Biological function and small molecule inhibitors of histone deacetylase 11.

HDAC11, as a rising star in the histone deacetylase (HDAC) family, has attracted widespread interest in the biomedical field in recent years specially owing to its high defatty-acylase activity compared its innate deacetylase activity. Numerous studies have provided evidence indicating the crucial involvement of HDAC11 in cancers, immune responses, and metabolic processes. Several potent and selective HDAC11 inhibitors have been discovered and identified, which is crucial for exploring the function of HDAC11 and its potential therapeutic applications. Herein, we present a critical overview of the current advances in the biological function of HDAC11 and its inhibitors. We initially discuss the physiological functions of HDAC11 and its pathological roles in relevant diseases. Subsequently, our main focus centers on the design strategy and development process of HDAC11 inhibitors. Additionally, we address significant challenges and outline future directions in this field. This perspective may provide guidance for the further development of HDAC11 inhibitors and their prospects in disease treatment.

Marine Cytotoxin Santacruzamate A Derivatives as Potent HDAC1-3 Inhibitors and Their Synergistic Anti-Leukemia Effects with Venetoclax.

Acute myeloid leukemia (AML) is a hematologic malignancy characterized by infiltration of the blood and bone marrow, exhibiting a low remission rate and high recurrence rate. Current research has demonstrated that class I HDAC inhibitors can downregulate anti-apoptotic proteins, leading to apoptosis of AML cells. In the present investigation, we conducted structural modifications of marine cytotoxin Santacruzamate A (SCA), a compound known for its inhibitory activity towards HDACs, resulting in the development of a novel series of potent class I HDACs hydrazide inhibitors. Representative hydrazide-based compound 25c exhibited concentration-dependent induction of apoptosis in AML cells as a single agent. Moreover, 25c exhibited a synergistic anti-AML effect when combined with Venetoclax, a clinical Bcl-2 inhibitor employed in AML therapy. This combination resulted in a more pronounced downregulation of anti-apoptotic proteins Mcl-1 and Bcl-xL, along with a significant upregulation of the pro-apoptotic protein cleaved-caspase3 and the DNA double-strand break biomarker γ-H2AX compared to monotherapy. These results highlighted the potential of 25c as a promising lead compound for AML treatment, particularly when used in combination with Venetoclax.

Design, synthesis, and biological evaluation of novel HDAC/CD13 dual inhibitors for the treatment of cancer.

Aminopeptidase N (APN/CD13) plays a role in tumors progression, but its inhibitor lacks cytotoxicity and is used as an adjuvant drug in cancer treatment. Histone deacetylases (HDACs) are a type of epigenetic targets, and HDAC inhibitors are cytotoxic and exhibit synergistic effects with other anticancer agents. Herein, a novel series of HDAC/CD13 dual inhibitors were rationally designed and synthesized to combine the anti-metastasis and anti-invasion of CD13 inhibitor with the cytotoxic of HDAC inhibitor. The representative compound 12 exhibited more potent inhibitory activity against human CD13, HDAC1-3, and antiproliferative activity than positive controls bestatin and SAHA. Compound 12 effectively induced apoptosis in MV4-11 cells, while arresting A549 cells in G2/M phase. Moreover, 12 exhibited significantly better anti-metastasis and anti-invasion effects than mono-inhibitors 32 and 38, indicating that it is a promising anti-cancer agent for further investigation.

Analysis of the risk factors for intraoperative acute diffuse brain swelling in patients with isolated traumatic acute subdural haematomas.

BACKGROUND: The purpose of this retrospective study was to investigate the risk factors for intraoperative acute diffuse brain swelling in patients with isolated traumatic acute subdural haematomas (ASDH). METHODS: A total of 256 patients who underwent decompressive craniectomy for isolated traumatic ASDH between April 2013 and December 2020 were included. We evaluated the risk factors for intraoperative acute diffuse brain swelling using a multivariate logistic regression analysis. RESULTS: The incidence of intraoperative acute diffuse brain swelling in patients with isolated traumatic ASDH was 21.88% (56/256). Dilated pupils (OR = 24.78), subarachnoid haemorrhage (OR = 2.41), and the time from injury to surgery (OR = 0.32) were independent risk factors for intraoperative acute diffuse brain swelling, while no independent associations were observed between these risk factors and sex, age, the mechanism of injury, the Glasgow Coma Scale score, site of haematoma, thickness of haematoma, midline shift and the status of the basal cistern, although the mechanism of injury, the Glasgow Coma Scale score and the status of the basal cistern were correlated with the incidence of intraoperative acute diffuse brain swelling in the univariate analyses. CONCLUSIONS: This study identified the risk factors for intraoperative acute diffuse brain swelling in patients with isolated traumatic ASDH. An increased risk of intraoperative acute diffuse brain swelling occurs in patients with bilaterally dilated pupils, subarachnoid haemorrhage and a shorter time from injury to surgery. These findings should help neurosurgeons obtain information before surgery about intraoperative acute diffuse brain swelling in patients with isolated traumatic ASDH.

Design, synthesis and biological evaluation of hybrid of ubenimex-fluorouracil for hepatocellular carcinoma therapy.

In our previous study, we discovered a ubenimex-fluorouracil (5FU) conjugates BC-02, which displays significant in vivo anti-tumor activity, however, the instability of BC-02 in plasma limits its further development as a drug candidate. Herein, we designed and synthesized four novel ubenimex-5FU conjugates by optimizing the linkers between ubenimex and 5FU based on BC-02. Representative compound 20 is more stable than BC-02 in human plasma and displays about 100 times higher CD13 inhibitory activity than the positive control ubenimex. Meanwhile, the antiproliferative activity of 20 was comparable with 5FU in vitro. The preliminary mechanism study indicated that compound 20 exhibited significant anti-invasion and anti-angiogenesis activities in vitro. Furthermore, compound 20 obviously inhibits tumor growth and metastasis in vivo and prolong the survival time of tumor-bearing mice. Our study may have an important implication reference for the design of more druglike mutual prodrug, and compound 20 can be used as a lead compound for further design and development.

A systematic review of radiomics in osteosarcoma: utilizing radiomics quality score as a tool promoting clinical translation.

OBJECTIVES: To assess the methodological quality and risk of bias in radiomics studies investigating diagnosis, therapy response, and survival of patients with osteosarcoma. METHODS: In this systematic review, literatures on radiomics in osteosarcoma were included and assessed for methodological quality through the radiomics quality score (RQS). The risk of bias and concern of application was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool. A meta-analysis of studies focusing on predicting osteosarcoma response to neoadjuvant chemotherapy was performed. RESULTS: Twelve radiomics studies exploring osteosarcoma were identified, and five were included in meta-analysis. The RQS reached an average of 20.4% (6.92 of 36) with good inter-rater agreement (ICC 0.95, 95% CI 0.85-0.99). Four studies validated results with an internal dataset, none of which used external dataset; one study was prospectively designed, and another one shared part of the dataset. The risk of bias and concern of application were mainly related to index test aspect. The meta-analysis showed a diagnostic odds ratio of 43.68 (95%CI 13.5-141.31) for predicting response to neoadjuvant chemotherapy with high heterogeneity and low methodological quality. CONCLUSIONS: The overall scientific quality of included studies is insufficient; however, radiomics remains a promising technology for predicting treatment response, which might guide therapeutic decision-making and related to prognosis. Improvements in study design, validation, and open science needs to be made to demonstrate the generalizability of findings and to achieve clinical applications. Widespread application of RQS, pre-trained RQS scoring procedure, and modification of RQS in response to clinical needs are necessary. KEY POINTS: • Limited radiomics studies were established in osteosarcoma with mean RQS of 20.4%, commonly due to unvalidated results, retrospective study design, and absence of open science. • Meta-analysis of radiomics studies predicting osteosarcoma response to neoadjuvant chemotherapy showed high diagnostic odds ratio 43.68, while high heterogeneity and low methodological quality were the main concerns. • A previously trained data extraction instrument allowed reaching moderate inter-rater agreement in RQS applications, while RQS still needs improvement to become a wide adaptive tool in reviews of radiomics studies, in routine self-check before manuscript submitting and in study design.

The coexistence of recurrent pituitary adenoma and meningioma: case report.

The coexistence of pituitary adenoma and meningioma is very rare. Here, we present a case of recurrent non-functioning pituitary adenoma and temporal lobe meningioma in a patient without previous irradiation. A 73-year-old woman underwent a right-sided craniotomy of pituitary adenoma for visual deficits 30 years ago. She presented again with a 2-year history of lack of alertness, confusion and visual deficits. Brain magnetic resonance imaging (MRI) demonstrated a recurrent pituitary adenoma and a left temporal lobe tumour. The patient underwent a left frontotemporal craniotomy. After the surgery, the patient showed improvement in neurological symptoms. The histology of the sellar region tumour revealed that it was a pituitary adenoma, and the histology of the temporal lobe tumour demonstrated that it was a meningioma of transitional type. The coexistence of pituitary adenoma and meningioma is a very rare surgical entity, especially in a patient with recurrent pituitary adenoma. Although this co-occurrence is rare, more cases and additional studies are necessary to explain these unusual findings.

Abnormal increase of miR-4262 promotes cell proliferation and migration by targeting large tumor suppressor 1 in gliomas.

BACKGROUND: miRNA was recently detected as tumor suppressor or inducer in various cancers including gliomas. Due to the abnormal expression of miR-4262 in glioma cancer, we supposed that miR-4262 made efforts in proliferation and migration in glioma cancer. METHODS: CCK-8, Transwell migration Assay and Wound-healing assay were appraisal assays for cell proliferation and migration. qRT-PCR and western blot were performed to test the expression of miR-4262, MMP2, MMP13 and LATS1 in glioma cancers tissues and cancer cells. The targeting detection between miR-4262 and LATS1 was detected by luciferase reporter assay. RESULTS: miR-4262 expression was dramatically higher in glioma tumor tissues than in para-tumor control. Inhibition of miR-4262 in glioma cancer cells prominently inhibited cell proliferation and migration. Mechanically, downregulation of miR-4262 inhibited expression of matrix metalloproteinase (MMP) -2, -13. In addition, miR-4262 directly and negatively modulated expression of large tumor suppressor 1 (LATS1). Moreover, we discovered that overexpression of LATS1 could reverse the effects of miR-4262 on cell proliferation and migration, as well as the production of MMP-2, -13. CONCLUSIONS: In glioma cancer, miR-4262 regulated cell proliferation and migration mediated by LATS1. This indicated that miR-4262 is a tumor inducer in glioma cancer and may be a feasible target for glioma therapy.

A 30-year retrospective study of rare ectopic seminal tract opening cases.

Ectopic seminal tract opening is a rare congenital malformation. Until recently, there has been a lack of comprehensive reporting on the condition. The purpose of this retrospective study is to summarize the experience of diagnosis and treatment of this condition based on 28 clinical practice cases throughout the past 30 years. We conducted auxiliary examinations on such patients including routine tests, imaging examinations, and endoscopy. Among these 28 cases, there were ectopic opening of vas deferens into enlarged prostatic utricles (6 cases); ejaculatory ducts into enlarged prostatic utricles, Müllerian ducts cysts, and urethras (18 cases, 2 cases, and 1 case, respectively); and ectopic opening of the unilateral vas deferens and the contralateral ejaculatory duct into enlarged prostatic utricle (1 case). The size of the enlarged prostatic utricle, the type of ectopic seminal tract opening, and the opening's location effectively assisted in the selection of clinical treatment methods, including transurethral fenestration of the utricle, transurethral cold-knife incision, open operation, laparoscopic operation, and conservative treatment. Satisfactory effect was achieved during follow-up. In conclusion, a definite diagnosis and personalized treatment are especially important for patients with ectopic seminal tract opening.

FOXM1 contributes to docetaxel resistance in castration-resistant prostate cancer by inducing AMPK/mTOR-mediated autophagy.

Docetaxel-mediated chemotherapy is the first line therapy for metastatic castration-resistant prostate cancer (CRPC) patients, but its therapeutic benefit is limited by the development of resistance. Although Forkhead box protein M1 (FOXM1) has been implicated in prostate tumorigenesis and metastasis, its role in docetaxel resistance has not been studied. Here, we showed that FOXM1 expression was upregulated in the docetaxel resistant CRPC cell lines (PC3-DR and VCaP-DR) and knockdown of FOXM1 sensitized the cells to docetaxel both in vitro and in vivo. In addition, autophagy was found to be significantly enhanced in resistant cells. Moreover, FOXM1 overexpression cells showed increased autophagic flux and higher numbers of autophagosomes. Knockdown of ATG7, beclin-1 or cotreatment with chloroquine, partly restored sensitivity to docetaxel in the FOXM1-overexpressing cells. Mechanistically, FOXM1 targeted AMPK/mTOR to activate the autophagy pathway and altered docetaxel response in CRPC. These findings identify the role of FOXM1 as well as the mechanism underlying FOXM1 action in docetaxel sensitivity and may, therefore, aid in design of CRPC therapies.

Management of subdural effusion and hydrocephalus following decompressive craniectomy for posttraumatic cerebral infarction in a patient with traumatic brain injury: a case report.

BACKGROUND: Subdural effusion with hydrocephalus (SDEH) is a rare complication of traumatic brain injury, especially following decompressive craniectomy (DC) for posttraumatic cerebral infarction. The diagnosis and treatment are still difficult and controversial for neurosurgeons. CASE PRESENTATION: A 45-year-old man developed traumatic cerebral infarction after traumatic brain injury and underwent DC because of the mass effect of cerebral infarction. Unfortunately, the complications of traumatic subdural effusion (SDE) and hydrocephalus occurred in succession following DC. Burr-hole drainage and subdural peritoneal shunt were performed in sequence because of the mass effect of SDE, which only temporarily improved the symptoms of the patient. Cranioplasty and ventriculoperitoneal shunt were performed ultimately, after which SDE disappeared completely. However, the patient remains severely disabled, with a Glasgow Outcome Scale of 3. CONCLUSIONS: It is important for neurosurgeons to consider the presence of accompanying hydrocephalus when treating patients with SDE. Once the diagnosis of SDEH is established and the SDE has no mass effect, timely ventriculoperitoneal shunt may be needed to avoid multiple surgical procedures, which is a safe and effective surgical method to treat SDEH.

Correction: Limited Clinical Utility of Remote Ischemic Conditioning in Renal Transplantation: A Meta-Analysis of Randomized Controlled Trials.

[This corrects the article DOI: 10.1371/journal.pone.0170729.].

Efficacy of gefitinib­celecoxib combination therapy in docetaxel­resistant prostate cancer.

Resistance to docetaxel is a major clinical problem in castration­resistant prostate cancer (CRPC). We have previously reported that the combined inhibition of epidermal growth factor receptor (EGFR) and cyclooxygenase­2 (COX­2) led to an increased antitumor activity of docetaxel in CRPC. In the present study, we explored the efficacy of the combination of EGFR inhibition (by gefitinib) and COX­2 inhibition (by celecoxib) as a potential treatment for docetaxel­resistant CRPC. We established two docetaxel­resistant prostate cancer cell lines, PC3/DR and DU145/DR, by culturing PC3 and DU145 cells in docetaxel in a dose­escalating manner. The EGFR and COX­2 protein expression levels were determined. The effects of gefitinib and celecoxib on cell proliferation, apoptosis and invasion in vitro and in vivo were evaluated. In vitro changes in Bcl­2, FOXM1 and ABCB1 expression were analyzed. The expression of Ki­67 and cleaved­caspase­3 was also examined in DU145/DR tumor tissue. The enhanced expression of EGFR and COX­2 was observed in docetaxel­resistant CRPC relative to the parental cell lines. MTT, clone formation and fluorescence­activated cell sorting (FACS) analyses demonstrated that gefitinib and celecoxib in combination decreased cell viability and enhanced the rate of apoptosis when compared with either drug used alone. Additionally, the combination treatment was superior in inhibiting cell invasion and induced significant decreases in Bcl­2, FOXM1 and ABCB1 expression levels. Furthermore, the gefitinib­celecoxib combination inhibited DU145/DR tumor growth to a greater extent than either treatment used individually. The expression of Ki­67 was reduced, whereas cleaved­caspase­3 protein expression was increased in the tumors from the combination therapy group. In conclusion, the combined inhibition of EGFR and COX­2 by gefitinib and celecoxib may overcome docetaxel resistance in human CRPC. These findings provided a molecular basis for the clinical application of a novel combination therapy for docetaxel­resistant CRPC.

[Anti-hepatoma effects of Smac analogue Birinapant and its related molecular mechanism].

OBJECTIVE: To investigate the effects of Birinapant on hepatocellular carcinoma cells and its related molecular mechanisms. METHODS: Human hepatocellular carcinoma cells QGY-7701 were treated with 0, 1, 5, 25 and 125 nmol/L Birinapant for 24, 48 and 72 hours respectively, each experiment 3 wells.The proliferation activity of cells, the apoptosis levels, the cells nuclear type, the mitochondrial membrane potential, the transcription and expression levels of genes and the cytotoxicity of Birinapant were analyzed.At the same time, 4-week-old male BALB/C mice were randomly divided into 5 groups, with 20 mice in each group.The mice were inguinal injected with QGY-7701 cells, and then subcutaneous injected with Birinapant (concentrations ranging from 0, 1, 5, 25, 125 µg/kg) in each group after two days, once every other day.On 18th day since first Birinapant injection, 10 mice were killed in each group to weigh tumor tissue and survival time was recorded from the remaining 10 mice.The effects of Birinapant on the growth of the tumor and the survival time of tumor-bearing mice were observed. RESULTS: Compared with the negative control (NC) group, the proliferation activity of QGY-7701 was inhibited significantly after Birinapant treatment and the apoptosis levels were increased significantly (P<0.01).The cell mitochondrial membrane potential was decreased and the karyotype was changed (P<0.01).At the same time, the transcription and expression levels of genes cellular inhibitor of apoptosis protein 1(cIAP-1), cellular inhibitor of apoptosis protein 2(cIAP-2), ras, raf, mek and erk were significantly decreased (P<0.01), while the expression levels of caspase-3 and caspase-9 genes were up-regulated (P<0.01).Compared with the model group (MG), the growth of the tumor was inhibited significantly and the survival time of the tumor-bearing mice was prolonged after Birinapant treatment (P<0.01). CONCLUSIONS: Birinapant can inhibit the expression of cIAP-1, cIAP-2 and the proteins of Ras-Raf-MEK-ERK signal pathways, so as to activate the mitochondria mediated endogenous apoptosis pathway.Birinapant shows a certain inhibitory effect on liver cancer.

A BAP1 Mutation-specific MicroRNA Signature Predicts Clinical Outcomes in Clear Cell Renal Cell Carcinoma Patients with Wild-type BAP1.

Background: Clear cell renal cell carcinoma (ccRCC) is the most prevalent histologic subtype of kidney cancers in adults, which could be divided into two distinct subgroups according to the BRCA1 associated protein-1 (BAP1) mutation status. In the current study, we comprehensively analyzed the genome-wide microRNA (miRNA) expression profiles in ccRCC, with the aim to identify the differentially expressed miRNAs between BAP1 mutant and wild-type tumors, and generate a BAP1 mutation-specific miRNA signature for ccRCC patients with wild-type BAP1. Methods: The BAP1 mutation status and miRNA profiles in BAP1 mutant and wild-type tumors were analyzed. Subsequently, the association of the differentially expressed miRNAs with patient survival was examined, and a BAP1 mutation-specific miRNA signature was generated and examined with Kaplan-Meier survival, univariate and multivariate Cox regression analyses. Finally, the bioinformatics methods were adopted for the target prediction of selected miRNAs and functional annotation analyses. Results: A total of 350 treatment-naïve primary ccRCC patients were selected from The Cancer Genome Atlas project, among which 35 (10.0%) subjects carried mutant BAP1 and had a shorter overall survival (OS) time. Furthermore, 33 miRNAs were found to be differentially expressed between BAP1 mutant and wild-type tumors, among which 11 (miR-149, miR-29b-2, miR-182, miR-183, miR-21, miR-365-2, miR-671, miR-365-1, miR-10b, miR-139, and miR-181a-2) were significantly associated with OS in ccRCC patients with wild-type BAP1. Finally, a BAP1 mutation-specific miRNA signature consisting of 11 miRNAs was generated and validated as an independent prognostic parameter. Conclusions: In summary, our study identified a total of 33 miRNAs differentially expressed between BAP1 mutant and wild-type tumors, and generated a BAP1 mutation-specific miRNA signature including eleven miRNAs, which could serve as a novel prognostic biomarker for ccRCC patients with wild-type BAP1.

Targeting AXL overcomes resistance to docetaxel therapy in advanced prostate cancer.

Resistance to docetaxel is a major clinical problem in advanced prostate cancer. The overexpression of AXL receptor tyrosine kinase (AXL) has been correlated with chemotherapeutic drug resistance. However, the role of AXL expression in docetaxel resistance in prostate cancer is yet unclear. In this study, we demonstrate that AXL is overexpressed and activated independent of Gas6 in docetaxel-resistant prostate cancer cells (PC3-DR and DU145-DR). Moreover, we show that forced overexpression of AXL in PC3 and DU145 cells is sufficient to induce resistance to docetaxel in these cell lines. Notably, genetic or pharmacologic inhibition of AXL in the resistant models suppressed cell proliferation, migration, invasion, and tumor growth, and these effects were significantly augmented when AXL inhibition was combined with docetaxel treatment. Mechanistically, we found that AXL inhibition led to reversion of the epithelial-mesenchymal transition (EMT) phenotype and decreased the expression of ATP-binding cassette B1 (ABCB1). Overall, our results identify AXL as an important mediator of docetaxel resistance in prostate cancer. We propose that AXL-targeted therapy, in combination with docetaxel, has the potential to improve the response to docetaxel therapy and reduce resistance induced by prolonged docetaxel therapy in prostate cancer.

Limited Clinical Utility of Remote Ischemic Conditioning in Renal Transplantation: A Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: We conducted this meta-analysis of randomized controlled trials (RCTs) to investigate whether remote ischemic conditioning (RIC) could improve graft functions in kidney transplantation. METHODS: PubMed, Web of Science, and Cochrane Library were comprehensively searched to identify all eligible studies by October 5, 2016. The treatment effects were examined with risk ratio (RR) and weighted mean difference with the corresponding 95% confidence intervals (CI). The statistical significance and heterogeneity were assessed with both Z-test and Q-test. RESULTS: A total of six RCTs including 651 recipients, were eventually identified. Compared to the controls, RIC could reduce the incidence of delayed graft function (DGF) after kidney transplantation (random-effects model: RR = 0.89; fixed-effect model: RR = 0.84). However, the decrease did not reveal statistical significance. The subgroup analysis by RIC type demonstrated no significant difference among the three interventions in protecting renal allografts against DGF. Furthermore, no significant difference could be observed in the incidence of acute rejection, graft loss, 50% fall in serum creatinine, as well as the estimated glomerular filtration rate and hospital stay between the RIC and Control groups. CONCLUSIONS: This meta-analysis suggested that RIC might exert renoprotective functions in human kidney transplantation, and further well-designed RCTs with large sample size are warranted to assess its clinical efficacy.

[Expression of AXL enhances docetaxel-resistance of prostate cancer cells].

OBJECTIVE: To explore the effect of the AXL expression on the chemosensitivity of prostate cancer PC-3 and DU145 cells to docetaxel and possible mechanisms. METHODS: Using Western blot, we examined the expressions of the AXL protein, p-AXL and Gas6 in the docetaxel-resistant PC-3 (PC-3-DR) and DU145 (DU145-DR) cells stimulated with gradually increased concentrations of docetaxel. We transfected the PC-3 and DU145 cells with negative NC ShRNA and AXL-ShRNA, respectively, which were confirmed to be effective, detected the proliferation, apoptosis and cycle distribution of the cells by CCK8, MTT and flow cytometry after treated with the AXL-inhibitor MP470 and/or docetaxel, and determined the expression of the ABCB1 protein in the PC-3-DR and DU145-DR cells after intervention with the AXL-inhibitor R428 and/or docetaxel. RESULTS: The expression of the AXL protein in the PC-3 and DU145 cells was significantly increased after docetaxel treatment (P <0.05). The expressions AXL and p-AXL were remarkably higher (P <0.05) while that of Gas6 markedly lower (P <0.05) in the PC-3 and DU145 than in the PC-3-DR and DU145-DR cells. The inhibitory effect of docetaxel on the proliferation and its enhancing effect on the apoptosis of the PC-3 and DU145 cells were significantly decreased at 48 hours after AXL transfection (P <0.05). MP470 obviously suppressed the growth and promoted the apoptosis of the PC-3-DR and DU145-DR cells, with a higher percentage of the cells in the G2/M phase when combined with docetaxel than used alone (P <0.05). R428 markedly reduced the expression of ABCB1 in the PC-3-DR and DU145-DR cells, even more significantly in combination with docetaxel than used alone (P <0.05). CONCLUSIONS: The elevated expression of AXL enhances the docetaxel-resistance of PC-3 and DU145 prostate cancer cells and AXL intervention improves their chemosensitivity to docetaxel, which may be associated with the increased cell apoptosis in the G2/M phase and decreased expression of ABCB1.