Iliopsoas plane block does not improve pain after primary total hip arthroplasty in the presence of multimodal analgesia: a single institution randomized controlled trial.

BACKGROUND: The clinical analgesic efficacy of iliopsoas plane block remains a subject of discussion. This study aimed to assess the analgesic efficacy of iliopsoas plane block under general anesthesia using multimodal analgesia. METHODS: Fifty-six adult patients who underwent elective primary hip arthroplasty were enrolled. Patients were randomized to receive either a single-shot iliopsoas plane block (10 mL 0.75% ropivacaine with 1:200 000 epinephrine) or a sham block (10 mL normal saline). All patients received general anesthesia, multimodal analgesia (preoperative buprenorphine patch, 5 µg/h), intraoperative intravenous dexamethasone (8 mg) and nefopam (20 mg), and round-the-clock acetaminophen and celecoxib. The primary outcome was the numeric rating scale pain score at rest 6 hour after surgery. RESULTS: Iliopsoas plane block did not have a notable advantage over the sham block in terms of pain relief at rest, as assessed by the numeric rating scale score, 6 hour after total hip arthroplasty (iliopsoas plane block: median, 4.0; IQR, 2.0-5.8; sham: median, 5.5; IQR, 2.3-6.8; median difference, -1.0; 95% CI -2.0 to 0.0; p≥0.999). Linear mixed model analysis showed no differences in pain scores, opioid consumption, quadriceps strength, or quality of recovery between the groups. CONCLUSIONS: Iliopsoas plane block did not improve postoperative analgesia following total hip arthroplasty under general anesthesia with a multimodal analgesic regimen. The blockade of sensory femoral branches supplying the anterior hip capsule using iliopsoas plane block may not yield additional benefits concerning patient outcomes in the aforementioned clinical context. TRIAL REGISTRATION NUMBER: NCT05212038, https://clinicaltrials.gov/ct2/show/NCT05212038.

Comparison of the incidence of intravascular injection using the Tuohy and Quincke needles during ultrasound-guided caudal epidural block: a prospective randomized controlled study.

INTRODUCTION: Intravascular injection of a local anesthetic can lead to life-threatening complications, such as deficits in neurological function after caudal epidural block. This study aimed to determine whether the intravascular injection rate of the Tuohy needle is lower than that of the Quincke needle during an ultrasound-guided caudal block. METHODS: Two-hundred and thirty patients were randomized into the Quincke (n=115) and the Tuohy (n=115) needle groups. The randomly selected needle was introduced at a 45° angle until it penetrated the sacrococcygeal ligament under ultrasound guidance, and intravenous injections were analyzed using contrast-dyed digital subtraction angiography. The relationship between the incidence of intravascular injection and independent variables, including needle type, patient demographics, history of lumbosacral surgery, use of anticoagulants, anatomic variables of the sacrum, presence of bony contact during the procedure, and the number of needle repositioning under ultrasound guidance, were examined. RESULTS: Intravascular uptake of contrast medium was surveyed in 25/230 (10.9%) caudal blocks using digital subtraction angiography (DSA). The incidence of intravascular uptake was 13.9% (16/115) using the Quincke needle and 7.8% (9/115) using the Tuohy needle (p=0.14). Although the needle tip type was not associated with the rate of intravascular injection, the occurrence of bony contact during the procedure demonstrated a relationship with the intravenous injection (p<0.01). CONCLUSIONS: The overall incidence of inadvertent intravascular injections during ultrasound-guided caudal block confirmed using DSA was 10.9%. Tuohy needles did not reduce intravascular injection rates during the ultrasound-guided caudal block. TRIAL REGISTRATION NUMBER: NCT05504590.

PSMD1 as a prognostic marker and potential target in oropharyngeal cancer.

BACKGROUND: Despite the diverse genetic mutations in head and neck cancer, the chemotherapy outcome for this cancer has not improved for decades. It is urgent to select prognostic factors and therapeutic targets for oropharyngeal cancer to establish precision medicine. Recent studies have identified PSMD1 as a potential prognostic marker in several cancers. We aimed to assess the prognostic significance of PSMD1 expression in oropharyngeal squamous cell carcinoma (OPSCC) patients using immunohistochemistry. METHODS: We studied 64 individuals with OPSCC tissue from surgery at Seoul National University Bundang Hospital between April 2008 and August 2017. Immunostaining analysis was conducted on the tissue microarray (TMA) sections (4 µm) for p16 and PSMD1. H-score, which scale from 0 to 300, was calculated from each nucleus, cytoplasm, and cellular expression. Clinicopathological data were compared with Chi-squared test, Fisher's exact test, t-test, and logistic regression. Survival data until 2021 were achieved from national statistical office of Korea. Kaplan-Meier method and cox-regression model were used for disease-specific survival (DSS) analysis. RESULTS: H-score of 90 in nucleus was appropriate cutoff value for 'High PSMD1 expression' in OPSCC. Tonsil was more frequent location in low PSMD1 group (42/52, 80.8%) than in high PSMD1 group (4/12, 33.3%; P = .002). Early-stage tumor was more frequent in in low PSMD1 group (45/52, 86.5%) than in high PSMD1 group (6/12, 50%; P = .005). HPV was more positive in low PSMD1 group (43/52, 82.7%) than in high PSMD1 group (5/12, 41.7%; P = .016). Patients with PSMD1 high expression showed poorer DSS than in patients with PSMD1 low expression (P = .006 in log rank test). In multivariate analysis, PSMD1 expression, pathologic T staging, and specimen age were found to be associated with DSS (P = .011, P = .025, P = .029, respectively). CONCLUSIONS: In our study, we established PSMD1 as a negative prognostic factor in oropharyngeal squamous cell carcinoma, indicating its potential as a target for targeted therapy and paving the way for future in vitro studies on drug repositioning.

Effect of bacterial resistant zwitterionic derivative incorporation on the physical properties of resin-modified glass ionomer luting cement.

Biofilms induce microbial-mediated surface roughening and deterioration of cement. In this study, zwitterionic derivatives (ZD) of sulfobetaine methacrylate (SBMA) and 2-methacryloyloxyethyl phosphorylcholine, were added in concentrations of 0, 1, and 3% to three different types of commercially available resin-modified glass ionomer cement (RMGIC) (RMC-I: RelyX Luting 2, RMC-II: Nexus RMGI, and RMC-III: GC FujiCEM 2). The unmodified RMGICs served as the control group for comparison. The resistance of Streptococcus mutans to ZD-modified RMGIC was evaluated with a monoculture biofilm assay. The following physical properties of the ZD-modified RMGIC were assessed: wettability, film thickness, flexural strength, elastic modulus, shear bond strength, and failure mode. The ZD-modified RMGIC significantly inhibited biofilm formation, with at least a 30% reduction compared to the control group. The addition of ZD improved the wettability of RMGIC; however, only 3% of the SBMA group was statistically different (P < 0.05). The film thickness increased in proportion to the increasing ZD concentrations; there was no statistical difference within the RMC-I (P > 0.05). The experimental groups' flexural strength, elastic modulus, and shear bond strength showed an insignificant decrease from the control group; there was no statistical difference within the RMC-I (P > 0.05). The mode of failure differed slightly in each group, but all groups showed dominance in the adhesive and mixed failure. Thus, the addition of 1 wt.% ZD in RMGIC favorably enhanced the resistance to Streptococcus mutans without any tangible loss in flexural and shear bond strength.

Anatomical and Radiological Assessments of Injectate Spread Stratified by the Volume of the Pericapsular Nerve Group Block.

BACKGROUND: The pericapsular nerve group (PENG) block was recently suggested as a regional technique for managing acute pain after hip surgery. However, few anatomical studies have confirmed the spread of injectate during the PENG block. This cadaver study aimed to analyze injectate spread to the target nerves during single-injection ultrasound-guided PENG block. METHODS: Ultrasound-guided PENG block with 3 different injectate volumes (10, 20, or 30 mL) was performed in 18 cadavers. Injectate spread by the volume was first evaluated on computed tomography, followed by cadaver dissection. The spread of the dye over the pelvis and lower limb was evaluated. RESULTS: The articular branches of the femoral nerve were stained nearly sufficiently with 20- and 30-mL specimens. The femoral nerve itself was stained simultaneously in six of 12 (50%) 20-mL specimens and 12 of 12 (100%) 30-mL specimens. The accessory obturator nerve was observed only in three (9%) of 36 specimens. The articular branches of the obturator nerve were rarely affected, regardless of injectate volume (1/12, 10 mL specimens; 2/12, 20 mL specimens; 1/12, 30 mL specimens; P > .999). Rather, the obturator nerve was affected. However, the obturator nerve was not stained consistently even with 30 mL of injectate (50%). CONCLUSIONS: After combining the dissection and radiological findings, the single-injection ultrasound-guided PENG blocks with volumes of 10, 20, and 30 mL do not support motor sparing or selective anterior hip capsule innervation in a clinical setting. If early rehabilitation is needed, high-volume PENG block might not be the ideal option, and persisting pain after PENG block might be attributed in part to the lack of obturator nerve articular branches blockade.

Effect of Previous Caudal Block to Predict Successful Outcome after Adhesiolysis using a Steerable Catheter in Lumbar Failed Back Surgery Syndrome: A Retrospective Study.

Adhesiolysis is minimally invasive and commonly used for pain associated with adhesion after lumbar spine surgery. Caudal epidural block may be used for radiating pain due to failed back surgery syndrome. We evaluated the predictive value of response to caudal block performed prior to adhesiolysis in failed back surgery syndrome. Between January 1, 2013 and June 30, 2020, 150 patients with failed back surgery syndrome were treated with adhesiolysis using a steerable catheter at the pain clinic of a tertiary hospital after failed conservative treatment (including caudal block). Patient demographics, pain duration, and lumbar magnetic resonance imaging findings were examined. Response to previous caudal block was determined as a binary result (yes or no). Patients were followed up 3 months after adhesiolysis. Successful outcome was defined as a ≥2-point reduction in the numeric rating scale scores for radicular pain 3 months after adhesiolysis, evident in 81/150 (46%) patients. Multivariable logistic regression analysis revealed that caudal block response was an independent predictor of successful adhesiolysis (odds ratio = 4.403; p = 0.015). Response to prior caudal block is a positive predictor of successful adhesiolysis.

Prognostic Factors for Successful Percutaneous Disc Decompression Using the Navigable Device L'DISQ™ in Patients with Lumbar Discogenic Pain.

BACKGROUND: The navigable percutaneous disc decompression (PDD) device L'DISQ is an effective and safe option for the treatment of lumbar discogenic pain. However, few studies have evaluated the prognostic factors of successful PDD using this device. OBJECTIVE: This study aimed to evaluate the prognostic factors associated with the successful outcome of PDD using the L'DISQ for treating lumbar discogenic pain by following up patients before and one, 2, 3, and 6 months after the procedure. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary university hospital. METHODS: A successful outcome was defined as a >= 50% reduction in the numeric rating scale scores for pain and a >= 40% reduction in the Oswestry Disability Index scores at 6 months after the procedure. Clinical parameters and patient demographics, including pain duration, history of surgery, number of treatment levels, and the radiographic findings of lumbar magnetic resonance imaging (MRI), were also examined. RESULTS: Of the 106 patients included, 80 (75.5%) had successful outcomes at 6 months. Multivariable logistic regression analysis revealed that the presence of high-intensity zones (HIZs) (P = 0.016) was an independent positive predictor of successful PDD outcomes; conversely, migration of the herniated disc (P = 0.017) and bilaterally herniated discs (P = 0.001) were negative predictors. LIMITATIONS: The limitations of this study were its retrospective design, absence of a control group, and difficulty in predicting the effect when multiple levels were involved because of the use of MRI characteristics of the disc as a predictor. CONCLUSIONS: The presence of HIZs, the absence of migration of herniated discs, and the presence of unilaterally herniated discs are positive predictors of successful outcomes of PDD using the L'DISQ.

Nepetoidin B from Salvia plebeia R. Br. Inhibits Inflammation by Modulating the NF-κB and Nrf2/HO-1 Signaling Pathways in Macrophage Cells.

Salvia plebeia has been used to treat a variety of inflammatory diseases, as well as colds and bronchitis. Macrophages have antioxidant defense mechanisms to cope with the intracellular reactive oxygen species (ROS) produced as part of the immune response. The nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase (HO)-1 pathway in inflamed macrophages is an appealing target due to its protective effect against ROS-induced cell damage. In this study, nepetoidin B (NeB) was first isolated from S. plebeia and identified by nuclear magnetic resonance spectroscopy. NeB reduced pro-inflammatory mediators (nitric oxide and prostaglandin E2) and cytokines (tumor necrosis factor-α, interleukin (IL)-6, and IL-1ß) in LPS-activated RAW 264.7 cells by inhibiting the NF-κB signaling pathway. In the NeB-treated group, catalase and superoxide dismutase levels were significantly higher, and ROS expression decreased. By activating Nrf2 signaling, NeB enhanced HO-1 expression. Furthermore, when the cells were pretreated with tin protoporphyrin (an HO-1 inhibitor), the anti-inflammatory effects of NeB were reduced. Therefore, NeB may activate the Nrf2/ HO-1 pathway. These results reveal the NeB isolated from S. plebeia exerts anti-inflammatory effects by modulating NF-κB signaling and activating the Nrf2/HO-1 pathway in LPS-stimulated RAW 264.7 cells.

Intrathecal drug delivery to treat intractable neuropathic pain following Sjögren's syndrome-induced transverse myelitis: A case report.

RATIONALE: Transverse myelitis (TM) is a spinal cord inflammatory myelopathy that causes motor/sensory loss and urinary retention below the level of the affected spinal cord. Although a few case reports have described the control of neuropathic pain in patients with TM via spinal cord stimulation, no documented case regarding the control of severe allodynia following TM via intrathecal pump has been described. PATIENT CONCERNS: A 37-year-old woman was referred to a pain clinic for severe intractable pain below the T5 level followed by Sjögren's syndrome-induced TM. DIAGNOSES: A neurological examination revealed paresthesia and allodynia below the T5 level. The sensory evaluation was limited by extreme pain and jerking movements. The muscle strength of both lower limbs was grade 3. INTERVENTIONS: Intrathecal pump was inserted into the left lower abdomen. Catheter tip was placed at the midline of the T8 level. OUTCOMES: The numeric rating scale (NRS) for pain score decreased from 10 to 5. Functional Independence Measure score increased from 67 before implantation to 92 at the time of discharge, while the patient's Barthel score increased from 31 to 46. LESSONS: Neuropathic pain due to Sjögren's syndrome-related TM could be controlled effectively using the intrathecal morphine pump.

Factors Predicting the Success of Adhesiolysis Using a Steerable Catheter in Lumbar Failed Back Surgery Syndrome: A Retrospective Study.

Failed back surgery syndrome (FBSS) is a commonly encountered disease after lumbar surgery. There are many cases where it is difficult to choose a treatment because no specific cause can be found. Nevertheless, according to recent reports, adhesiolysis has shown reasonable evidence. However, considering its poor cost-effectiveness, adhesiolysis cannot be used as the first line of treatment. FBSS patients often suffer from chronic pain; accordingly, they become frustrated when this treatment produces a poor response. Therefore, before the procedure, the target group must be selected carefully. We sought to identify the pre-procedure factors predicting the effect of adhesiolysis in FBSS. A total of 150 patients were evaluated and analyzed retrospectively. Of these 150 patients, 69 were classified as responders three months after the procedure (46%). The outer diameter of the catheter during the procedure and grade of foraminal stenosis were correlated with the procedure effect. In conclusion, of the 2.1 mm diameter of the catheter, 1.7 mm of it was used during the procedure, and the milder the foraminal stenosis, the greater the pain reduction effect was three months after the procedure.

Analysis of Subdural Injection During Lumbar Interlaminar Epidural Injection in Failed Back Surgery Syndrome.

Persistent or recurrent back and leg pain following spinal surgery, known as failed back surgery syndrome (FBSS), significantly limits daily life activities. A lumbar epidural injection can reduce adhesions, inflammation, and nerve compression, although the epidural space can be distorted due to dura mater and epidural tissues changes after spinal surgery. This study analyzed subdural injection during lumbar epidural injection in FBSS patients. We retrospectively analyzed data from 155 patients who received a lumbar interlaminar epidural injection to manage FBSS. We grouped the patients based on the injected contrast medium appearance in the subdural (group S) or epidural spaces (group E) in fluoroscopic contrast images. Demographic, clinical, surgical and fluoroscopic data were recorded and evaluated, as were the pain scores before and after injection. There were 59 patients (38.1%) in the subdural group. Injection distance from the surgery level differed between the groups. Risk of subdural injection at level 1 distance from the surgery level had an odds ratio of 0.374, and at level ≥2, it was 0.172, when compared to level 0. Subdural incidence differed with the distance from surgical site. Physicians should strive to reduce subdural incidence when the injection is planned at surgery site in FBSS.

Does central sensitization affect hyperalgesia after staged bilateral total knee arthroplasty? A randomized controlled trial.

OBJECTIVE: Osteoarthritis (OA) patients who undergo staged bilateral total knee arthroplasty (TKA) feel postoperative hyperalgesia in the second operated knee compared with the first knee. Ketamine is an important drug for central temporal summation and inhibition of secondary mechanical hyperalgesia. This study investigated whether central sensitization has a significant effect on hyperalgesia after consecutive operations. METHODS: Seventy-one of 80 OA patients were randomly allocated to the ketamine or saline group. A bolus of ketamine (group K) or saline (group C) (0.5 mg/kg) was injected before induction and at an infusion rate of 3 µg/kg/minute during surgery. A visual analog scale (VAS) was used to assess resting and moving pain and opioid consumption on postoperative days 1, 2, and 3. RESULTS: The difference in the VAS score between stages 1 and 2 (DV2-V1) was higher in the ketamine compared with the saline group. DV2-V1 for movement between the two groups was not inferior for all periods. Ketamine did not show a large analgesic effect on second-operated knee hyperalgesia in staged bilateral TKAs. CONCLUSIONS: We could not confirm that hyperalgesia was only related to central sensitization with low-dose ketamine. Other factors might be also associated with the hyperexcitability of nociceptive stimuli.Clinical Research Information Service (CRIS) trial registry no: KCT0001481.

Co-treatment With HIV Protease Inhibitor Nelfinavir Greatly Increases Late-phase Apoptosis of Drug-resistant KBV20C Cancer Cells Independently of P-Glycoprotein Inhibition.

BACKGROUND/AIM: The study focused on identifying the mechanisms or drugs that might sensitize resistant KBV20C human oral squamous carcinoma cells overexpressing P-glycoprotein (P-gp) to antimitotic drug treatment. MATERIALS AND METHODS: Five HIV protease inhibitors (atazanavir, nelfinavir, darunavir, lopinavir, and ritonavir) were tested to identify drugs that could be used at a relatively low dose for sensitizing antimitotic drug-resistant KBV20C cells. Fluorescence-activated cell sorting, annexin V analyses, and rhodamine uptake tests were performed to further investigate the mechanism of action. RESULTS: Co-treatment with nelfinavir or lopinavir had a high sensitizing effect on vincristine-treated KBV20C cells. Nelfinavir and lopinavir reduced cell viability, increased G2 phase arrest, and up-regulated apoptosis when used as a co-treatment with vincristine. We also demonstrated that eribulin co-treatment with nelfinavir and lopinavir similarly increased sensitization of KBV20C cells. Only lopinavir was found to have a high P-gp-inhibitory activity (similar to verapamil). Interestingly, nelfinavir had very low P-gp-inhibitory activity, suggesting that vincristine-nelfinavir sensitization is independent of the P-gp-inhibitory effect of nelfinavir. We also demonstrated this same combination mainly caused sensitization due to late apoptosis in P-gp-overexpressing drug-resistant KBV20C cells. CONCLUSION: Highly antimitotic drug-resistant KBV20C cells can be sensitized by co-treatment with the repositioned HIV protease inhibitors nelfinavir and lopinavir. In particular, the sensitizing effect of co-treatment with nelfinavir on antimitotic drug-resistant cancer cells was found to be strong and independent of P-gp-inhibitory activity. As P-gp inhibition can be toxic to normal cells, selecting nelfinavir may be safer for normal cells in patients with drug-resistant cancer.

Tyrosine Kinase Inhibitors Imatinib and Erlotinib Increase Apoptosis of Antimitotic Drug-resistant KBV20C Cells Without Inhibiting P-gp.

BACKGROUND/AIM: This study investigated drugs able to sensitize P-glycoprotein (P-gp)-overexpressing resistant KBV20C cancer cells to vincristine or eribulin treatment and assessed their associated mechanisms of action. MATERIALS AND METHODS: Eight tyrosine kinase inhibitors (lapatinib, gefitinib, imatinib, erlotinib, nilotinib, pazopanib, cediranib, and vandetanib) and one serine/threonine kinase inhibitor (selumetinib) were evaluated for their sensitizing effects on vincristine-resistant KBV20C cells at relatively low doses. Fluorescence-activated cell sorting, annexin V analyses, and rhodamine uptake tests were further performed to investigate their mechanisms of action. RESULTS: Co-treatment of KBV20C cells with lapatinib, gefitinib, imatinib, or erlotinib at low doses highly sensitized them to vincristine treatment. These drugs reduced cellular viability, increased G2 arrest, and up-regulated apoptosis when co-administered with vincristine. In a detailed quantitative analysis using lower doses, we demonstrated that lapatinib, with high P-gp inhibitory activity, yielded the best pairing for sensitizing P-gp-overexpressing KBV20C cells to vincristine. Co-treatment with eribulin and lapatinib, gefitinib, or erlotinib also increased the sensitivity of KBV20C cells, suggesting that they can be combined with other antimitotic drugs to sensitize resistant cancer cells. Lapatinib was shown to have a higher P-gp-inhibitory activity than verapamil, even at lower doses, indicating that its sensitizing of cells to vincristine involves its P-gp-inhibitory effects. However, interestingly, imatinib- and erlotinib-sensitizing of cells to vincristine appears to be independent of their P-gp inhibition. CONCLUSION: These findings provide valuable information regarding the sensitizing of drug-resistant cells and indicate that imatinib and erlotinib may be used in patients with potentially resistant cancer without any toxic effects from P-gp inhibition.

Histamine Receptor Antagonists, Loratadine and Azelastine, Sensitize P-gp-overexpressing Antimitotic Drug-resistant KBV20C Cells Through Different Molecular Mechanisms.

BACKGROUND/AIM: Previously, we showed that KBV20C cancer cells highly resistant to antimitotic drugs were sensitized by co-treatment with a repositioned drug fluphenazine. MATERIALS AND METHODS: Considering that fluphenazine plays a role as a histamine receptor antagonist, we investigated low doses of 21 other histamine receptor antagonists (lidocaine, cimetidine, chlorpromazine, diphenhydramine, promethazine, ranitidine, famotidine, clemastine, chlorpheniramine, desloratadine, loratadine, cyproheptadine, azelastine, brompheniramine, carbinoxamine, fexofenadine, hydroxyzine, levocetirizine, meclizine, nizatidine, and pemirolast) to identify repositioned drugs for their sensitizing effects on antimitotic drug-resistant KBV20C cells at relatively low doses. RESULTS: Co-treatment with loratadine, and with azelastine highly sensitized KBV20C cells to vincristine treatment. Loratadine and azelastine reduced cell viability, increased G2 arrest, and up-regulated apoptosis when co-administered with vincristine. In detailed quantitative analysis, combination of vincristine with loratadine had a higher sensitization effect than that with azelastine. Azelastine had a higher P-glycoprotein (P-gp)-inhibitory activity, similar to that of verapamil, indicating that sensitization by vincristine-azelastine involved the P-gp-inhibitory effects of azelastine. However, loratadine had a very low P-gp-inhibitory activity, suggesting that loratadine sensitization to vincristine is independent of the P-gp-inhibition. Co-treatment with eribulin and loratadine increased the sensitization of KBV20C cells, suggesting that loratadine can be combined with other antimitotic drugs to sensitize resistant cancer cells. CONCLUSION: These findings provide important information regarding the sensitization of drug-resistant cells and indicate that loratadine may be used in patients with potentially resistant cancer without any toxic effects from P-gp inhibition.

P-gp Inhibition by the Anti-psychotic Drug Pimozide Increases Apoptosis, as well as Expression of pRb and pH2AX in Highly Drug-resistant KBV20C Cells.

BACKGROUND/AIM: The present study was designed to identify drugs that could sensitize P-glycoprotein (P-gp)-overexpressing resistant KBV20C cancer cells to treatment with Halaven (HAL) or vincristine (VIC). MATERIALS AND METHODS: Using relatively low doses or IC50 concentrations of drugs to sensitize anti-mitotic drug-resistant KBV20C cells, pimozide (PIM) sensitized HAL-resistant KBV20C cancer cells, with higher P-gp inhibitory activity than another anti-psychotic drug, fluphenazine (FLU). RESULTS: The first-generation P-gp inhibitor verapamil required a dose that was similar to that of PIM for P-gp inhibition, suggesting that PIM has a similar specificity for binding P-gp to prevent efflux of anti-mitotic drugs. Furthermore, co-treatment with PIM and another anti-mitotic drug, VIC, also increased sensitization of KBV20C cells, suggesting that PIM can be combined with other anti-mitotic drugs to sensitize resistant cancer cells. PIM caused a reduction in cell viability and an increase in the number of cells arresting at the G2 phase of the cell cycle. PIM induced both early and late apoptosis in KBV20C cells in response to HAL treatment. Furthermore, the DNA damage marker pH2AX, the cell-cycle protein pRb, and the pro-apoptotic protein C-PARP levels increased after HAL-PIM co-treatment, indicative of a mechanism involving G2 phase arrest and an increase in the number of cells undergoing apoptosis. CONCLUSION: PIM may be a promising therapeutic agent for the treatment of cancers that are resistant to anti-mitotic drugs.

Low Doses of the Anti-psychotic Drug Aripiprazole Have Strong P-gp-inhibitory Activity and Sensitize Anti-mitotic Drug-resistant Cancer Cells.

BACKGROUND/AIM: The present study was designed to identify conditions that would increase the sensitivity of resistant cancer cells to anti-mitotic drugs. MATERIALS AND METHODS: Previously, we showed that KBV20C cancer cells highly resistant to Halaven® (HAL) were sensitized by co-treatment with fluphenazine (FLU). In this study, we found that low doses of aripiprazole (ARI), another antipsychotic drug, sensitized HAL-resistant KBV20C cancer cells. We then investigated the mechanisms and roles of ARI in the sensitization of HAL-treated KBV20C cancer cells. RESULTS: First-generation P-glycoprotein (P-gp) inhibitor verapamil required a dose that was nearly four-fold higher than that of ARI for P-gp inhibition, which suggested that ARI had a high specificity for P-gp binding to prevent efflux of anti-mitotic drugs. ARI was also found to sensitize HAL-treated KBV20C cells at a low dose, approximately 4-fold lower than that of verapamil. Co-treatment of ARI with another anti-mitotic drug, vincristine, also increased the sensitization of KBV20C cells. ARI caused a reduction in cell viability, increased G2 arrest, and up-regulated expression of the DNA damage protein, pH2AX, when co-treated with HAL. Moreover, G2 phase arrest and apoptosis in HAL-ARI co-treated cells resulted from the up-regulation of retinoblastoma protein, reduced extracellular signal-regulated kinase pathway activity, and down-regulation of cell division cyclin protein. CONCLUSION: Cancer cells that are highly resistant to HAL can be sensitized with the antipsychotic drug, ARI, which exerts specific P-gp inhibitory effects at a low dose.

Aging-related Repositioned Drugs, Donepezil and Sildenafil Citrate, Increase Apoptosis of Anti-mitotic Drug-resistant KBV20C Cells Through Different Molecular Mechanisms.

BACKGROUND/AIM: The study focused on identifying the mechanisms or drugs that could sensitize P-glycoprotein (P-gp)-overexpressing resistant KBV20C cancer cells to halaven (HAL) or vincristine (VIC) treatment. MATERIALS AND METHODS: Based on the relatively low dose or IC50 values for sensitizing anti-mitotic drug-resistant KBV20C cells, the aging-related drugs donepezil (DON) and sildenafil citrate (SID) were selected. Fluorescence-activated cell sorting (FACS), western blotting, and annexin V analyses were performed to investigate the mechanism of action of DON and SID in HAL-treated KBV20C cells. RESULTS: DON or SID reduced cell viability, increased G2 arrest, and up-regulated the expression of the DNA damaging protein pH2AX when used as co-treatment with HAL. DON and SID induced both early and late apoptosis in KBV20C cells in response to HAL treatment, without increasing autophagy. VIC-DON and VIC-SID co-treatments increased sensitization of KBV20C cells, suggesting that DON and SID can be combined with other anti-mitotic drugs for sensitizing resistant cancer cells. When the sensitization efficacies of DON and SID were compared to that of the anti-psychotic repositioned drug fluphenazine (FLU), HAL-SID or HAL-FLU co-treatments were found to have better sensitization effects than HAL-DON suggesting that HAL-SID sensitization mechanism is different from that of HAL-DON. In addition, DON was found to have higher P-gp inhibitory activity than FLU or SID. CONCLUSION: These results suggest that HAL-FLU or HAL-SID sensitization in KBV20C cells involves both cytotoxic and P-gp inhibitory effects, whereas HAL-DON sensitization may involve only P-gp inhibitory activity of DON.

P-gp Inhibition by XL019, a JAK2 Inhibitor, Increases Apoptosis of Vincristine-treated Resistant KBV20C Cells with Increased p21 and pH2AX Expression.

The present study was designed to identify conditions that could increase the sensitivity of resistant cancer cells to antimitotic drugs. We investigated whether a Janus kinase 2 (JAK2) inhibitor used in clinical trials, XL019, sensitizes antimitotic drug-resistant KBV20C cells. XL019 reduced cellular viability and increased apoptosis in vincristine-treated KBV20C cells, independently of the JAK/signal transducer and activator of transcription (STAT) pathway. Based on the ATP-binding cassette protein B1 [ABCB1, P-glycoprotein (P-gp)] inhibitory assay, we demonstrated that XL019 functions as a P-gp inhibitor in drug-resistant KBV20C cells. Considering that another JAK2 inhibitor, CEP-33779, also inhibited P-gp and sensitized drug-resistant cancer cells in a previous study, we concluded that JAK2 inhibitors can be used as P-gp inhibitors in drug-resistant cancer cells. Fluorescence-activated cell sorting, western blot, and annexin V analyses were used to further investigate the mechanism of action of XL019 in vincristine-treated KBV20C cells. XL019 induced early apoptosis of KBV20C cells in response to vincristine treatment via increased G2 phase arrest. Moreover, G2 phase arrest and apoptosis of cells co-treated with vincristine and XL019 resulted from the up-regulation of phosphorylated retinoblastoma protein (pRb), p21, and the DNA-damage protein, phosphorylated H2A histone family, member X (pH2AX). Additionally, the P-gp-inhibitory effect of XL019 was less than that of CEP-33779, and a more than 2-fold higher dose was required to sensitize vincristine-treated KBV20C cells. Furthermore, lower doses of XL019 were required to sensitize KBV20C cells to a degree similar to that obtained with the established P-gp inhibitor verapamil, suggesting that XL019 has higher specificity than verapamil. Our results showed that JAK2 inhibitors inhibited P-gp action via a direct binding mechanism, which was similar to that of verapamil. These findings indicate that JAK2 inhibitors may be promising therapeutics for the treatment of cancer that is resistant to antimitotic drugs.

Antarctic Krill Oil Diet Protects against Lipopolysaccharide-Induced Oxidative Stress, Neuroinflammation and Cognitive Impairment.

Oxidative stress and neuroinflammation are implicated in the development and pathogenesis of Alzheimer's disease (AD). Here, we investigated the anti-inflammatory and antioxidative effects of krill oil. Oil from Euphausia superba (Antarctic krill), an Antarctic marine species, is rich in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). We examined whether krill oil diet (80 mg/kg/day for one month) prevents amyloidogenesis and cognitive impairment induced by intraperitoneal lipopolysaccharide (LPS) (250 µg/kg, seven times daily) injections in AD mice model and found that krill oil treatment inhibited the LPS-induced memory loss. We also found that krill oil treatment inhibited the LPS-induced expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and decreased reactive oxygen species (ROS) and malondialdehyde levels. Krill oil also suppresses IκB degradation as well as p50 and p65 translocation into the nuclei of LPS-injected mice brain cells. In association with the inhibitory effect on neuroinflammation and oxidative stress, krill oil suppressed amyloid beta (1-42) peptide generation by the down-regulating APP and BACE1 expression in vivo. We found that eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (50 and 100 µM) dose-dependently decreased LPS-induced nitric oxide and ROS generation, and COX-2 and iNOS expression as well as nuclear factor-κB activity in cultured microglial BV-2 cells. These results suggest that krill oil ameliorated impairment via anti-inflammatory, antioxidative, and anti-amyloidogenic mechanisms.