Isoflurane, like sepsis, decreases CYP1A2 liver enzyme activity in intensive care patients: a clinical study and network model.

PURPOSE: Liver function of intensive care patients is routinely monitored by static blood pathology. For specific indications, liver specific cytochrome activity may be measured by the commercially available maximum liver function capacity (LiMAx) test via quantification of the cytochrome P450 1A2 (CYP1A2) dependent C-methacetin metabolism. Sedation with the volatile anesthetic isoflurane was suspected to abrogate the correlation of LiMAx test with global liver function. We hypothesized that isoflurane has a CYP1A2-activity and LiMAx test result decreasing effect. METHODS: In this monocentric, observational clinical study previously liver healthy intensive care patients, scheduled to be changed from propofol to isoflurane sedation, were enrolled. LiMAx testing was done before, during and after termination of isoflurane sedation. RESULTS: The mean LiMAx value decreased during isoflurane sedation. Septic patients (n = 11) exhibited lower LiMAx values compared to non-septic patients (n = 11) at all time points. LiMAx values decreased with isoflurane from 140 ± 82 to 30 ± 34 µg kg-1 h-1 in the septic group and from 253 ± 92 to 147 ± 131 µg kg-1 h-1 in the non-septic group while laboratory markers did not imply significant hepatic impairment. Lactate increased during isoflurane inhalation without clinical consequence. CONCLUSION: Sepsis and isoflurane have independently demonstrated an effect on reducing the hepatic CYP1A2-activity. A network model was constructed that could explain the mechanism through the influence of isoflurane on hypoxia inducible factor (HIF-1α) by upregulation of the hypoxia-inducible pathway and the downregulation of CYP1A2-activity via the ligand-inducible pathway. Thus, the increased anaerobic metabolism may result in lactate accumulation. The influence of isoflurane sedation on the validated correlation of global liver function with CYP1A2-activity measured by LiMAx testing needs to be investigated in more detail.

Methylated Septin9 identified patients with colorectal carcinoma and showed higher sensitivity than conventional biomarkers in detecting tumor.

INTRODUCTION: It is worth noting the limitations in sensitivity of the existing biomarkers carcinoembryonic antigen (CEA) and carbohydrate antigen (CA 19-9) in detection of colorectal cancer (CRC). In our study, we address the performance of the liquid biopsy biomarker "methylated septin 9" (mSEPT9) in the detection and disease surveillance of CRC. MATERIALS AND METHODS: The monocentric prospective survey encompassed 120 patients diagnosed with CRC who underwent planned curative resection between December 2018 and December 2020. Blood samples were collected from the participants preoperatively as well as at 7 days, 6 weeks, and 3 months postoperatively. The presence of mSEPT9, CEA, and CA 19-9 was detected using the pro Epi Colon® 2.0 CE test, Elecsys® CEA, and Elecsys® CA19-9 electrochemiluminescence immunoassay, respectively. RESULTS: In the preoperative setting, mSEPT9 demonstrated superior capability in identifying patients with CRC compared to CEA and CA 19-9, with detection rates of 57%, 32%, and 18% respectively. Combining all three biomarkers increased the overall sensitivity to 66% preoperatively. In considering UICC stage and T-status, mSEPT9 exhibited higher sensitivity across all stages in comparison with conventional tumor markers, and 65% of patients with metastases were identified postoperatively through mSEPT9. Tumor recognition after surgery was achieved with the sensitivity of 72% and specificity of 91%. CONCLUSIONS: We recommend using mSEPT9 as a non-invasive diagnostic tool for the ongoing monitoring of patients with CRC. The sensitivity and specificity exhibited by mSEPT9 in recognition of tumor after surgery, highlights its particular potential for monitoring of CRC patients.

Hemoadsorption with CytoSorb® and the early course of linezolid plasma concentration during septic shock.

Hemoadsorption with CytoSorb® becomes increasingly established in treatment of various, predominantly inflammation-associated diseases. In septic shock, results suggest improvements in hemodynamics and organ function. However, little is known about the in vivo adsorption properties for various antibiotics. We present the case of a 61-year-old female patient with known Ulrich Turner syndrome who treated supportively with CytoSorb® and with linezolid due to a Staphylococcus epidermidis bloodstream infection as part of her intensive care treatment for septic shock. After establishment of a new adsorber, 600 mg of linezolid administered over 1 h. Linezolid levels measured before adsorber inlet (cpre) and after adsorber outlet (cpost) at 0, 15, 60, 120 and 480 min after starting infusion. Out of the ten samples, only the cpre samples 60 min (3.25 mg/l) and 120 min (4.7 mg/l) showed sufficiently high linezolid levels (therapeutic range 3-9 mg/l). After 480 min, cpre decreased to 2.8 mg/l, cpost increased to 1.85 mg/l, and thus clearance decreased to 67.86 ml/min (from 200 ml/min at 60 min), with greatly reduced adsorption capacity of CytoSorb® after 8 h. A loading dose (additional 600 mg) would have been urgently needed. Linezolid therapy under hemadsorption with CytoSorb® requires a clear indication and close monitoring of levels to avoid underdosing.

Profound decrease of liver maximum function capacity test of isoflurane sedated patients: A report of three cases.

LiMAx 13C-methacetin breath test results should be interpreted with caution in patients sedated with isoflurane.

Chemical Gastroenterocolitis after Dental Root Canal Therapy with Camphorated and Mentholated Chlorophenol.

A 78-year-old man with a history of pancolitis, after the treatment of dental abscess with oral antibiotics and local application of camphorated and mentholated chlorophenol (CMCP), presented with abdominal pain of 4-day duration, as well as hair loss in the area of moustache and finger nail lifting. He was already treated with rectal application of budesonide because of pancolitis, diagnosed 6 weeks ago and interpreted as an allergic reaction to clindamycin. For further investigation, we performed gastroscopy and colonoscopy, which showed the edematous mucosa with polypus-like changes of the whole mucosa of the stomach, duodenum, first part of the jejunum, distal ileum, complete colon, and rectum. The diagnosis was complicated and was achieved in synopsis with anamnestic details, such as endodontic application of camphorated chlorophenol. The patient symptoms abated after he commenced on mesalazine therapy.

Pericarditis Caused by Enterococcus faecium with Acute Liver Failure Treated by a Multifaceted Approach including Antimicrobials and Hemoadsorption.

BACKGROUND: Sepsis and septic shock are still life-threatening diseases with a high mortality rate. We report a complex case of peritonitis with pericarditis and acute liver failure caused by septic shock. Potentially hepatotoxic antibiotic therapy levels were monitored using the liver maximum capacity (LiMAx®) test, and standard treatment was supplemented by adjunctive hemoadsorption with CytoSorb®. Case Presentation. The case features a 29-year-old woman with a history of Crohn's disease and cachexia. Peritonitis caused by Enterococcus faecium was diagnosed later due to an ileum perforation. The hematogenic spread led to pericarditis. In addition, sepsis-related acute liver failure complicated antimicrobial therapy further. The combination of standard therapy, anti-infective medication, and blood purification was associated with inflammation control, hemodynamic stabilization, and a concomitant decrease in vasopressor support. An efficient, sustained reduction in plasma bilirubin levels was achieved while maintaining liver function. CONCLUSIONS: This case shows how complex infectious diseases with an atypical infectious focus resulting in septic shock can be successfully treated. A combination of antimicrobial (tigecycline and caspofungin) and long-term adjunctive hemoadsorption therapy was administered while hepatotoxic antibiotic medication was monitored by liver function testing.

[Morbidity and Mortality of Single Incision Cholecystectomy: Results of a 3-Year Register Analysis]. / Morbidität und Letalität der Single-Incision-Cholezystektomie: eine 3-Jahres-Registeranalyse.

INTRODUCTION: Two decades ago, single-incision surgery was established as a new concept in minimally invasive surgery. Single incision cholecystectomy is the most frequently performed procedure in clinical routine. Most of the results have been based on randomised trials. Large prospective multicentre observational datasets from clinical routine do not exist. This analysis of clinical health service research is based on the SILAP study (single-incision multiport/single port laparoscopic abdominal surgery study). PATIENTS AND METHODS: The data of the register were collected in 47 hospitals in the period of 2012 to 2014. Overall morbidity and mortality were the primary outcome. Multiple linear and logistic regression analyses were performed. Statistical significance was set at p < 0.05. RESULTS: Data from 975 patients in clinical routine with single incision cholecystectomy were collected. Intraoperative complications were recorded in 3.2% of cases. Bile duct injuries were registered in 0.1% of cases. Postoperative complications were detected in 3.7% of cases. The mortality rate was 0.2%.The median operating time dropped from 60.0 to 51.5 min (p < 0.001) during the study. The use of an extra trocar was necessary in 10.3% of cases. Conversion to open surgery was performed in 0.7% of cases. Body mass index (p = 0.024), male gender (p = 0.012) and operating time (p < 0.001) had a significant effect on intraoperative complications in multivariate analysis. Classification of ASA III (p = 0.001) and modification or conversion of single incision technique (p = 0.001) were significantly associated with postoperative complications. CONCLUSION: The register analysis of the prospective multicentre data shows that single incision cholecystectomy is feasible in clinical routine even outside the selective criteria of randomised studies. The only limitation is a BMI > 30 kg/m2 which has a significant influence on the intraoperative rate of complications in mild adverse events.

MRI-Based Use of Neoadjuvant Chemoradiotherapy in Rectal Carcinoma: Surgical Quality and Histopathological Outcome of the OCUM Trial.

BACKGROUND: Preoperative magnetic resonance imaging (MRI) allows highly reliable imaging of the mesorectal fascia (mrMRF) and its relationship to the tumor. The prospective multicenter observational study OCUM uses these findings to indicate neoadjuvant chemoradiotherapy (nCRT) in rectal carcinoma. METHODS: nCRT was indicated in patients with positive mrMRF (≤ 1 mm) in cT4 and cT3 carcinomas of the lower rectal third. RESULTS: A total of 527 patients (60.2%) underwent primary total mesorectal excision, and 348 patients (39.8%) underwent long-term nCRT followed by surgery. The mrMRF was involved in 4.6% of the primary surgery group and 80.7% of the nCRT group. Rates of resections within the mesorectal plane (90.8%), sparing of pelvic nerves on both sides (97.8%), and number of regional lymph nodes (95.3% with ≥ 12 lymph nodes examined) are indicative of high-quality surgery. Resection was classified as R0 in 98.3%, the pathological circumferential resection margin (pCRM) was negative in 95.1%. Patients in the nCRT group had more advanced carcinomas with a significantly higher rate of abdominoperineal excision. Independent risk factors for pCRM positivity were advanced stage (T4), metastatic lymph nodes, resection in the muscularis propria plane, and location in the lower third. CONCLUSIONS: The risk classification of rectal cancer patients by MRI seems to be highly reliable and allows the restriction of nCRT to approximately half of the patients with clinical stage II and III rectal carcinoma, provided there is a high-quality MRI diagnostic protocol, high-quality surgery, and standardized examination of the resected specimen.

Dosing of Antimycotic Treatment in Sepsis-Induced Liver Dysfunction by Functional Liver Testing with LiMAx®.

BACKGROUND: Sepsis-treatment is one of the major challenges in our time. Especially fungal infections play an important role in patient's morbidity and mortality. In patients with septic shock, liver function is often significantly impaired and therefore also hepatic drug metabolism is altered. CASE PRESENTATION: We report about a 56-year-old man suffering from invasive fungal infection with multiorgan failure, after complicated medical history due to symptomatic infrarenal aortic aneurysm. On the first postoperative day, a CT scan was undertaken due to massive back pain showing renal infarction on both sides. As qualitative and quantitative renal function was impaired, hemodialysis was started immediately. Subsequently, the patient developed a compartment syndrome of the left leg and underwent fasciotomy. On admission day 7, the patient presented with hematochezia leading to colonoscopy. During this procedure, an ischemic colitis was observed. As conservative treatment failed, the patient underwent Hartmann's procedure due to progredient ischemia followed by a worsening of the clinical status due to sepsis. The patient suffered from an invasive fungal infection with Candida spp. and Aspergillus spp. Systemic antifungal treatment was initiated. Although azoles are considered first-line treatment in these cases we chose the echinocandin caspofungin for its presumed lower impact on liver function compared to azoles like voriconazole or Amphothericin B. However, caspofungin is also metabolised in the liver and can cause hepatotoxic effects. Therefore we measured metabolic liver function capacity using LiMAx®and adapted the patient's dose of caspofungin to the evaluated liver function capacity to achieve an effective and liver-protective level of the active drug. After complicated medical history with 15 weeks of hospital stay, the patient was discharged in general good condition. CONCLUSIONS: To our knowledge, this is the first report that relates antimycotic drug dosing to a functional liver test. We provide a new approach for sepsis treatment considering liver function capacity to optimize dosage of hepatically metabolised drugs with potential hepatotoxic effects.

Single-Incision Multiport/Single Port Laparoscopic Abdominal Surgery (SILAP): A Prospective Multicenter Observational Quality Study.

BACKGROUND: Increasing experience with minimally invasive surgery and the development of new instruments has resulted in a tendency toward reducing the number of abdominal skin incisions. Retrospective and randomized prospective studies could show the feasibility of single-incision surgery without any increased risk to the patient. However, large prospective multicenter observational datasets do not currently exist. OBJECTIVE: This prospective multicenter observational quality study will provide a relevant dataset reflecting the feasibility and safety of single-incision surgery. This study focuses on external validity, clinical relevance, and the patients' perspective. Accordingly, the single-incision multiport/single port laparoscopic abdominal surgery (SILAP) study will supplement the existing evidence, which does not currently allow evidence-based surgical decision making. METHODS: The SILAP study is an international prospective multicenter observational quality study. Mortality, morbidity, complications during surgery, complications postoperatively, patient characteristics, and technical aspects will be monitored. We expect more than 100 surgical centers to participate with 5000 patients with abdominal single-incision surgery during the study period. RESULTS: Funding was obtained in 2012. Enrollment began on January 01, 2013, and will be completed on December 31, 2018. As of January 2016, 2119 patients have been included, 106 German centers are registered, and 27 centers are very active (>5 patients per year). CONCLUSIONS: This prospective multicenter observational quality study will provide a relevant dataset reflecting the feasibility and safety of single-incision surgery. An international enlargement and recruitment of centers outside of Germany is meaningful. TRIAL REGISTRATION: German Clinical Trials Register: DRKS00004594; https://drks-neu.uniklinik-freiburg.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00004594 (Archived by WebCite at http://www.webcitation.org/6jK6ZVyUs).

Association of the GNAS1 T393C polymorphism with tumor stage and survival in gastric cancer.

AIM: To analyze the impact of the GNAS1 T393C polymorphism on prognosis and histopathology of gastric cancer. METHODS: Genomic DNA was extracted from paraffin-embedded tissues of 122 patients with primary gastric carcinoma and from the blood of 820 healthy white individuals. Allelic discrimination was performed by quantitative real-time polymerase chain reaction. Genotyping was correlated with histopathologic parameters and with overall survival according to the Kaplan-Meier approach and with multivariate analysis by multiple stepwise regression. RESULTS: Thirty-nine (32%) patients displayed a CC genotype, 57 (46.7%) a CT genotype and 26 (21.3%) a TT genotype. The frequency of the C allele (fC) in the patient group was 0.55, which was not significantly different from that of healthy blood donors. The distribution was compatible with the Hardy-Weinberg equilibrium. Analysis of clinicopathological parameters did not show any significant correlation of the T393C genotype with gender (P = 0.50), differentiation (P = 0.29), pT-category (P = 0.19), pN-category (P = 0.30), pM-category (P = 0.25), R-category (P = 0.95), the classifications according to WHO (P = 0.34), Laurén (P = 0.16), Goseki (P = 1.00) and Ming (P = 0.74). Dichotomization between C+ (CC+CT) and C-genotypes (TT), however, revealed significantly more advanced tumor stages (P = 0.023) and lower survival rates (P = 0.043) for C allele carriers. CONCLUSION: The present study provides strong evidence to suggest that the GNAS1 T393C allele carrier status influences tumor progression and survival in gastric cancer with higher tumor stages and a worse outcome for C allele carriers.

Combined analysis of hypoxia-inducible factor 1 alpha and metallothionein indicates an aggressive subtype of colorectal carcinoma.

PURPOSE: Hypoxia-inducible factor 1 (HIF-1) is a hypoxia-induced transcription factor that regulates gene expression in critical pathways involved in tumour growth and metastasis. Metallothionein (MT) is a group of small molecular weight cysteine-rich proteins with a broad variety of functions. The present study aimed to analyse the prognostic impact of HIF-1alpha and MT expression in colorectal cancer and to evaluate a possible link of combined HIF-1alpha and MT expression with colorectal cancer progression. MATERIALS AND METHODS: We investigated the relationship of HIF-1alpha and MT with each other and clinicopathological parameters including proliferative activity (Ki67) and apoptosis (terminal desoxyribonucleotide transferase-mediated dUTP nick-end labelling) using immunohistochemistry. RESULTS: HIF-1alpha expression was identified as an independent prognostic parameter in multivariate survival analysis and characterised an aggressive cancer phenotype. In addition, HIF-1alpha was significantly linked to an increased expression of MT. CONCLUSIONS: HIF-1alpha expression qualified as an independent prognostic and characterised an aggressive cancer phenotype associated with an increased expression of MT. Our study suggests that MT can be added to the complex biological pathways induced by hypoxia in human cancer tissue.

Increased etheno-DNA adducts in affected tissues of patients suffering from Crohn's disease, ulcerative colitis, and chronic pancreatitis.

Chronic inflammatory processes induce oxidative stress and lipid peroxidation (LPO), hereby generating DNA-reactive aldehydes such as trans-4-hydroxy-2-nonenal (HNE). Etheno-modified DNA bases are inter alia generated by reaction of DNA with HNE. Using an immunoaffinity-(32)P-postlabeling method, the authors have investigated etheno-DNA adduct levels 1,N (6)-ethenodeoxyadenosine (epsilondA) and of 3,N (4)-ethenodeoxycytidine (epsilondC) in the pancreas of chronic pancreatitis patients and in the colon of patients with inflammatory bowel disease. Both epsilondA and epsilondC levels were found to be significantly, 3 and 28 times, respectively, elevated in the inflamed pancreatic tissue. In contrast, only epsilondC was found to be increased in affected colonic mucosa of Crohn's disease (19 times) and of ulcerative colitis patients (4 times) when compared to asymptomatic tissues. In all three cancer-prone diseases, the mean epsilondC-levels in tissues were five- to ninefold higher than those of epsilondA. Differential or impaired DNA repair pathways of these adducts, known to occur by two different glycosylases are implicated. K-ras in pancreatic tumors and K-ras and p53 in colon mucosa in long-standing inflammatory bowel disease are known to be highly mutated. The conclusion is that promutagenic etheno-DNA adducts are generated as a consequence of chronic inflammation, acting as a driving force to malignancy in cancer-prone inflammatory diseases.

Non-invasive detection of colorectal tumours by the combined application of molecular diagnosis and the faecal occult blood test.

The treatment of early-stage tumours decreases the overall mortality of colorectal tumour patients. In this retrospective study we determined the sensitivity and the specificity of the faecal occult blood test (FOBT) and the molecular diagnosis (MD). We analysed 57 stool samples from patients with colorectal carcinomas for the presence of occult blood using a standard FOBT and for alterations in the three different tumour relevant markers APC, BAT26 and L-DNA. Stool samples from 44 control donors were analysed to determine the specificity of the applied methods. Twenty-nine (51%; 95% confidence interval (CI): 38-63%) stool samples of the cancer patients gave positive FOBT results. Thirty-seven (65%; CI: 52-76%) samples showed alterations in at least one DNA marker. Sixteen (28%) samples were positive only in the FOBT, and 24 (42%) samples showed a positive result exclusively in MD. The combined application of both methods resulted in a sensitivity of 93% (CI: 83-97%) and an overall specificity of 89% (CI: 76-95%). The combined application of FOBT and MD resulted in an overall sensitivity, which could not be achieved by any of the methods alone and which is in the range of invasive diagnostic methods.

GNAS1 T393C polymorphism and survival in patients with sporadic colorectal cancer.

PURPOSE: Signaling via the G protein Galpha s pathway is linked to proapoptotic processes in cancer cell lines. We have recently shown an association between the GNAS1 T393C polymorphism and disease progression in patients with bladder cancer with homozygous TT genotypes displaying increased transcription of Galpha s and a more favorable clinical course compared with C-allele carriers. EXPERIMENTAL DESIGN: In the present study, 151 patients with sporadic colorectal cancer were retrospectively genotyped to examine a potential association between T393C genotypes and survival. Moreover, two other single-nucleotide polymorphisms in common haplotype blocks within the gene GNAS1 and their interaction with the T393C polymorphism were investigated. RESULTS: The allele frequency in the patients group was not significantly different from that of healthy blood donors. Kaplan-Meier curves for overall survival (mean follow-up, 43 months) showed that in International Union Against Cancer (UICC) stages I to II, the 5-year survival rate was significantly higher in TT genotypes (87.8%) compared with TC (71.0%) and CC genotypes (50.0%; P = 0.009), whereas no genotype effect could be observed for UICC stages III to IV. In multivariate Cox proportional analysis the T393C polymorphism was an independent prognostic factor for survival. Homozygous CC patients were at highest risk for death (hazard ratio, 12.1; P = 0.006) compared with TT genotypes. Heterozygous patients had an intermediate risk compatible with a gene-dose effect. The two haplotype blocks investigated were not associated with clinical outcome. CONCLUSIONS: The results support the role of the T393C polymorphism as a marker for survival in patients with colorectal cancer stages I to II and in the identification of patients who may benefit from adjuvant chemotherapy.

sTNF-RII: is it useful for the early diagnosis of rejection and for prognosis after renal transplantation?

Changes in soluble tumour necrosis factor receptor II (sTNF-RII) correlate with transplant rejection, and it increases in the course of sepsis. These changes might help to identify rejection early, and thus lead to more effective treatment. Serum and urine sTNF-RII levels were measured in 70 patients during the first 3 weeks after kidney transplantation and correlated with clinical and laboratory findings. Retrospectively, three groups were identified: I. stable transplant function ( n=23), II. at least one rejection episode ( n=38) and III. other complications (infection or reperfusion injury) ( n=9). The pre-operative maximum for serum sTNF-RII was 22.4 +/- 10.7 ng/ml. In group I it decreased to 9.5 +/- 6.7 ng/ml on day 6 after transplantation ( P<0.01), while in group II sTNF-RII serum levels were significantly higher on day 6 (24.9 +/- 15.0 ng/ml, P<0.01). High levels of sTNF-RII in serum (>40 ng/ml for at least 2 days) predicted a higher risk of an unfavourable outcome. High serum levels of sTNF-RII are not specific but seem to be a prognostic indicator of a complicated course; sTNF-RII in urine has no diagnostic value.

Early identification of peritonitis by peritoneal cytokine measurement.

PURPOSE: The assessment of plasma cytokine levels adds a useful tool to the diagnostic measures in severe inflammatory diseases. Proinflammatory cytokine levels in abdominal fluid after abdominal surgery have been shown to far exceed plasma cytokine levels. Thus, we investigated the local release of interleukin 1beta, interleukin 6, and tumor necrosis factor-alpha in patients after colorectal surgery during the early postoperative period to evaluate whether it may serve as an indicator of evolving peritonitis. METHOD: In a prospective, observational pilot study, the first 12 consecutive patients who did not develop any postoperative complications (Group I), and the first 12 patients with secondary peritonitis caused by an anastomotic leakage (Group II), were included in the study. Interleukin 6, interleukin 1beta, and tumor necrosis factor-alpha levels were determined in the abdominal exudate and compared between the groups within the first four days after colorectal surgery. RESULTS: Abdominal fluid interleukin 6 levels in Group II patients were higher (162,500 +/- 105,800 pg/ml) as early as the first postoperative day compared with Group I (27,940 +/- 13,860 pg/ml; P < 0.0001); this lasted for the whole observation period. The same applies to tumor necrosis factor-alpha levels (461.4 +/- 167.8 pg/ml vs. 175.8 +/- 178.6 pg/ml on day 1; P = 0.0007). The difference in interleukin 1beta cytokine levels became statistically significant on the third postoperative day. Moreover, abdominal fluid cytokine levels rose in Group II, whereas they remained virtually unchanged or even tended to decrease over time in Group I. CONCLUSION: We suggest that the estimation of the peritoneal cytokine levels might be an additional diagnostic tool that can support the early recognition of peritonitic complications in colorectal surgery.

The new sulindac derivative IND 12 reverses Ras-induced cell transformation.

The nonsteroidal anti-inflammatory drug Sulindac has chemopreventive and antitumorigenic properties. Its metabolites induce apoptosis and inhibit signaling pathways critical for malignant transformation, including the Ras pathway. Here we show that the new Sulindac derivative IND 12 reverses the phenotype of Ras-transformed MDCK-f3 cells and restores an untransformed epithelioid morphology characterized by growth in monolayers with regular cell-cell adhesions. Moreover, IND 12 treatment induces the expression at membranes of the cell adhesion protein E-cadherin and increases the level of the E-cadherin-bound beta-catenin. As a consequence, IND 12-treated MDCK-f3 cells lose their invasion capacity and regain the ability to aggregate. In the presence of IND 12, MDCK-f3 cells show regenerated expression and activity ratios of the small GTPases Rac and Rho normally found in untransformed MDCK cells. Strikingly, IND 12 treatment decreases the levels of phosphorylated mitogen-activated protein kinases, which are downstream substrates of the Ras-regulated Raf/mitogen-activated protein kinase pathway, and the level of Ras-induced activation of gene expression. Our findings identify a novel drug with high potential in cancer therapy by targeting Ras-induced cell transformation.

New indene-derivatives with anti-proliferative properties.

Metabolites of the non-steroidal anti-inflammatory drug Sulindac inhibit cell proliferation by affecting several intracellular signaling pathways including the tumorigenic Ras/Raf/MAPK pathway. Here, we report the synthesis of eight new indene derivatives derived from the Sulindac structure, and present data on their anti-proliferative properties and their effects on the p21ras protein.