaling molecules SHP2, STAT5, and Gab2 to compare the efficacy and specificity of molecularly defined therapeutics with that of conventional cytotoxic drugs (cytarabine, doxorubicin, etoposide) in a conditional BCR-ABL cell culture model. IC(50) values were determined for each drug in TonB cells cultured either with interleukin-3 (IL-3) or BCR-ABL, and molecularly defined therapies were studied using lentivirally expressed shRNAs. We demonstrate that conventional anti-leukemic drugs have small or no differential effects under different cell culture conditions, whereas both imatinib and specific RNAi significantly inhibit proliferation of TonB cells in the presence of BCR-ABL but not IL-3. To study molecularly defined combination therapy, we evaluated either imatinib in TonB cells with target-specific RNAi or we used lentiviral vectors to induce combinatorial RNAi through simultaneous expression of two shRNAs. These combination therapies result in increased efficacy without loss in specificity. Interestingly, combinatorial RNAi can specifically deplete TonB cell cultures in the presence of BCR-ABL, even without targeting the oncogene itself. This model provides a tool to evaluate potential therapeutic targets and to quantify efficacy and specificity preclinically of new combination therapies in BCR-ABL-positive cells.     

Exosomes derived from imatinib-resistant chronic myeloid leukemia cells mediate a horizontal transfer of drug-resistant trait by delivering miR-365

Chronic myeloid leukemia (CML) is a malignant disorder of hematopoietic stem/progenitor cells. Majority of patients can be effectively treated with tyrosine kinase inhibitors (TKIs) such as imatinib, but a portion of patients will develop drug resistance. Accumulated evidences have identified exosomes in cancer as promoters of tumor progression. Herein, we found that exosomes derived from imatinib resistant CML cells can be internalized into sensitive CML cells and confer drug-resistance traits. We also demonstrated a significant higher level of miR-365 in exosomes derived from drug-resistant CML cells compared with those from sensitive ones using microarray and qRT-PCR. The imatinib sensitive CML cells transfected with pre-miR-365 displayed lower chemosensitivity and apoptosis rate compared with controls. We further confirmed that exosomal transfer of miR-365 induced drug resistance by inhibiting expression of pro-apoptosis protein in sensitive CML cells. In conclusion, our study reveals that exosomes mediate a horizontal transfer of drug-resistant trait in chronic myeloid leukemia cell by delivering miR-365.     

The first total synthesis of the marine fatty acid (+/-)-2-methoxy-13-methyltetradecanoic acid: a cytotoxic fatty acid to leukemia cells

The recently discovered marine fatty acid (+/-)-2-methoxy-13-methyltetradecanoic acid was synthesized for the first time in six steps (26% overall yield) starting from commercially available methyl 12-methyltridecanoate. The synthetic approach provided enough material to corroborate the structure of the acid, which was recently identified in the sponge Amphimedon complanata from Aguadilla, Puerto Rico, and to test its cytotoxicity to three leukemia cell lines. The key step in the synthesis was the addition of trimethylsilyl cyanide to 12-methyltridecanal under triethylamine catalysis. Nuclear magnetic resonance data are provided for the first time for this methoxylated fatty acid and the synthetic approach utilized is of general applicability since it can be used in the synthesis of other methyl-branched 2-methoxylated fatty acids. We also report that the acid (+/-)-2-methoxy-13-methyltetradecanoic acid is cytotoxic to human chronic myelogenous leukemia K-562 (EC50=238 microM), histiocytic lymphoma U-937 (EC50=250 microM), and promielocytic leukemia HL-60 (EC50=476 microM) in RPMI 1640 medium.     

Protein-acrylamide copolymer hydrogels for array-based detection of tyrosine kinase activity from cell lysates

We describe the development of an array-based assay for the molecular level detection of tyrosine kinase activity directly from cellular extracts. Glutathione S-transferase-Crkl (GST-Crkl) fusion proteins are covalently immobilized into polyacrylamide gel pads via copolymerization of acrylic monomer and acrylic-functionalized GST-Crkl protein constructs on a polyacrylamide surface. The resulting hydrogels resist nonspecific protein adsorption, permitting quantitative and reproducible determination of Abl tyrosine kinase activity and inhibition, even in the presence of a complex cell lysate mixture. Half-maximal inhibition (IC50) values for imatinib mesylate inhibition of GST-Crkl (SH3) phosphorylation by v-Abl in a purified system and Bcr-Abl within a K562 cell lysate were determined to be 1.5 and 20 microM, respectively. Additionally, the protein-acrylamide copolymer arrays detected CML cell levels as low as 15% in a background of Bcr-Abl- leukemic cells and provided the framework for the parallel evaluation of six tyrosine kinase inhibitors. Such a system may have direct application to the detection and treatment of cancers resulting from upregulated tyrosine kinase activity, such as chronic myeloid leukemia (CML). These findings also establish a basis for screening tyrosine kinase inhibitors and provide a framework on which protein-protein interactions in other complex systems can be studied.     

Dasatinib preferentially induces apoptosis by inhibiting Lyn kinase in nilotinib-resistant chronic myeloid leukemia cell line

Nilotinib is approved for treatment of newly diagnosed chronic myeloid leukemia (CML) and it is shown superiority over imatinib in first-line treatment for patients of CML. In this study, we established a nilotinib-resistant cell line, K562NR, and evaluated the resistance to nilotinib and efficacy of dasatinib. We found activation of Lyn plays a dominant role in survival of the nilotinib-resistant cell line. We found dasatinib induces the apoptosis of nilotinib-resistant cells and inhibits Lyn kinase activity. This novel nilotinib-resistant CML cell line may help to explore novel therapy for CML.     

Hemin reduces cellular sensitivity to imatinib and anthracyclins via Nrf2

Heme plays an important biomodulating role in various cell functions. In this study, we examined the effects of hemin on cellular sensitivity to imatinib and other anti-leukemia reagents. Hemin treatment of human BCR/ABL-positive KCL22 leukemia cells increased IC(50) values of imatinib, that is, the drug resistance, in a dose-dependent manner without any change in the BCR/ABL kinase activity. Imatinib-induced apoptosis was also suppressed by hemin treatment in KCL22 cells. Hemin treatment increased the activity of gamma-glutamylcysteine synthetase (gamma-GCS) light subunit gene promoter, which contains a Maf recognition element (MARE). Protein levels of gamma-GCS and heme oxygenase-1 (HO-1), two MARE-containing genes, were also increased after hemin treatment. Knockdown of Nrf2 expression by RNA interference largely abolished the effect of hemin on imatinib-treated cells, suggesting that Nrf2 recognition of MARE is essential for the hemin-mediated protective effect. Similar to hemin, treatment of cells with delta-aminolevulinic acid (delta-ALA), the obligatory heme precursor, also increased IC(50) values of imatinib. In contrast, inhibition of cellular heme synthesis by succinylacetone increased the sensitivity of cells to imatinib in two imatinib-resistant cell lines, KCL22/SR and KU812/SR. Hemin treatment also decreased the sensitivity of cells to four anthracyclins, daunorubicin, idarubicin, doxorubicin, and mitoxantrone, in BCR/ABL-negative leukemia U937 and THP-1 cells, as well as in KCL22 cells. These findings thus indicate that cellular heme level plays an important role in determining the sensitivity of cells to imatinib and certain other anti-leukemia drugs and that the effect of heme may be mediated via its ability to upregulate Nrf2 activity.     

RPS27a promotes proliferation,regulates cell cycle progression and inhibits apoptosis of leukemia cells

Ribosomal protein S27a (RPS27a) could perform extra-ribosomal functions besides imparting a role in ribosome biogenesis and post-translational modifications of proteins. The high expression level of RPS27a was reported in solid tumors, and we found that the expression level of RPS27a was up-regulated in advanced-phase chronic myeloid leukemia (CML) and acute leukemia (AL) patients. In this study, we explored the function of RPS27a in leukemia cells by using CML cell line K562 cells and its imatinib resistant cell line K562/G01 cells. It was observed that the expression level of RPS27a was high in K562 cells and even higher in K562/G01 cells. Further analysis revealed that RPS27a knockdown by shRNA in both K562 and K562G01 cells inhibited the cell viability, induced cell cycle arrest at S and G2/M phases and increased cell apoptosis induced by imatinib. Combination of shRNA with imatinib treatment could lead to more cleaved PARP and cleaved caspase-3 expression in RPS27a knockdown cells. Further, it was found that phospho-ERK(p-ERK) and BCL-2 were down-regulated and P21 up-regulated in RPS27a knockdown cells. In conclusion, RPS27a promotes proliferation, regulates cell cycle progression and inhibits apoptosis of leukemia cells. It appears that drugs targeting RPS27a combining with tyrosine kinase inhibitor (TKI) might represent a novel therapy strategy in TKI resistant CML patients.