Early enteral nutrition within 24 h after surgery has become a recommended procedure. In the present study, we retrospectively examined whether initiating EN within 24 h after esophagectomy improves the postoperative course.
Among 103 patients who underwent thoracic esophagectomy for esophageal cancer, we enrolled the cases in which EN was initiated within 72 h after surgery. The patients were divided into two groups: EN started within 24 h (Group D1) and EN started at 24 - 72 h (Group D2-3). Clinical factors including days for first fecal passage, dose of postoperative albumin infusion, difference in serum albumin between pre- and postoperation, incidence of postoperative infection, and use of total parenteral nutrition were compared. Statistical analyses were performed by the Mann-Whitney U test and Chi square test, with significance defined as P < 0.05.
There was no significant difference between the groups in clinical factors. While pneumonia was significantly more frequent in Group D1 than in Group D2-3 (P = 0.0308), the frequency of infectious complications was comparable between the groups.
Initiating EN within 24 h showed no advantage for the postoperative course in esophageal cancer, and thus EN should be scheduled within 24 - 72 h, based on the patient condition.
Early enteral nutrition; Esophageal cancer; Infectious complication; Pneumonia
Fenestral and stomatal diaphragms are endothelial subcellular structures of unknown function that form on organelles implicated in vascular permeability: fenestrae, transendothelial channels and caveolae. PV1 protein is required for diaphragm formation in vitro. Here, we report that deletion of the PV1-encoding Plvap gene in mice results in the absence of diaphragms and decreased survival. Loss of diaphragms did not affect the fenestrae and transendothelial channels formation but disrupted the barrier function of fenestrated capillaries causing a major leak of plasma proteins. This disruption results in early death of animals due to severe non-inflammatory protein loosing enteropathy. Deletion of PV1 in endothelium, but not the hematopoietic compartment, recapitulates the phenotype of global PV1 deletion, whereas endothelial reconstitution of PV1 rescues the phenotype. Taken together, these data provide genetic evidence for the critical role of the diaphragms in fenestrated capillaries in the maintenance of blood composition.
Anaplastic carcinoma of the pancreas (ACP) is a rare neoplasm of the pancreas. ACPs are aggressive neoplasms with a poorer prognosis than poorly differentiated ductal adenocarcinomas of the pancreas. The 3-year survival rate of patients with ACP is less than 3%, with a life expectancy of 10 to 20 months. We describe here a 64-year-old man with ACP mimicking a submucosal gastric tumor. The patient was found to have a giant mass mimicking a submucosal tumor. Total gastrectomy with splenectomy and partial resection of the tail of the pancreas were performed. The pathological diagnosis was ACP, with immunohistological findings showing pleomorphic-type ACP. Because the surgery was noncurative, the patient received adjuvant chemotherapy with paclitaxel but died of peritoneal dissemination and multiple liver metastases 4 months after surgery.
Both the PI3K→Akt→mTOR and MAPK signaling pathways are often deregulated in prostate tumors with poor prognosis. Here we describe a new genetically-engineered mouse model of prostate cancer in which PI3K-Akt-mTOR signaling is activated by inducible disruption of PTEN, and ERK1/2 MAP kinase signaling is activated by inducible expression of a BRAFV600E oncogene. These tissue-specific compound mutant mice develop lethal prostate tumors that are inherently resistant to castration. These tumors bypass cellular senescence and disseminate to lymph nodes, bone marrow and lungs where they form overt metastases in ~30% of the cases. Activation of PI3K→Akt→mTOR and MAPK signaling pathways in these prostate tumors cooperate to upregulate c-Myc. Accordingly, therapeutic treatments with Rapamycin and PD0325901 to target these pathways, respectively, attenuate c-Myc levels and reduce tumor and metastatic burden. Together, our findings suggest a generalized therapeutic approach to target c-Myc activation in prostate cancer by combinatorial targeting of the PI3K→Akt→mTOR and ERK1/2 MAPK signaling pathways.
Akt/mTOR signaling; MAP kinase signaling; genetically engineered mouse models; Braf; Myc
Regulatory T cells (Tregs) maintain immune homeostasis by limiting inflammatory responses. TRAF6 plays a key role in the regulation of innate and adaptive immunity by mediating signals from various receptors including the T-cell receptor (TCR). T cell-specific deletion of TRAF6 has been shown to induce multiorgan inflammatory disease, but the role of TRAF6 in Tregs remains to be investigated. Here, we generated Treg-specific TRAF6-deficient mice using Foxp3-Cre and TRAF6-flox mice. Treg-specific TRAF6-deficient (cKO) mice developed allergic skin diseases, arthritis, lymphadenopathy and hyper IgE phenotypes. Although TRAF6-deficient Tregs possess similar in vitro suppression activity compared to wild-type Tregs, TRAF6-deficient Tregs did not suppress colitis in lymphopenic mice very efficiently due to reduced number of Foxp3-positive cells. In addition, the fraction of TRAF6-deficient Tregs was reduced compared with wild-type Tregs in female cKO mice without inflammation. Moreover, adoptive transfer of Foxp3 + Tregs into Rag2-/- mice revealed that TRAF6-deficient Tregs converted into Foxp3- cells more rapidly than WT Tregs under lymphopenic conditions. Fate-mapping analysis also revealed that conversion of Tregs from Foxp3+ to Foxp3- (exFoxp3 cells) was accelerated in TRAF6-deficient Tregs. These data indicate that TRAF6 in Tregs plays important roles in the maintenance of Foxp3 in Tregs and in the suppression of pathogenic Th2 type conversion of Tregs.
We have developed a new internal cooled electrode for radiofrequency ablation (RFA) (Japan Application no. 2006-88228) suitable for forceps channel bronchoscopy. Here, we present our clinical experience with bronchoscopy-guided RFA under computed tomography (CT) monitoring for patients with peripheral-type non-small-cell lung cancer (NSCLC). Bronchoscopy-guided RFA was performed in two patients (80 and 70 years old) with NSCLC, who had no lymph node involvement and distant metastases (T1N0M0), but not indicated for surgery because of other complications, such as advanced age, poor pulmonary function, and refusal of thoracic surgery. The locations of the tumors were right S2 and left S3, respectively. Although the tumors showed ground-glass opacity (GGO) with solid components in both cases, radiographic findings changed to reduced mass-like shadow and remained stable for 4 and 3.5 years after bronchoscopy-guided RFA. As the former case developed progressive disease on chest CT, bronchoscopy-guided RFA was repeated in the same lesion, resulting in no change for the subsequent 1 year. There were no adverse reactions during the procedures. Thus, bronchoscopy-guided RFA is a safe and feasible procedure that represents a potentially useful therapeutic tool in local control in medically inoperable patients with stage I NSCLC.
While the prognosis for clinically localized prostate cancer is now favorable, there are still no curative treatments for castration-resistant prostate cancer and, therefore, remains fatal. In this study, we investigate a new therapeutic approach for treatment of castration-resistant prostate cancer, which involves dual targeting of a major signaling pathway that is frequently deregulated in the disease. We found that dual targeting of the Akt and mTOR signaling pathways with their respective inhibitors, MK-2206 and ridaforolimus (MK-8669), is highly effective for inhibiting castration-resistant prostate cancer in preclinical studies in vivo using a refined genetically-engineered mouse model of the disease. The efficacy of the combination treatment contrasts with their limited efficacy as single agents, since delivery of MK-2206 or MK-8669 individually had a modest impact in vivo on the overall tumor phenotype. In human prostate cancer cell lines, although not in the mouse model, the synergistic actions of MK-2206 and ridaforolimus (MK-8669) are due in part to limiting the mTORC2-feedback activation of Akt. Moreover, the effects of these drugs are mediated by inhibition of cellular proliferation via the retinoblastoma (RB) pathway. Our findings suggest that dual targeting the Akt and mTOR signaling pathways using MK-2206 and ridaforolimus (MK-8669) may be effective for treatment of castration-resistant prostate cancer, particularly for patients with deregulated RB pathway activity.
Akt/mTOR signaling; castration-resistant prostate cancer; genetically engineered mouse models; preclinical analyses; Pten; RB
In the majority of castration-resistant prostate cancer (CRPC), prostate-specific antigen (PSA), product of a gene that is almost exclusively regulated by the androgen receptor (AR), still acts as a serum marker reflecting disease burden, indicating that AR signaling is activated even under castrate level of serum androgen. Accumulated evidence shows that transcriptional ability of AR is activated both in ligand-dependent and -independent manners in CRPC cells. Some androgen-independent sublines derived from originally androgen-dependent LNCaP prostate cancer cells overexpress the AR and PSA, for which silencing the AR gene suppresses cellular proliferation. The overexpression of the AR confers androgen-independent growth ability on androgen-dependent prostate cancer cells. Some patient-derived prostate cancer xenograft lines also acquire castration-resistant growth ability secreting PSA. More recent publications have shown that the AR activated in CRPC cells regulates distinct gene sets from that in androgen-dependent status. This concept provides very important insights in the development of novel anti-prostate cancer drugs such as new generation anti-androgens and CYP17 inhibitors.
prostate cancer; castration resistant; androgen receptor; molecular target
The development of a symptomatic herniated cervical disc before the age of 20 is extremely rare. Sporadically reported cases of patients with cervical disc herniation under the age of 20 usually have had underlying disease.
Case 1: A 19-year-old Asian man visited our clinic and presented with progressive pain in his upper left scapula and weakness of the left deltoid and biceps brachii muscles. C5 radiculopathy by soft disc herniation at C4-C5 without calcification was diagnosed. Microsurgical posterior foraminotomy was performed and he recovered completely eight weeks after the surgery.
Case 2: A 15-year-old Asian man presented with difficulty in lifting his arm and neck pain on the right side. Neurological examination showed weakness of the right deltoid and biceps brachii muscles. A magnetic resonance imaging scan demonstrated a herniated intervertebral disc in the right C4-C5 foramen. The patient was treated conservatively and put under observation only, and had completely recovered eight weeks after admission.
Although extremely rare, symptomatic cervical disc herniations may occur even in the younger population under the age of 20 without any trauma or underlying disease. Favorable outcomes can be achieved by conventional treatments for cervical disc herniation.
There is a critical need to identify treatment options for patients at high risk for developing muscle invasive bladder cancer that avoid surgical removal of the bladder (cystectomy). In the current study, we have performed preclinical studies to investigate the efficacy of intravesical delivery of chemotherapy for preventing progression of bladder cancer. We evaluated three chemotherapy agents, namely cisplatin, gemcitabine, and docetaxel, which are currently in use clinically for systemic treatment of muscle invasive bladder cancer and/or have been evaluated for intravesical therapy. These preclinical studies were done using a genetically-engineered mouse (GEM) model that progresses from carcinoma in situ (CIS) to invasive, metastatic bladder cancer. We performed intravesical treatment in this GEM model using cisplatin, gemcitabine, and/or docetaxel, alone or by combining two agents, and evaluated whether such treatments inhibited progression to invasive, metastatic bladder cancer. Of the three single agents tested, gemcitabine was most effective for preventing progression to invasive disease, as assessed by several relevant endpoints. However, the combinations of two agents, and particularly those including gemcitabine, were more effective for reducing both tumor and metastatic burden. Our findings suggest combination intravesical chemotherapy may provide a viable bladder-sparing treatment alternative for patients at high risk for developing invasive bladder cancer, which can be evaluated in appropriate clinical trials.
Non-muscle invasive bladder cancer; intravesical therapy; genetically engineered mouse models; preclinical studies
Conjugated linoleic acid l-menthyl ester was hydrolyzed in water by the lipase from Candida rugosa with the addition of an organic solvent. The degree of hydrolysis (yield) greatly improved when a tertiary alcohol, such as t-butyl alcohol, was added. However, the addition of a less polar solvent, such as hexane, decreased the degree of hydrolysis, and some water-miscible solvents, such as acetone, caused inactivation of the lipase. With the addition of t-butyl alcohol, the reaction mixture formed a one- or two-phase system, and the mixing ratio of substrates and t-butyl alcohol determined the number of phases. Although the degree of hydrolysis at 10 d was higher in the one-phase system, the initial reaction rate was generally lower. Meanwhile, the reaction was much faster in the two-phase system while maintaining a moderate degree of hydrolysis.
Conjugated linoleic acid; Ester; Hydrolysis; Lipase; Organic solvent
A 77 year-old female was found with FAB M4Eo acute myeloid leukemia. Although CBFB-MYH11 mRNA was detected in RT-PCR, the conventional cytogenetic analysis failed to reveal inv(16). Fluorescence in situ hybridization (FISH) and the sequence analysis revealed a fusion between the exon 5 of CBFB and the exon 8 of MYH11, resulting in a minor variant fusion product previously reported as type D. In order to detect the cryptic inv(16) type D, both FISH and RT-PCR are required, and furthermore, the primers for the sequence analysis needs to be selected for the proper diagnosis.
Acute myeloid leukemia; inversion 16; CBFB-MYH11; RT-PCR; fluorescence in situ hybridization
E26 transformation-specific-1 (ETS-1), an ETS family transcription factor, has been reported to play an important role in a variety of physiological and pathological processes, but clinical implications of ETS-1 expression in prostate cancer (PCa), particularly high-risk cases, including response to androgen-deprivation therapy (ADT) have yet to be elucidated. We examined the expression of ETS-1 using immunohistochemical staining of paraffin-embedded prostate carcinoma tissue obtained by needle biopsy from 69 mostly advanced PCa patients. ETS-1 expression was compared with the clinicopathological characteristics of the 69 patients, including 25 who underwent ADT as a primary treatment. As a result, PCa patients with higher expression of ETS-1 were significantly more likely to be of high stage and high Gleason score (P<0.05). There was no significant association between ETS-1 expression and the initial prostate-specific antigen (PSA) level. In the 25 patients treated by ADT, the staining score for ETS-1 was significantly associated with rapid development of castration-resistant disease within 24 months (P<0.05), whereas the Gleason score and PSA level were not. In conclusion, increased ETS-1 expression was associated with a higher stage, higher Gleason score and shorter time to castration-resistant progression. These data suggest that immunostaining for ETS-1 could be a molecular marker for predicting a poor clinical outcome for PCa patients, particularly those with high-risk disease.
castration resistant; E26 transformation-specific-1 (ETS-1); immunohistochemistry; prostate cancer
The title compound, C16H12O4, crystallizes with two half-molecules in the asymmetric unit, each of which is completed by a crystallographic inversion center. The two crystallographically independent molecules have almost the same geometry and are almost planar [maximum deviations = 0.018 (3) and 0.049 (3) Å]. They adopt a conformation in which the Cmethyl—O bonds are directed along the molecular short axis [C—C—O—C torsion angles of 179.6 (2) and 178.0 (2)°]. In the crystal, the molecular packing is characterized by a combination of a columnar stacking and a herringbone-like arrangement. The molecules form slipped π-stacks along the b axis, in which there are two kinds of columns differing from each other in their slippage. The interplanar distances between neighboring molecules are 3.493 (3) for one column and 3.451 (2) Å for the other.
Molecules of the title compound, C18H16O6, are almost planar [maximum deviation = 0.096 (4) Å] and reside on crystallographic centres of inversion. They adopt a conformation in which the Cmethyl—O bonds are directed along the molecular short axis [C—C—O—C torsion angles of −175.3 (3) and 178.2 (3)°]. In the crystal, molecules adopt a slipped-parallel arrangement with π–π stacking interactions along the a axis with an interplanar distance of 3.392 (4) Å. Weak C—H⋯O interactions link the molecules into sheets parallel to (10-2).
To improve the quality of life of colorectal cancer patients, it is important to establish new screening methods for early diagnosis of colorectal cancer.
We performed serum metabolome analysis using gas-chromatography/mass-spectrometry (GC/MS). First, the accuracy of our GC/MS-based serum metabolomic analytical method was evaluated by calculating the RSD% values of serum levels of various metabolites. Second, the intra-day (morning, daytime, and night) and inter-day (among 3 days) variances of serum metabolite levels were examined. Then, serum metabolite levels were compared between colorectal cancer patients (N = 60; N = 12 for each stage from 0 to 4) and age- and sex-matched healthy volunteers (N = 60) as a training set. The metabolites whose levels displayed significant changes were subjected to multiple logistic regression analysis using the stepwise variable selection method, and a colorectal cancer prediction model was established. The prediction model was composed of 2-hydroxybutyrate, aspartic acid, kynurenine, and cystamine, and its AUC, sensitivity, specificity, and accuracy were 0.9097, 85.0%, 85.0%, and 85.0%, respectively, according to the training set data. In contrast, the sensitivity, specificity, and accuracy of CEA were 35.0%, 96.7%, and 65.8%, respectively, and those of CA19-9 were 16.7%, 100%, and 58.3%, respectively. The validity of the prediction model was confirmed using colorectal cancer patients (N = 59) and healthy volunteers (N = 63) as a validation set. At the validation set, the sensitivity, specificity, and accuracy of the prediction model were 83.1%, 81.0%, and 82.0%, respectively, and these values were almost the same as those obtained with the training set. In addition, the model displayed high sensitivity for detecting stage 0–2 colorectal cancer (82.8%).
Our prediction model established via GC/MS-based serum metabolomic analysis is valuable for early detection of colorectal cancer and has the potential to become a novel screening test for colorectal cancer.
A retrospective study.
To examine the efficacy and safety for a posterior-approach circumferential decompression and shortening reconstruction with a titanium mesh cage for lumbar burst fractures.
Overview of Literature
Surgical decompression and reconstruction for severely unstable lumbar burst fractures requires an anterior or combined anteroposterior approach. Furthermore, anterior instrumentation for the lower lumbar is restricted through the presence of major vessels.
Three patients with an L1 burst fracture, one with an L3 and three with an L4 (5 men, 2 women; mean age, 65.0 years) who underwent circumferential decompression and shortening reconstruction with a titanium mesh cage through a posterior approach alone and a 4-year follow-up were evaluated regarding the clinical and radiological course.
Mean operative time was 277 minutes. Mean blood loss was 471 ml. In 6 patients, the Frankel score improved more than one grade after surgery, and the remaining patient was at Frankel E both before and after surgery. Mean preoperative visual analogue scale was 7.0, improving to 0.7 postoperatively. Local kyphosis improved from 15.7° before surgery to -11.0° after surgery. In 3 cases regarding the mid to lower lumbar patients, local kyphosis increased more than 10° by 3 months following surgery, due to subsidence of the cages. One patient developed severe tilting and subsidence of the cage, requiring additional surgery.
The results concerning this small series suggest the feasibility, efficacy, and safety of this treatment for unstable lumbar burst fractures. This technique from a posterior approach alone offers several advantages over traditional anterior or combined anteroposterior approaches.
Lumbar spine; Burst fracture; Posterior approach
The mobilization of hematopoietic stem cells does not require osteoclasts, which may even have an inhibitory effect.
Hematopoietic stem cells (HSCs) are maintained in a specific bone marrow (BM) niche in cavities formed by osteoclasts. Osteoclast-deficient mice are osteopetrotic and exhibit closed BM cavities. Osteoclast activity is inversely correlated with hematopoietic activity; however, how osteoclasts and the BM cavity potentially regulate hematopoiesis is not well understood. To investigate this question, we evaluated hematopoietic activity in three osteopetrotic mouse models: op/op, c-Fos-deficient, and RANKL (receptor activator of nuclear factor kappa B ligand)-deficient mice. We show that, although osteoclasts and, by consequence, BM cavities are absent in these animals, hematopoietic stem and progenitor cell (HSPC) mobilization after granulocyte colony-stimulating factor injection was comparable or even higher in all three lines compared with wild-type mice. In contrast, osteoprotegerin-deficient mice, which have increased numbers of osteoclasts, showed reduced HSPC mobilization. BM-deficient patients and mice reportedly maintain hematopoiesis in extramedullary spaces, such as spleen; however, splenectomized op/op mice did not show reduced HSPC mobilization. Interestingly, we detected an HSC population in osteopetrotic bone of op/op mice, and pharmacological ablation of osteoclasts in wild-type mice did not inhibit, and even increased, HSPC mobilization. These results suggest that osteoclasts are dispensable for HSC mobilization and may function as negative regulators in the hematopoietic system.
Background. S-1 plus cisplatin has been established to be standard first-line chemotherapy for advanced gastric cancer in Japan. The optimal second-line treatment refractory to S-1 plus cisplatin remains unclear. Methods. We retrospectively studied the efficacy, toxicity, and survival of irinotecan plus mitomycin C in patients with advanced gastric cancer refractory to a fluoropyrimidine plus cisplatin. Results. Twenty-four patients were studied. Prior chemotherapy was S-1 plus cisplatin in 15 patients, S-1 plus cisplatin and docetaxel in 8, and 5-fluorouracil plus cisplatin with radiotherapy in 1. The overall response rate was 17.4%. The median overall survival was 8.6 months, and the median progression-free survival was 3.6 months. Grade 3 or 4 toxicities included leukopenia (33%), neutropenia (50%), anemia (33%), thrombocytopenia (4%), anorexia (13%), diarrhea (4%), and febrile neutropenia (13%). Conclusion. A combination of irinotecan and mitomycin C is potentially effective in patients with advanced gastric cancer refractory to a fluoropyrimidine plus cisplatin.
We retrospectively investigated the incidence of pancreatic ductal adenocarcinoma among patients with intraductal papillary mucinous neoplasms of the pancreas. Based on imaging in 195 such patients, we chose surgery as initial treatment for 54, and periodic evaluation over 6 to 192 months (mean, 52) for 141. In 6 of the 141 patients observed for intraductal papillary mucinous neoplasm (4.2%), pancreatic ductal adenocarcinoma developed. Further, careful monitoring for cancer occurrence in the remnant pancreas proved essential in the surgical resection group; 2 of 26 patients (7.7%) subsequently developed pancreatic ductal adenocarcinoma in the remnant pancreas, at 41 months and 137 months after surgery. Serial observation of patients with intraductal papillary mucinous neoplasms by contrast-enhanced computed tomography or magnetic resonance cholangiopancreatography therefore is critical, whether or not surgical treatment initially was performed.
To elucidate current issues related to health statistics dissemination efforts on the Internet in Indonesia and to propose a new dissemination website as a solution.
A cross-sectional survey was conducted. Sources of statistics were identified using link relationship and Google™ search. Menu used to locate statistics, mode of presentation and means of access to statistics, and available statistics were assessed for each site. Assessment results were used to derive design specification; a prototype system was developed and evaluated with usability test.
49 sources were identified on 18 governmental, 8 international and 5 non-government websites. Of 49 menus identified, 33% used non-intuitive titles and lead to inefficient search. 69% of them were on government websites. Of 31 websites, only 39% and 23% used graph/chart and map for presentation. Further, only 32%, 39% and 19% provided query, export and print feature. While >50% sources reported morbidity, risk factor and service provision statistics, <40% sources reported health resource and mortality statistics. Statistics portal website was developed using Joomla!™ content management system. Usability test demonstrated its potential to improve data accessibility.
Discussion and conclusion:
In this study, government’s efforts to disseminate statistics in Indonesia are supported by non-governmental and international organizations and existing their information may not be very useful because it is: a) not widely distributed, b) difficult to locate, and c) not effectively communicated. Actions are needed to ensure information usability, and one of such actions is the development of statistics portal website.
public health; public information; statistics; web services; usability
The molecule of the title compound, C28H32, is located on a crystallographic inversion center. The ethyl groups are essentially coplanar with the tetracene ring, making a torsion angle of −0.4 (4)°. The isopropyl groups adopt an asymmetric conformation with their terminal methyl groups positioned on opposite sides of the tetracene plane [the Me—C—C—C torsion angles are −22.5 (4) and 100.9 (3)°]. In the crystal, the molecules adopt an arrangement without significant π–π interactions along the stacking direction (y axis).
A 59-year-old man was diagnosed with IgG4-related tubulointerstitial nephritis. His symptoms as well as laboratory and imaging findings were improved after initiation of steroid therapy. Serologically, he showed hypocomplementemia (C3 23 mg/dl, C4 <2 mg/dl, CH50 <7 U/ml) with high levels of IgG (IgG4 1,970 mg/dl) and immune complexes (C1q assay 8.1 μg/ml) and a low level of C1q (<2.0 mg/dl). Histologically, he also showed linear depositions of IgG, IgM, C3, C4d, C1q, membrane attack complex and all IgG subclasses (IgG1, IgG2, IgG3 and IgG4) along the tubular basement membrane, as well as granular depositions of these components in the renal interstitium. However, mannose-binding lectin and L-ficolin were not detected in these tissues. Homogeneous electron-dense deposits were observed by electron microscopy in the tubular basement membrane. It appears that the immune complexes might activate the classical pathway of the complement in both blood and local tissues in a patient with IgG4-related tubulointerstitial nephritis.
IgG4; Tubulointerstitial nephritis; Complement; Classical pathway; Immune complex
Docetaxel-based combination chemotherapy remains the predominant treatment for castration-resistant prostate cancer. However, taxane-related drug resistance and neurotoxicity have prompted us to develop substitute treatment strategies. Eg5 (kinesin spindle protein), which is crucial for bipolar spindle formation and duplicated chromosome separation during the early phase of mitosis, has emerged as an attractive target for cancer chemotherapy. The aim of this study was to investigate the anticancer efficacy of S-(methoxytrityl)-ℒ-cysteine (S(MeO)TLC), a novel Eg5 inhibitor in prostate cancer. Eg5 expression was examined in human prostate cancer cell lines and tissue microarrays were constructed from clinical specimens. Antiproliferative activity of S(MeO)TLC in prostate cancer cells was assessed by a cell viability assay. The anticancer effect and inhibitory mechanism of S(MeO)TLC in prostate cancer cells was further explored by Hoechst staining, flow cytometry and immunofluorescence. In addition, the antitumor effect of S(MeO)TLC on subcutaneous xenograft models was assessed. Eg5 expression was identified in PC3, DU145 and LNCaP cells. More than half of prostate cancer clinical specimens displayed Eg5 expression. S(MeO)TLC exhibited more powerful anticancer activity in prostate cancer cells compared with the other four Eg5 inhibitors tested. S(MeO)TLC induced cell death after arresting dividing cells at mitosis with distinct monopolar spindle formation. S(MeO)TLC exhibited its significant inhibitory activity (P<0.05) on subcutaneous xenograft models also through induction of mitotic arrest. We conclude that Eg5 is a good target for prostate cancer chemotherapy, and S(MeO)TLC is a potent promising anticancer agent in prostate cancer.
Eg5 protein; prostate cancer; S-(methoxytrityl)-ℒ-cysteine