Metastatic Superscan in 18F PSMA PET/CT of a Patient with Prostate Carcinoma.

A biopsy-proven patient with prostate carcinoma aged 70 years was referred to the department of nuclear medicine for radionuclide-based therapy. His prostate-specific antigen levels were >1000 ng/mL, and prostatic magnetic resonance imaging showed an enlarged prostate with a heterogeneous signal and size 3.8x3.7x3.5 cm with few small heterogeneous nodular signals in the transition zone. He was scheduled for 18F prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) scan before therapy. 18F PSMA PET/CT revealed PSMA-expressing prostate lesions (maximum standardized uptake value ~10.2) with extension into the urinary bladder along with bilateral supraclavicular, mediastinal, retrocrural, retroperitoneal, and pelvic lymph nodes and sclerotic lesions in the entire axial and appendicular skeleton.

Endobronchial Squamous Cell Carcinoma Presenting as Long Continuous Bronchial Thickening on 18Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography.

A 67-year-old man is presented with complaints of chest pain and productive cough for 1½ years. Chest X-ray was suggestive of right upper lobe Koch's lesion. Sputum was positive for mycobacterium tuberculosis. His symptoms got relieved partially by antitubercular treatment but the patient had an aggravation of symptoms for which he was evaluated. Computed tomography (CT) thorax revealed an endobronchial lesion in the right upper lobe bronchus. Bronchoscopy showed a mass in the right main bronchus and biopsy was suggestive of moderately differentiated squamous cell carcinoma (SCC). 18Fluoro-deoxy-glucose positron emission tomography/CT was performed for staging. There would have been chances of coexisting tuberculosis with SCC.

Synthesis and Antitumor Activity of Brominated-Ormeloxifene (Br-ORM) against Cervical Cancer.

Aberrant regulation of ß-catenin signaling is strongly linked with cancer proliferation, invasion, migration, and metastasis, thus, small molecules that can inhibit this pathway might have great clinical significance. Our molecular modeling studies suggest that ormeloxifene (ORM), a triphenylethylene molecule that docks with ß-catenin, and its brominated analogue (Br-ORM) bind more effectively with relatively less energy (-7.6 kcal/mol) to the active site of ß-catenin as compared to parent ORM. Herein, we report the synthesis and characterization of a Br-ORM by NMR and FTIR, as well as its anticancer activity in cervical cancer models. Br-ORM treatment effectively inhibited tumorigenic features (cell proliferation and colony-forming ability, etc.) and induced apoptotic death, as evident by pronounced PARP cleavage. Furthermore, Br-ORM treatment caused cell cycle arrest at the G1-S phase. Mechanistic investigation revealed that Br-ORM targets the key proteins involved in promoting epithelial-mesenchymal transition (EMT), as demonstrated by upregulation of E-cadherin and repression of N-cadherin, Vimentin, Snail, MMP-2, and MMP-9 expression. Br-ORM also represses the expression and nuclear subcellular localization of ß-catenin. Consequently, Br-ORM treatment effectively inhibited tumor growth in an orthotopic cervical cancer xenograft mouse model along with EMT associated changes as compared to vehicle control-treated mice. Altogether, experimental findings suggest that Br-ORM is a novel, promising ß-catenin inhibitor and therefore can be harnessed as a potent anticancer small molecule for cervical cancer treatment.

A Rare Case of Thyroid Cartilage Metastases Detected on 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography.

The thyroid cartilage metastatic involvement is an extremely rare entity. It can be asymptomatic at the earlier stage and can become symptomatic later on. Involvement of thyroid cartilage is frequent in melanoma and renal and rarely reported in an advanced stage of carcinoma prostate, breast, and lung. These cases were usually reported on positron emission tomography/computed tomography (PET/CT) as can often easily be missed on computed tomography scan alone. We present a case report of metastatic involvement of thyroid cartilage in squamous cell carcinoma of buccal mucosa detected on the whole-body 18F-fluorodeoxyglucose PET/CT.

Intracranial Dural Arteriovenous Fistulas with Cortical Venous Drainage: Radiosurgery as an Effective Alternative Treatment.

OBJECTIVE: To evaluate the clinical and radiological outcome of Gamma Knife radiosurgery (GKS) in treatment of intracranial dural arteriovenous fistula (DAVF) with cortical venous drainage (CVD) and compare it with the outcome of endovascular therapy. METHODS: Patients who underwent GKS or endovascular therapy for intracranial DAVF with CVD over 10 years (January 2007 to December 2016) at the All India Institute of Medical Sciences, New Delhi, were included. Demographics, clinical presentation, imaging details, and follow-up clinical status were reviewed retrospectively. Clinical follow-up was conducted once every 6 months. Radiological follow-up using digital subtraction angiography was performed at a mean 24 months after intervention. Patients with clinical follow-up of <1 year were excluded from the study. RESULTS: The study included 35 patients (26 in embolization group and 9 in GKS group) who had intracranial DAVF with CVD were included in the study. Clinical improvement was seen in 77.78% of the patients who received GKS and 57.7% of the patients who underwent embolization (P = 0.431). Complete obliteration of DAVF was seen in 55.56% of the patients in the GKS group and 57.7% of the patients in the embolization group (P = 1). GKS was at least as effective as embolization in terms of clinical and radiological outcome in treatment of intracranial DAVF with CVD. CONCLUSIONS: Contrary to popular perception, GKS should be considered as an effective first-line treatment alternative of intracranial DAVF with CVD.

Surface-Induced in Situ Sonothermodynamically Controlled Functionalized Graphene Oxide for in Vitro Cytotoxicity and Antioxidant Evaluations.

Graphene oxide-based advanced functional materials offer an ultimate solution for wider biomedical applications. In situ thermodynamically ultrasound-assisted direct covalent functionalization of graphene oxide (GO) with sulfanilamide (SA) has synthesized f-(SA)GO. Raman spectroscopy, X-ray diffraction, high-resolution transmission electron microscopy, selected area electron diffraction pattern, scanning electron microscopy, atomic force microscopy, Fourier transform infrared spectroscopy, ultraviolet-visible spectroscopy, thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC) have analyzed the f-(SA)GO structure for functional activities, expressed through synergistic impact of heteroatomic domains (SIHAD). The TGA of GO and f-(SA)GO demonstrates their total weight losses of 82.0 and 61.1%, respectively. Enhanced thermal stability of f-(SA)GO infers an exothermic behavior obtained with DSC. The surface-induced in situ thermodynamically controlled nonspontaneous reaction for f-(SA)GO has facilitated calculations for activation energy (E a) = - 2.65 × 103 kJ mol-1 and Gibbs free energy (ΔG) = 8.3741 kJ mol-1, energetics for biological activities with sulforhodamine B assay on MCF-7 and Vero cell lines and antioxidant potential by free radical scavenging activity with DPPH (2,2-diphenyl-1-picrylhydrazyl). Cell viabilities are >89.8% for Vero and >90.1% for MCF-7 with f-(SA)GO over 10 to 80 µg mL-1. Its cytocompatibility infers establishment of a new material. The morphological effect on MCF-7 and Vero cell lines confirm its structurally stable biocompatibility. The SIHAD of f-(SA)GO scavenges radical activity, and its heteroatomic structure causes valuable physiochemical activities. f-(SA)GO could emerge as an advanced functional biomaterial for structurally and thermally stable biocompatible nanocoatings.

Ormeloxifene nanotherapy for cervical cancer treatment.

BACKGROUND: Cervical cancer (CxCa) ranks as the fourth most prevalent women-related cancer worldwide. Therefore, there is a crucial need to develop newer treatment modalities. Ormeloxifene (ORM) is a non-steroidal, selective estrogen receptor modulator (SERM) that is used as an oral contraceptive in humans. Recent investigations suggest that ORM exhibits potent anti-cancer activity against various types of cancers. Nanoparticulates offer targeted delivery of anti-cancer drugs with minimal toxicity and promise newer approaches for cancer diagnosis and treatment. Therefore, the nanotherapy approach is superior compared to traditional chemotherapy, which is not site-specific and is often associated with various side effects. METHODS: Pursuing this novel nanotherapy approach, our lab has recently developed ORM-loaded poly [lactic-co-glycolic acid] (PLGA), an FDA-approved biodegradable polymer, nanoparticles to achieve targeted drug delivery and improved bioavailability. Our optimized PLGA-ORM nanoformulation showed improved internalization in both dose- and energy-dependent manners, through endocytosis-mediated pathways in both Caski and SiHa cell lines. Additionally, we employed MTS and colony forming assays to determine the short- and long-term effects of PLGA-ORM on these cells. RESULTS: Our results showed that this formulation demonstrated improved inhibition of cellular proliferation and clonogenic potential compared to free ORM. Furthermore, the PLGA-ORM nanoformulation exhibited superior anti-tumor activities in an orthotopic cervical cancer mouse model than free ORM. CONCLUSION: Collectively, our findings suggest that our novel nanoformulation has great potential for repurposing the drug and becoming a novel modality for CxCa management.

A triphenylethylene nonsteroidal SERM attenuates cervical cancer growth.

Selective estrogen receptor modulator drug molecules of triphenylethylene family have gained considerable attention as anti-cancer agents. Despite recent advances in screening and development of HPV vaccines, cervical cancer remains one of the deadliest malignancies as advanced stage metastatic disease is mostly untreatable, thus warrants newer therapeutic strategies. Ormeloxifene (ORM) is a well-known SERM of triphenylethylene family that has been approved for human use, thus represents an ideal molecule for repurposing. In this study, we for the first time have demonstrated the anti-cancerous properties of ormeloxifene in cervical cancer. Ormeloxifene efficiently attenuated tumorigenic and metastatic properties of cervical cancer cells via arresting cell cycle at G1-S transition, inducing apoptosis, decreasing PI3K and Akt phosphorylation, mitochondrial membrane potential, and modulating G1-S transition related proteins (p21, cyclin E and Cdk2). Moreover, ORM repressed the expression of HPV E6/ E7 oncoproteins and restored the expression of their downstream target tumor suppressor proteins (p53, Rb and PTPN 13). As a result, ormeloxifene induces radio-sensitization in cervical cancer cells and caused potent tumor growth inhibition in orthotopic mouse model. Taken together, ormeloxifene represents an alternative therapeutic modality for cervical cancer which may have rapid clinical translation as it is already proven safe for human use.

Toxicity evaluation of magnetic iron oxide nanoparticles reveals neuronal loss in chicken embryo.

Magnetic iron oxide nanoparticles (IONs) display the ability to cross blood - brain barrier and are envisioned as diagnostic and therapeutic applications, but there are few studies on their potential embryonic toxicity in higher vertebrates. This study investigates interaction of IONs with egg albumen and its subsequent toxicity on chicken embryo. Physicochemical interactions of IONs with egg albumen revealed alterations in friccohesity and secondary structural changes due to weak Vander Waals forces. Toxicity assessment of IONs (10, 25, 50, 100, and 200 µg/ml doses) on chicken embryo accounted for 100% mortality at 200 µg/ml dose due to Fe2+ ions overload. However, lower doses (50 and 100 µg/ml) recorded decrement in whole weights and crown-rump lengths of chicken embryo possibly due to ION-albumen interactions. Histology of brain tissue revealed degeneration of neurons (50-60%) at 10-100 µg/ml dose range of IONs. Toxicity studies of IONs with diverse animal models are needed to set a toxicity benchmark for preventing embryonic toxicity prior to its use in biomedical applications. This is the first study on toxicity assessment of IONs in chicken embryo.

Prevalence & factors associated with depression among schoolgoing adolescents in Chandigarh, north India.

BACKGROUND & OBJECTIVES: Depression among adolescents is a rising problem globally. There is a need to understand the factors associated with depression among adolescents. This study was conducted to ascertain the prevalence of depressive disorders and associated factors among schoolgoing adolescents in government and private schools in Chandigarh, India. METHODS: A cross-sectional study was conducted among 542 randomly selected schoolgoing adolescents (13-18 yr), from eight schools by multistage sampling technique. Depression was assessed using Patient Health Questionnaire-9 (PHQ-9) and associated factors by pretested semistructured interview schedule. Multivariate analysis was done to identify significant associated factors. RESULTS: Two-fifth (40%) of adolescents had depressive disorders, 7.6 per cent major depressive disorders and 32.5 per cent other depressive disorders. In terms of severity, 29.7 per cent had mild depression, 15.5 per cent had moderate depression, 3.7 per cent had moderately severe depression and 1.1 per cent had severe depression. Significant associated factors included being in a government school, studying in class Xth and XIIth, rural locality, physical abuse by family members, alcohol use and smoking by father, lack of supportive environment in school, spending less time in studies, lower level of participation in cultural activities and having a boy/girlfriend. Significant predictors on binary logistic regression analysis were being in class Xth [odds ratio (OR)=5.3] and lack of self-satisfaction with own academic performance (OR=5.1). INTERPRETATION & CONCLUSIONS: Our study showed that a significant proportion of schoolgoing adolescents suffered from depression. The presence of depression was associated with a large number of modifiable risk factors. There is a need to modify the home as well as school environment to reduce the risk of depression.

Dispersion enhancing effect of sonochemically functionalized graphene oxide for catalysing antioxidant efficacy of curcumin.

The non-hazardous sonochemical approach has been developed for the functionalization of graphene oxide (GrO) with 5-Aminoindazole (5-AIND). The formation of f-(5-AIND) GrO is confirmed with 13C solid state NMR, HRXPS, XRD, Raman, TGA, DSC, FTIR etc. The >80% cell viabilities on MCF-7 and Vero cell lines have confirmed the high cytocompatibility of f-(5-AIND) GrO. Additionally, the morphological impact on Vero cell line has evidently confirmed the biocompatibility of f-(5-AIND) GrO. As compared to GrO, the f-(5-AIND) GrO has demonstrated an enhanced antioxidant efficacy of 69.4-72%, evaluated with 2, 2-diphenyl-1-picrylhydrazyl (DPPH) free radical assay. With a similar objective (0.01-0.05)mL peanut oil based curcumin micro and nanoemulsions have been prepared using ethanol and glycerol as co-solvent and co-surfactant respectively. The prepared emulsions are subsequently characterised with respect to morphological and physicochemical parameters via density, surface tension, viscosity, friccohesity measurement and DLS analysis. Henceforth, with an expectation to achieve higher dispersion, an ethanolic dispersion of f-(5-AIND) GrO has been mixed with curcumin carrying emulsions in 1:1. Notably, the radical scavenging activities (RSA) of the combined formulations are significantly enhanced to an extent of 26.6%.

Ormeloxifene Suppresses Prostate Tumor Growth and Metastatic Phenotypes via Inhibition of Oncogenic ß-catenin Signaling and EMT Progression.

Ormeloxifene is a clinically approved selective estrogen receptor modulator, which has also shown excellent anticancer activity, thus it can be an ideal repurposing pharmacophore. Herein, we report therapeutic effects of ormeloxifene on prostate cancer and elucidate a novel molecular mechanism of its anticancer activity. Ormeloxifene treatment inhibited epithelial-to-mesenchymal transition (EMT) process as evident by repression of N-cadherin, Slug, Snail, vimentin, MMPs (MMP2 and MMP3), ß-catenin/TCF-4 transcriptional activity, and induced the expression of pGSK3ß. In molecular docking analysis, ormeloxifene showed proficient docking with ß-catenin and GSK3ß. In addition, ormeloxifene induced apoptosis, inhibited growth and metastatic potential of prostate cancer cells and arrested cell cycle in G0-G1 phase via modulation of cell-cycle regulatory proteins (inhibition of Mcl-1, cyclin D1, and CDK4 and induction of p21 and p27). In functional assays, ormeloxifene remarkably reduced tumorigenic, migratory, and invasive potential of prostate cancer cells. In addition, ormeloxifene treatment significantly (P < 0.01) regressed the prostate tumor growth in the xenograft mouse model while administered through intraperitoneal route (250 µg/mouse, three times a week). These molecular effects of ormeloxifene were also observed in excised tumor tissues as shown by immunohistochemistry analysis. Our results, for the first time, demonstrate repurposing potential of ormeloxifene as an anticancer drug for the treatment of advanced stage metastatic prostate cancer through a novel molecular mechanism involving ß-catenin and EMT pathway. Mol Cancer Ther; 16(10); 2267-80. ©2017 AACR.

In situ sonochemical reduction and direct functionalization of graphene oxide: A robust approach with thermal and biomedical applications.

The rapid, robust, scalable and non-hazardous sonochemical approach for in situ reduction and direct functionalization of graphene oxide has been developed for non-toxic biomedical applications. The graphene oxide (GrO) was directly functionalized with tryptamine (TA) without using any hazardous acylating and coupling reagents. The reaction was completed within 20min. An impact of ultrasound was inferred for a direct functionalization with other conventional methods. The evolved electronic states were confirmed with near edge X-ray absorption fine structure (NEXAFS). The direct covalent functionalization and formation of f-(TA) GrO was proven with FTIR, 13C solid state NMR, XPS, XRD, Raman' HRTEM, AFM and TGA. The total percentage weight loss in TGA confirms an enhanced thermal stability of f-(TA) GrO. The f-(TA) GrO was further explored for an investigation of in vitro antimicrobial activity to ensure the health and environmental safety. An outstanding antibacterial activity of f-(TA) GrO was found against gram positive Staphylococcus aureus at MIC 128mgmL-1. It confirms a suitability of f-(TA) GrO for thermally stable antibacterial coating. The f-(TA) GrO showed 39.14-48.9% antioxidant activities, evaluated with 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical assay. The inherent cytotoxicity of f-(TA) GrO was evaluated with SRB assay to living cells, MCF-7 and Vero. The estimated cell viabilities were >80% upon addition of f-(TA) GrO over a wide concentration range of 10-80µgmL-1. The high cytocompatibility of f-(TA) GrO confirms the low toxicity and an excellent biocompatibility. The morphological effect on Vero cell line, evidently confirmed the biocompatibility of f-(TA) GrO. Therefore, f-(TA) GrO was emerged as an advanced functional biomaterial for thermal and biomedical applications.

Ultrasound assisted simultaneous reduction and direct functionalization of graphene oxide with thermal and cytotoxicity profile.

The new sonochemical approach for simultaneous reduction and direct functionalization of graphene oxide (GrO) has been developed. The GrO was functionalized with 2-Aminobenzoxazole (2-ABOZ) in twenty min with complete deletion of hazardous steps. The significance of ultrasound was exemplified with the comparative conventional methods. The newly prepared f-(2-ABOZ)GrO was extensively characterized with near edge X-ray absorption fine structure (NEXAFS) spectroscopy, 13C solid state NMR, XPS, XRD, HRTEM, SAED, AFM, Raman, UV-vis, FTIR and TGA. The thermal stability of f-(2-ABOZ)GrO was confirmed with total percentage weight loss in TGA. The biological activity of f-(2-ABOZ)GrO was explored with MCF-7 and Vero cell lines. The inherent cytotoxicity was evaluated with SRB assay at 10, 20, 40 and 80µgmL-1. The estimated cell viabilities were >78% with f-(2-ABOZ) GrO. A high cytocompatibility of f-(2-ABOZ)GrO was ensured with in vitro evaluation on living cell lines, and low toxicity of f-(2-ABOZ)GrO was confirmed its excellent biocompatibility. The morphological effect on Vero cell line evidently supports the formation of biocompatible f-(2-ABOZ)GrO. Therefore, f-(2-ABOZ)GrO was emerged as an advanced functional material for thermally stable biocompatible coatings.

Biological Impact of Pd (II) Complexes: Synthesis, Spectral Characterization, In Vitro Anticancer, CT-DNA Binding, and Antioxidant Activities.

A new series of Pd (II) complexes of methyl substituted benzylamine ligands (BLs) has been synthesized and characterized via spectroscopic techniques such as UV/Vis. FTIR, LCMS, (1)H, and (13)C NMR. The UV/Vis study in DMSO, DMSO + water, and DMSO + PBS buffer (pH = 7.2) confirmed their molecular sustainability in liquids. Their in vitro anticancer activity against breast cancer cell lines such as MCF-7 and MDA-MB-231 makes them interesting for in vivo analysis. Their stronger DNA binding activity (DBA) compared with free ligand suggested them as a good DNA binder. DBA was further confirmed by physicochemical studies such as surface tension and viscosity of complex + DNA which inferred the disruption of DNA and intercalation of complexes, respectively. Their % binding activity, % disruption of DNA base pairs (DNABP), and % intercalating strength are reported in this paper for the first time for better understanding of DNA binding mechanism. Along with this, their scavenging activity (SA) determined through DPPH free radical and the results indicate good antioxidant behaviour of complexes.

Nanoparticle formulation of ormeloxifene for pancreatic cancer.

Pancreatic cancer is the fourth most prevalent cancer with about an 85% mortality rate; thus, an utmost need exists to discover new therapeutic modalities that would enhance therapy outcomes of this disease with minimal or no side effects. Ormeloxifene (ORM), a synthetic molecule, has exhibited potent anti-cancer effects through inhibition of important oncogenic and proliferation signaling pathways. However, the anti-cancer efficacy of ORM can be further improved by developing its nanoformulation, which will also offer tumor specific targeted delivery. Therefore, we have developed a novel ORM encapsulated poly(lactic-co-glycolic acid) nanoparticle (NP) formulation (PLGA-ORM NP). This formulation was characterized for particle size, chemical composition, and drug loading efficiency, using various physico-chemical methods (TEM, FT-IR, DSC, TGA, and HPLC). Because of its facile composition, this novel formulation is compatible with antibody/aptamer conjugation to achieve tumor specific targeting. The particle size analysis of this PLGA-ORM formulation (∼100 nm) indicates that this formulation can preferentially reach and accumulate in tumors by the Enhanced Permeability and Retention (EPR) effect. Cellular uptake and internalization studies demonstrate that PLGA-ORM NPs escape lysosomal degradation, providing efficient endosomal release to cytosol. PLGA-ORM NPs showed remarkable anti-cancer potential in various pancreatic cancer cells (HPAF-II, AsPC-1, BxPC-3, Panc-1, and MiaPaca) and a BxPC-3 xenograft mice model resulting in increased animal survival. PLGA-ORM NPs suppressed pancreatic tumor growth via suppression of Akt phosphorylation and expression of MUC1, HER2, PCNA, CK19 and CD31. This study suggests that the PLGA-ORM formulation is highly efficient for the inhibition of pancreatic tumor growth and thus can be valuable for the treatment of pancreatic cancer in the future.

Ormeloxifene suppresses desmoplasia and enhances sensitivity of gemcitabine in pancreatic cancer.

The management of pancreatic ductal adenocarcinoma (PDAC) is extremely poor due to lack of an efficient therapy and development of chemoresistance to the current standard therapy, gemcitabine. Recent studies implicate the intimate reciprocal interactions between epithelia and underlying stroma due to paracrine Sonic hedgehog (SHH) signaling in producing desmoplasia and chemoresistance in PDAC. Herein, we report for the first time that a nonsteroidal drug, ormeloxifene, has potent anticancer properties and depletes tumor-associated stromal tissue by inhibiting the SHH signaling pathway in PDAC. We found that ormeloxifene inhibited cell proliferation and induced death in PDAC cells, which provoked us to investigate the combinatorial effects of ormeloxifene with gemcitabine at the molecular level. Ormeloxifene caused potent inhibition of the SHH signaling pathway via downregulation of SHH and its related important downstream targets such as Gli-1, SMO, PTCH1/2, NF-κB, p-AKT, and cyclin D1. Ormeloxifene potentiated the antitumorigenic effect of gemcitabine by 75% in PDAC xenograft mice. Furthermore, ormeloxifene depleted tumor-associated stroma in xenograft tumor tissues by inhibiting the SHH cellular signaling pathway and mouse/human collagen I expression. Xenograft tumors treated with ormeloxifene in combination with gemcitabine restored the tumor-suppressor miR-132 and inhibited stromal cell infiltration into the tumor tissues. In addition, invasiveness of tumor cells cocultivated with TGFß-stimulated human pancreatic stromal cells was effectively inhibited by ormeloxifene treatment alone or in combination with gemcitabine. We propose that ormeloxifene has high therapeutic index and in a combination therapy with gemcitabine, it possesses great promise as a treatment of choice for PDAC/pancreatic cancer.

Ormeloxifene efficiently inhibits ovarian cancer growth.

Ovarian cancer continues to be a leading cause of cancer related deaths for women. Anticancer agents effective against chemo-resistant cells are greatly needed for ovarian cancer treatment. Repurposing drugs currently in human use is an attractive strategy for developing novel cancer treatments with expedited translation into clinical trials. Therefore, we examined whether ormeloxifene (ORM), a non-steroidal Selective Estrogen Receptor Modulator (SERM) currently used for contraception, is therapeutically effective at inhibiting ovarian cancer growth. We report that ORM treatment inhibits cell growth and induces apoptosis in ovarian cancer cell lines, including cell lines resistant to cisplatin. Furthermore, ORM treatment decreases Akt phosphorylation, increases p53 phosphorylation, and modulates the expression and localization patterns of p27, cyclin E, cyclin D1, and CDK2. In a pre-clinical xenograft mouse ORM treatment significantly reduces tumorigenesis and metastasis. These results indicate that ORM effectively inhibits the growth of cisplatin resistant ovarian cancer cells. ORM is currently in human use and has an established record of patient safety. Our encouraging in vitro and pre-clinical in vivo findings indicate that ORM is a promising candidate for the treatment of ovarian cancer.

Assessment of raloxifene, estradiol-17ß, dl-ormeloxifene and levormeloxifene on thrombin activity.

Abstract Background: Cancer is one of the leading causes of morbidity and mortality globally. Cancer-associated thrombosis is well established in clinical settings, and thrombin has been found to induce angiogenesis at cancer sites. This establishes a link between cardiovascular diseases and cancer, where cancer and thrombin have been intricately associated. Various selective estrogen receptor modulators (SERMs) have been reported to exhibit anticancer activity. Therefore, we investigated estradiol-17ß and SERMs dl-ormeloxifene (centchroman), raloxifene and levormeloxifene (l-centchroman) for their anticancer effects and their effect on thrombin activity. Methods: Anticancer activity was assessed against PC-3 cell line by flow cytometry following treatment with estradiol-17ß and SERMs at 10 nM-1 mM concentrations. The cells were stained with propidium iodide and the percentage of cells in the sub-G0/G1 region was considered apoptotic. Thrombin inhibitory effect was evaluated by thrombin inhibition assay in vitro following incubation with 100 nM-3 mM concentrations of estradiol-17ß or various SERMs. Further, the effect of estradiol-17ß and SERMs on endogenous thrombin generation potential (ETP) was assessed by thrombin generation assay on rat plasma in vitro. Results: These compounds exhibited >90% cell death in PC-3 cell lines at 1 mM concentration except estradiol-17ß. Neither estradiol-17ß, dl-ormeloxifene and levormeloxifene showed any thrombin inhibitory or enhancing activity in thrombin inhibition assay, nor did they show any effect on ETP on rat plasma in vitro. However, raloxifene inhibited thrombin activity in a concentration-dependent manner. Raloxifene decreased ETP of the plasma at 3 and 1 mM,which is equivalent to that of 30-100 U/mL of heparin. Interestingly, raloxifene increased thrombin generation at lower concentrations and it inhibited thrombin generation at higher concentrations. Conclusions: These observations suggest that dl-ormeloxifene, estradiol-17ß and levormeloxifene do not possess thrombin inhibitory activity. Raloxifene possesses thrombin modulatory effect in addition to its anticancer activity, and this observation may help us in understanding the thromboembolic complications associated with raloxifene.

Composition of Cassia fistula oil and its antifungal activity by disrupting ergosterol biosynthesis.

Cassia fistula oil was investigated for antifungal activities against standard and clinical isolates of Candida species. Gas chromatography coupled with mass spectrometric (GC-MS) analysis of C. fistula oil revealed the presence of antimicrobial compounds like beta-sitosterol, stigmasterol, ergosterol, betulinic acid, lupeol, fucosterol, alpha-amyrin and friedelin. The minimum inhibitory concentration (MIC) of the pulp and seed oils ranged between 250-300 and 350-500 microg/mL respectively. Both oils also inhibited by > or = 63.8% ergosterol bio-synthesis in Candida cell wall {fluconazole (standard) > or = 89.1%)}. The MICs were significantly correlated with the ergosterol content decrease in the cell wall (Student's t test p < or = 0.005). We can, therefore, conclude that active compounds are present in Cassia fistula oil that primarily target ergosterol biosynthesis in Candida cell wall.