Targeting histone deacetylase 1 (HDAC1) in the bone marrow stromal cells revers imatinib resistance by modulating IL-6 in Ph + acute lymphoblastic leukemia.

Bone marrow stromal cells (BMSCs) can promote the growth of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Histone deacetylases (HDACs) play essential roles in the proliferation and apoptosis resistance of Ph + ALL cells. In our previous study, inhibiting histone deacetylase 1 (HDAC1) decreases the proliferation of Ph + ALL cells. However, little is known regarding how HDAC1 in BMSCs of Ph + ALL patients affects the imatinib (IM) resistance. Therefore, the present work examined the roles of HDAC1 in BMSCs. Overexpression of HDAC1 was found in BMSCs of Ph + ALL patients with IM resistance. In addition, the Ph + ALL cell line SUP-B15 was co-cultured with BMSCs after lentivirus transfection for regulating HDAC1 expression. Knockdown of HDAC1 within BMSCs elevated the IM-mediated SUP-B15 cell apoptosis, while increasing HDAC1 expression had an opposite effect. IL-6 in BMSCs, which is an important factor for the microenvironment-associated chemoresistance, showed evident up-regulation in HDAC1-upregulated BMSCs and down-regulation in HDAC1-downregulated BMSCs. While recombinant IL-6 (rIL-6) can reversed the sensitivity of SUP-B15 cells to IM induced by downregulating HDAC1 expression in BMSCs. HDAC1 showed positive regulation on IL-6 transcription and secretion. Moreover, IL-6 secretion induced by HDAC1 in BMSCs might enhance IM resistance in Ph + ALL cells. With regard to the underlying molecular mechanism, NF-κB, an important signal responsible for IL-6 transcription in BMSCs, mediated the HDAC1-regulated IL-6 expression. Collectively, this study facilitated to develop HDAC1 inhibitors based not only the corresponding direct anti-Ph + ALL activity but also the regulation of bone marrow microenvironment.

Isolation and Characterization of a Biosurfactant Producing Strain Planococcus sp. XW-1 from the Cold Marine Environment.

One cold-adapted strain, named Planococcus sp. XW-1, was isolated from the Yellow Sea. The strain can produce biosurfactant with petroleum as sole source of carbon at low temperature (4 °C). The biosurfactant was identified as glycolipid-type biosurfactant species by thin-layer chromatography (TLC) and Fourier transform infrared spectroscopy (FTIR). It reduced the surface tension of water to 26.8 mN/m with a critical micelle concentration measurement of 60 mg/L. The produced biosurfactant possesses high surface activity at wide ranges of temperature (-18-105 °C), pH values (2-12), and salt concentrations (1-18%). The biosurfactant exhibited higher surface activity and higher growth rate of cells with hexadecane and diesel as carbon source. The strain Planococcus sp. XW-1 was also effective in degrading crude oil, after 21 days of growth at 4 °C in medium with 1% crude oil and 1% (v/v) bacteria broth, 54% of crude oil was degraded. The results suggest that Planococcus sp. XW-1 is a promising candidate for use in the bioremediation of petroleum-contaminated seawater in the Yellow Sea during winter. This study reported for the first time that Planococcus isolated from the Yellow Sea can produce biosurfactant using petroleum as the sole carbon source at low temperature (4 °C), showing its ecological role in the remediation of marine petroleum pollution.

Sirt1 gene confers Adriamycin resistance in DLBCL via activating the PCG-1α mitochondrial metabolic pathway.

Sirt1 is closely related to cells aging, and Sirt1 also plays an important role in diffuse large B-cell lymphoma (DLBCL). However, its mechanism remains unclear. Therefore, we investigated the mechanism of Sirt1 mediated drug-resistance in DLBCL, while the recombinant lentivirus was used to regulate Sirt1 gene expression in DLBCL cell lines. Subsequently, the effect of Sirt1 on DLBCL resistance to Adriamycin was analyzed in vitro. The results show that Sirt1 overexpression confers Adriamycin resistance in DLBCL cell lines. However, inhibition of Sirt1 sensitized DLBCL cell lines to Adriamycin cytotoxicity. Additionally, tumor-bearing mice were used to verify that Sirt1 overexpression confers Adriamycin resistance in vivo after chemotherapy. In addition, we used second-generation sequencing technology and bioinformatics analysis to find that Sirt1 mediated drug-resistance is related to the Peroxisome proliferator-activated receptor (PPAR) signaling pathway, especially to PGC-1α. Interestingly, the mitochondrial energy inhibitor, tigecycline, combined with Adriamycin reversed the cellular resistance caused by Sirt1 overexpression in vivo. Moreover, western blotting and CO-IP assay reconfirmed that Sirt1-mediated drug-resistance is associated with the increased expression of PGC1-α, which induce mitochondrial biogenesis. In summary, this study confirms that Sirt1 is a potential target for DLBCL treatment.

Shp2 activation in bone marrow microenvironment mediates the drug resistance of B-cell acute lymphoblastic leukemia through enhancing the role of VCAM-1/VLA-4.

B-cell acute lymphoblastic leukemia (B-ALL) is immune to the chemotherapy-induced apoptosis as a result of the protection of bone marrow mesenchymal stromal cells (BMSCs). However, the precise underlying mechanism of such protection remains unclear so far. In this experiment, protein tyrosine phosphatase 2 (Shp2), which was encoded by the PTPN11 gene, was highly expressed in BMSCs of the newly diagnosed and the recurrent B-ALL patients. The plasmid-induced (including Shp2 E76K) Shp2 activation in BMSCs (Shp2-activated BMSCs) markedly increased the BMSCs-mediated resistance of leukemia cells both in vitro and in vivo. Additionally, studies in vitro suggested that, the expression of vascular cell adhesion molecule 1 (VCAM-1) was markedly up-regulated in Shp2-activated BMSCs, and VCAM-1 expression in BMSCs of B-ALL patients was negatively correlated with Shp2 expression. Down-regulation of VCAM-1 in BMSCs using siRNA reversed the resistance of CCRF-SB cells mediated by the Shp2-activated BMSCs. As for the molecular mechanism, the PI3K/AKT pathway mediated the regulation of VCAM-1 by Shp2. Blocking the very late antigen-4 (VLA-4) by antibodies in CCRF-SB cells dramatically reversed the resistance of CCRF-SB cells mediated by the Shp2-activated BMSCs, and decreased the adhesion effects of both CCRF-SB cells and BMSCs. In conclusion, Shp2 activation in BMSCs up-regulates VCAM-1 expression through increasing the PI3K/AKT phosphorylation level, and targeting the VCAM-1/VLA-4 signaling may serve as a clinically relevant mechanism to overcome the BMSCs-mediated chemoresistance of B-ALL cells.

Betulinic acid restores imatinib sensitivity in BCR-ABL1 kinase-independent, imatinib-resistant chronic myeloid leukemia by increasing HDAC3 ubiquitination and degradation.

Although imatinib (IM) has been demonstrated to be an efficient treatment in chronic myeloid leukemia (CML), some patients still experience IM resistance and disease relapse. Through in vitro studies, we observed that HDAC3 levels were elevated in BCR-ABL1 kinase-independent, IM-resistant primary cells from CML patients and in IM-resistant K562 (K562R) cells and that downregulation of HDAC3 could enhance IM efficacy in K562R cells. Furthermore, betulinic acid (BA), a lupane-type pentacyclic triterpenoid saponin isolated from birch trees, restored IM sensitivity in the BCR-ABL1 kinase-independent, IM-resistant primary cells and in K562R cells, as well as in primary CD34+ bone marrow cells from CML patients. We found that BA restored IM sensitivity through inhibition of HDAC3 accumulation in cells, and that this was mediated by BA-dependent ubiquitination and degradation of HDAC3. BA at low dosage significantly increased IM antitumor effects on murine xenografts bearing K562R cells and inhibited HDAC3 expression in tumor tissue. Our findings demonstrated that HDAC3 is an essential factor in BCR-ABL1 kinase-independent IM resistance, and that BA in combination with IM may be a novel treatment strategy for overcoming IM resistance in CML.

CAY10683 and imatinib have synergistic effects in overcoming imatinib resistance via HDAC2 inhibition in chronic myeloid leukemia.

Imatinib (IM) is utilized for targeting the BCR-ABL fusion protein and as such, chronic myeloid leukemia (CML) is considered to be a curable disorder for which patients can achieve a long survival. However, 15-20% CML cases end up with IM resistance that will develop into the accelerated stage and eventually the blast crisis, thereby restricting the treatment choices and giving rise to a dismal survival rate. Histone deacetylases (HDACs) have been identified to modulate the oncogene as well as tumor suppressor gene activities, and they play crucial parts in tumorigenesis. It is found recently that IM combined with HDAC inhibitors (HDACi) can serve as a promising means of overcoming IM resistance in CML cases. Santacruzamate A (CAY10683) has been developed as one of the selective and powerful HDACi to resist HDAC2. Therefore, in this study, we aimed to examine whether CAY10683 combined with IM could serve as the candidate antitumor treatment for CML cases with IM resistance. The influences of CAY10683 combined with IM on the cell cycle arrest, apoptosis, and viability of CML cells with IM resistance were investigated, and it was discovered that the combined treatment exerted synergistic effects on managing the IM resistance. Moreover, further studies indicated that CAY10683 combined with IM mainly exerted synergistic effects through inhibiting HDAC2 in K562-R and LAMA84-R cells with IM resistance. Besides, the PI3K/Akt signal transduction pathway was found to mediate the HDAC2 regulation of CML cells with IM resistance. Eventually, it was also discovered, based on the xenograft mouse model, that the combined treatment dramatically suppressed CML proliferation in vivo. To sum up, findings in the current study indicate that CAY10683 combined with IM can be potentially used as the candidate treatment for CML with IM resistance.

CUDC-101 overcomes arsenic trioxide resistance via caspase-dependent promyelocytic leukemia-retinoic acid receptor alpha degradation in acute promyelocytic leukemia.

Although arsenic trioxide (ATO) treatment has transformed acute promyelocytic leukemia (APL) from the most fatal to the most curable hematological cancer, many high-risk APL patients who fail to achieve a complete molecular remission or relapse become resistant to ATO. Herein, we report that 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide (CUDC-101) exhibits specific anticancer effects on APL and ATO-resistant APL in vitro and in vivo, while showing negligible cytotoxic effect on the noncancerous cells including normal CD34 cells and bone marrow mesenchymal stem cells from APL patients. Further mechanistic studies show that CUDC-101 triggers caspase-dependent degradation of the promyelocytic leukemia-retinoic acid receptor alpha fusion protein. As a result, APL and ATO-resistant APL cells undergo apoptosis upon CUDC-101 treatment and this apoptosis-inducing effect is even stronger than that of ATO. Finally, using a xenograft mouse model, we demonstrated that CUDC-101 significantly represses leukemia development in vivo. In conclusion, these results suggested that CUDC-101 can serve as a potential candidate drug for APL, particularly for ATO-resistant APL.

Fenretinide-induced Apoptosis of Acute Myeloid Leukemia Cells via NR4A1 Translocation into Mitochondria and Bcl-2 Transformation.

OBJECTIVE: Fenretinide is reported to induce NR4A1-associated apoptosis in several types of cancer cells. However, it remains unclear about its specific role and the underlying mechanism in acute myeloid leukemia (AML). Therefore, this study aimed to explore the role and mechanism of fenretinide-induced apoptosis in AML. METHOD: Firstly, the NR4A1 mRNA level in the newly diagnosed AML patients was measured, then AML cells were treated with fenretinide at various time points and doses, and cell viability was investigated by using the cell-counting kit-8 (CCK-8) assay. Additionally, apoptosis and cell cycles were analyzed by using flow cytometry. Moreover, siNR4A1 was utilized to knockdown NR4A1 expression, and leptomycin B (LMB) was adopted to inhibit the nuclear export; afterwards, the apoptosis rate and expression of apoptotic proteins in AML cells were detected. In addition, the expression levels of NR4A1 in the nuclei and mitochondria of fenretinide-treated AML cells were also measured. Meanwhile, the interaction between NR4A1 and Bcl-2, as well as the Bcl-2 transformation, was also examined. The anti-leukemic effect of fenretinide on NOD/SCID mice was also determined through subcutaneous injection of HL-60 cells. RESULTS: NR4A1 expression in AML patients was markedly down-regulated compared with that in normal donors. Fenretinide induced the expression of NR4A1 and mitochondria-mediated apoptotic pathway-associated proteins in a time- and concentration-dependent manner. Importantly, both siNR4A1 alone or the combination of fenretinide with LMB could attenuate the fenretinide-induced apoptosis and expression of apoptotic proteins. Under the action of fenretinide, the NR4A1 protein expression was down-regulated in nuclear extracts whereas up-regulated in mitochondrial extracts. At the same time, fenretinide promoted NR4A1 translocation from nuclei into mitochondria, and enhanced the interaction between NR4A1 and Bcl-2, thereby exposing the BH3 domain of Bcl-2 to exert the anti-apoptotic effect. Moreover, fenretinide also exhibited an anti-leukemic effect and induced NR4A1 expression in the AML mouse model. CONCLUSIONS: Fenretinide exerts an obvious effect on AML cells both in vitro and in vivo. Besides, the NR4A1-mediated signaling pathway is highly involved in the fenretinide-induced apoptosis of AML cells.

Deletion of HO-1 blocks development of B lymphocytes in mice.

B lymphocytes, a key cluster of cells composing the immune system, can protect against abnormal biological factors. Heme oxygenase-1 (HO-1) plays important roles in cell proliferation and immune regulation, but its effects on the development and growth of B lymphocytes are still unknown. Herein, the count of B lymphocytes in HO-1 gene knockout (HO-1+/-) mice was significantly lower than that of the HO-1 gene wild-type (HO-1WT) mice. Meanwhile, the cell count of HO-1+/- mice did not recover after irradiation for one week, due to the G0/G1 phase arrest of Pro-B cells and the augmented apoptosis of Pre-B cells. Up-regulation of HO-1 by lentivirus attenuated the Pro-B cell cycle arrest and Pre-B cell apoptosis. To understand the molecular mechanism by which HO-1 knockout blocked B lymphocyte development, protein-to-protein interaction network and Western blot were used. The PI3K/AKT signaling pathway mediated the regulatory effects of HO-1 on B lymphocytes. In conclusion, HO-1 is a crucial transcriptional repressor for B cell development.

Overexpression of heme oxygenase-1 in microenvironment mediates vincristine resistance of B-cell acute lymphoblastic leukemia by promoting vascular endothelial growth factor secretion.

Chemoresistance often causes treatment failure of B-cell acute lymphoblastic leukemia (B-ALL). However, the mechanism remains unclear at present. Herein, overexpression of heme oxygenase-1 (HO-1) was found in the bone marrow stromal cells (BMSCs) from B-ALL patients developing resistance to vincristine (VCR), a chemotherapeutic agent. Two B-ALL cell lines Super B15 and CCRF-SB were cocultured with BMSCs transfected with lentivirus to regulate the expression of HO-1. Silencing HO-1 expression in BMSCs increased the apoptotic rates of B-ALL cell lines induced by VCR, whereas upregulating HO-1 expression reduced the rate. Cell cycle can be arrested in the G2/M phase by VCR. In contrast, B-ALL cells were arrested in the G0/G1 phase due to HO-1 overexpression in BMSCs, which avoided damage from the G2/M phase. Vascular endothelial growth factor (VEGF) in BMSCs, as a key factor in the microenvironment-associated chemoresistance, was also positively coexpressed with HO-1. VEGF secretion was markedly increased in BMSCs with HO-1 upregulation but decreased in BMSCs with HO-1 silencing. B-ALL cell lines became resistant to VCR when cultured with VEGF recombinant protein, so VEGF secretion induced by HO-1 expression may promote the VCR resistance of B-ALL cells. As to the molecular mechanism, the PI3K/AKT pathway mediated regulation of VEGF by HO-1. In conclusion, this study clarifies a mechanism by which B-ALL is induced to resist VCR through HO-1 overexpression in BMSCs, and provides a novel strategy for overcoming VCR resistance in clinical practice.

The efficacy of topical gentamycin application on prophylaxis and treatment of wound infection: A systematic review and meta-analysis.

OBJECTIVES: The purpose of this study was to conduct a systematic review and meta-analysis in patients with local wound infection or infective risk, evaluating effects of topical gentamycin application on prophylaxis and treatment of wound infection. METHODS: Embase, the Cochrane Library, Pubmed, Medline (from Ovid) and three Chinese literature databases (CNKI, VIP and WANFANG) were searched. Randomised controlled studies (RCTs) and observational studies (OSs) that assessed the efficacy of topical gentamycin application on prophylaxis and treatment of local wound infection were included. The primary outcome was clinical efficacy. Secondary outcomes included duration of recovery time and length of hospital stay. RESULTS: Fifteen studies (1781 patients) met inclusion criteria. Twelve studies were RCTs and other three studies were OSs. Compared with non-gentamycin group, topical gentamycin application had significantly higher rates of clinical efficacy (OR = 3.57, 95% CI 2.52-5.07). In terms of duration of wound healing, it's taken shorter time in gentamycin group than non-gentamycin group (OR = -4.94, 95% CI -8.37 to -1.51). However, the length of hospital stay had no significantly difference between the two groups (OR = -3.40, 95% CI -8.42 to 1.63). Subgroup analyses were conducted according to study design (RCTs or OSs), purpose and administration type. And the results showed that there were no significant difference of clinical efficacy in study design (P = 0.21, I2  = 35.4%), purpose (P = 0.32, I2  = 0%) and administration type subgroup (P = 0.74, I2  = 0%). However, topical gentamycin application had significantly shorter duration of wound healing in randomly controlled trials compared with observational studies, but had no difference in terms of administration type(P = 0.20, I2  = 38.6%). CONCLUSIONS: Studies to date show that topical gentamycin application significantly increases the rate of clinical efficacy and decreases the duration of wound healing in patients with local wound infection or infective risk.

Heme oxygenase-1 reduces the sensitivity to imatinib through nonselective activation of histone deacetylases in chronic myeloid leukemia.

Resistance towards imatinib (IM) remains troublesome in treating many chronic myeloid leukemia (CML) patients. Heme oxygenase-1 (HO-1) is a key enzyme of antioxidative metabolism in association with cell resistance to apoptosis. Our previous studies have shown that overexpression of HO-1 resulted in resistance development to IM in CML cells, while the mechanism remains unclear. In the current study, the IM-resistant CML cells K562R indicated upregulation of some of the histone deacetylases (HDACs) compared with K562 cells. Therefore, we herein postulated HO-1 was associated with HDACs. Silencing HO-1 expression in K562R cells inhibited the expression of some HDACs, and the sensitivity to IM was increased. K562 cells transfected with HO-1 resisted IM and underwent obvious some HDACs. These findings related to the inhibitory effects of high HO-1 expression on the reactive oxygen species (ROS) signaling pathway that negatively regulated HDACs. Increased expression of HO-1 activated HDACs by inhibiting ROS production. In summary, HO-1, which is involved in the development of drug resistance in CML cells by regulating the expression of HDACs, is probably a novel target for improving CML therapy.

Synergistic activity of imatinib and AR-42 against chronic myeloid leukemia cells mainly through HDAC1 inhibition.

AIMS: The aim of this study was to investigate the combinatorial effects of IM and a novel HDAC inhibitor AR-42 on the proliferation, apoptosis, cell cycle arrest, migration and invasion of CML cells, and to explore the underlying mechanisms. MAIN METHODS: We assessed the ability of the pan-HDAC inhibitor AR-42 and IM, to synergistically kill CML cells by survival, apoptosis, cell cycle, migration and invasion assays in vitro. We also assessed the HDAC1 expression by Western blot and real-time PCR. Synergy was calculated using combinatorial indices as determined by CalcuSyn. KEY FINDINGS: We found that Combining AR-42 with IM synergistically inhibited CML cell proliferation, enhanced cell apoptosis, induced cell cycle arrest, and decreased migration and invasion. The expression of HDAC1 in K562R cells was higher than that in K562 cells. AR-42 enhanced IM-induced HDAC1 expression inhibition in K562 and K562R cells. Importantly, HDAC1 overexpression partly reversed the apoptosis, G2/M phase arrest, migration and invasion of K562 cells induced by the combination of IM with AR-42. Moreover, HDAC1 knockdown partly promoted K562R cell apoptosis and G2/M phase arrest, migration and invasion induced by IM in combination with AR-42. SIGNIFICANCE: In conclusion, AR-42 may increase the sensitivity of CML cells to IM and reverse IM resistance by regulating HDAC1 expression. This study provides new insights into the effects of combined therapy using IM and pan-HDAC inhibitor AR-42, paving the way for overcoming IM resistance in clinical practice.

Effect of BCLAF1 on HDAC inhibitor LMK-235-mediated apoptosis of diffuse large B cell lymphoma cells and its mechanism.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of adult lymphoma. It is a group of malignant tumors with a large number of clinical manifestations and prognoses. Therefore, it is necessary to explore its unknown potential therapeutic targets. Histone deacetylase inhibitor (HDACi) is a novel drug for the treatment of DLBCL, however pan-HDACis cannot be ignored because of their clinical efficacy. By contrast, specific HDACi is well-tolerated, and LMK-235 is a novel HDACi that is a specific inhibitor of HDAC4 and HDAC5. In this study, we investigated the up-regulation of BCLAF1 through NF-κB signaling pathways in LMK-235, mediating the apoptosis of two diffuse large B-cell lymphoma cell lines, OCI-LY10 and OCI-LY3. Further studies showed that BCLAF1 expression was increased in DLBCL cells after treatment with the NF-κB inhibitor Bay11-7082. The combination of Bay11-7082 and siRNA si-HDAC4 significantly increased BCLAF1 expression and further increased apoptosis. These results indicate that BCLAF1 plays an important role in LMK-235-mediated apoptosis and may be a potential target for the treatment of diffuse large B-cell lymphoma.

Low expression of GFI-1 Gene is associated with Panobinostat-resistance in acute myeloid leukemia through influencing the level of HO-1.

To improve the treatment outcomes of acute myeloid leukemia (AML), epigenetic modification has been widely tested and used in recent years. However, drug-resistance is still a choke point to cure the malignancy. The growth factor independent 1 transcriptional repressor (GFI-1), as a zinc-finger transcriptional repressor, can bind histone deacetylases to allow the transcriptional repression. According to the finding of our study, AML patients with low level of GFI-1 not only implicated poor prognosis but also caused Panobinostat-resistance. In our prevent study revealed that heme oxygenase-1(HO-1) was one of the main factors leading to chemotherapy sensitivity to AML. Thus, this study tried to test the correlation between GFI-1 and HO-1. Our study discovered that AML patients with lower expression of GFI-1 had higher level of HO-1, HDAC1, HDAC2 and HDAC3, which resulted in poor prognosis in AML. The results of the in vitro study were the same. Panobinostat is a promising new class of anti-cancer drugs in AML. However, knocking down GFI-1 by siRNA could eliminate the Panobinostat-induced cell apoptosis. Subsequently, we utilized ZnPP to down regulate the level of HO-1, finding that the Panobinostat-resistance between the low level of GFI-1 and empty vector had eased. After further exploring the mechanism, it could be found that with knock down GFI-1, the phosphorylation of Akt and PI3K could be activated. Subsequently, Akt pathway and HO-1 inhibitor were utilized respectively and the resistance was reversed. It suggested that the resistance of Panobinostat to AML cells at low level of GFI-1 was mainly due to up-regulated level of HO-1 through the PI3K-Akt pathway.

Low-dose staurosporine selectively reverses BCR-ABL-independent IM resistance through PKC-α-mediated G2/M phase arrest in chronic myeloid leukaemia.

Imatinib (IM) resistance has become a critical problem for the treatment of patients with relapsed chronic myeloid leukaemia (CML), so novel therapies are in need. Various isotypes of protein kinases C (PKCs) are up-regulated in CML and related with BCR-ABL regulating several signalling pathways that are crucial to malignant cellular transformation. However, it is still unknown whether PKC isotypes play crucial roles in IM resistance. Therefore, we herein used a PKC pan-inhibitor staurosporine (St). To protect normal cells from damage, a proper dose of St was used, at which IM-resistant CML cells were selectively killed in combination with IM but normal cells survived. The IM resistance of CML cells was best reversed by 4 nM St alone, mainly depending on the G2/M phase arrest. Cell cycle-related proteins p21, CDK2, cyclin A and cyclin B were down-regulated. Meanwhile, PKC-α was more significantly decreased than other PKC isotypes at this concentration. The PKC-α-dependent G2/M phase arrest was induced by down-regulation of CDC23, an important regulator of mitotic progression. Low-dose St also reversed IM resistance in vivo. In conclusion, low-dose St selectively increased the sensitivity of IM-resistant CML to IM by arresting cell cycle in the G2/M phase through PKC-α-dependent CDC23 inhibition.