Neem leaf glycoprotein binding to Dectin-1 receptors on dendritic cell induces type-1 immunity through CARD9 mediated intracellular signal to NFκB.

BACKGROUND: A water-soluble ingredient of mature leaves of the tropical mahogany 'Neem' (Azadirachta indica), was identified as glycoprotein, thus being named as 'Neem Leaf Glycoprotein' (NLGP). This non-toxic leaf-component regressed cancerous murine tumors (melanoma, carcinoma, sarcoma) recurrently in different experimental circumstances by boosting prime antitumor immune attributes. Such antitumor immunomodulation, aid cytotoxic T cell (Tc)-based annihilation of tumor cells. This study focused on identifying and characterizing the signaling gateway that initiate this systemic immunomodulation. In search of this gateway, antigen-presenting cells (APCs) were explored, which activate and induce the cytotoxic thrust in Tc cells. METHODS: Six glycoprotein-binding C-type lectins found on APCs, namely, MBR, Dectin-1, Dectin-2, DC-SIGN, DEC205 and DNGR-1 were screened on bone marrow-derived dendritic cells from C57BL/6 J mice. Fluorescence microscopy, RT-PCR, flow cytometry and ELISA revealed Dectin-1 as the NLGP-binding receptor, followed by verifications through RNAi. Following detection of ß-Glucans in NLGP, their interactions with Dectin-1 were explored in silico. Roles of second messengers and transcription factors in the downstream signal were studied by co-immunoprecipitation, western blotting, and chromatin-immunoprecipitation. Intracellularization of FITC-coupled NLGP was observed by processing confocal micrographs of DCs. RESULTS: Considering extents of hindrance in NLGP-driven transcription rates of the cytokines IL-10 and IL-12p35 by receptor-neutralization, Dectin-1 receptors on dendritic cells were found to bind NLGP through the ligand's peripheral ß-Glucan chains. The resulting signal phosphorylates PKCδ, forming a trimolecular complex of CARD9, Bcl10 and MALT1, which in turn activates the canonical NFκB-pathway of transcription-regulation. Consequently, the NFκB-heterodimer p65:p50 enhances Il12a transcription and the p50:p50 homodimer represses Il10 transcription, bringing about a cytokine-based systemic-bias towards type-1 immune environment. Further, NLGP gets engulfed within dendritic cells, possibly through endocytic activities of Dectin-1. CONCLUSION: NLGP's binding to Dectin-1 receptors on murine dendritic cells, followed by the intracellular signal, lead to NFκB-mediated contrasting regulation of cytokine-transcriptions, initiating a pro-inflammatory immunopolarization, which amplifies further by the responding immune cells including Tc cells, alongside their enhanced cytotoxicity. These insights into the initiation of mammalian systemic immunomodulation by NLGP at cellular and molecular levels, may help uncovering its mode of action as a novel immunomodulator against human cancers, following clinical trials.

Engineered Artesunate-Naphthalimide Hybrid Dual Drug for Synergistic Multimodal Therapy against Experimental Murine Lymphoma.

Lymphoma can effectively be treated with a chemotherapy regimen that is associated with adverse side effects due to increasing drug resistance, so there is an emergent need for alternative small-molecule inhibitors to overcome the resistance that occurs in lymphoma management and overall increase the prognosis rate. A new series of substituted naphthalimide moieties conjugated via ester and amide linkages with artesunate were designed, synthesized, and characterized. In addition to the conjugates, to further achieve a theranostic molecule, FITC was incorporated via a multistep synthesis process. DNA binding studies of these selected derivatives by ultraviolet-visible (UV-vis), fluorescence spectroscopy, intercalating dye (EtBr, acridine orange)-DNA competitive assay, and minor groove binding dye Hoechst 33342-DNA competitive assay suggested that the synthesized novel molecules intercalated between the two strands of DNA due to its naphthalimide moiety and its counterpart artesunate binds with the minor groove of DNA. Napthalimide-artesunate conjugates inhibit the growth of lymphoma and induce apoptosis, including ready incorporation and reduction in cell viability. The remodeled drug has a significant tumoricidal effect against solid DL tumors developed in BALB/c mice in a dose-dependent manner. The novel drug appears to inhibit metastasis and increase the survival of the treated animals compared with untreated littermates.

Single Inhibitors versus Dual Inhibitors: Role of HDAC in Cancer.

Due to the multimodal character of cancer, inhibition of two targets simultaneously by a single molecule is a beneficial and effective approach against cancer. Histone deacetylase (HDAC) was widely investigated as a novel category of anticancer drug targets due to its crucial role in various biological processes like cell-proliferation, metastasis, and apoptosis. Numerous HDAC inhibitors such as vorinostat and panobinostat are clinically approved but have limited usage due to their low efficacy, nonselectivity, drug resistance, and toxicity. Therefore, HDACs with a dual targeting ability have attracted great attention. The strategy of combining a HDAC inhibitor with other antitumor agents has been proved advantageous for combating the nonselectivity and drug resistivity problems associated with single-target drugs. Henceforth, we have highlighted dual-targeting inhibitors to target HDAC along with topoisomerase, receptor tyrosine kinase inhibitors, and the zeste homolog 2 enzyme. Our Review mainly focuses on the impact of the substituent effect along with the linker variation of well-known HDAC-inhibitor-conjugated anticancer drugs.

γc cytokine-aided crosstalk between dendritic cells and natural killer cells together with doxorubicin induces a healer response in experimental lymphoma by downregulating FOXP3 and programmed cell death protein 1.

BACKGROUND AIMS: The stimulatory natural killer-dendritic cell axis in the tumor microenvironment could play a critical role in stimulating cytotoxic T cells and driving immune responses against cancer. METHODS: We established a novel treatment protocol by adroitly combining chemotherapy with doxorubicin and immunotherapy with dendritic cells and natural killer cells against a highly aggressive and malignant lymphoma called Dalton's lymphoma. RESULTS: Our data suggest that binary application of adoptive cell therapy and chemotherapy nearly cures (95%) early-stage experimental lymphoma. In the case of mid-stage cancer, the success rate was significantly lower but still impressive (75%). Our results demonstrated that the application of combination therapy in early-stage cancer significantly reduced the tumor volume and extended the lifespan of the experimental animal in addition to reinvigorating the immune system, including restoring the effector functions of dendritic cells and natural killer cells. The novel protocol limits the metastasis of tumor cells in vascularized organs and rearms the adaptive immune response mediated by dendritic cells and CD4+ and CD8+ T cells. CONCLUSIONS: Combination therapy in the early stage alters the cytokine profile, increases interferon-γ and tumor necrosis factor-α in the serum of treated animals and downregulates programmed cell death protein 1 expression in CD8+ T cells. Thus, cooperative and cognitive interactions between dendritic cells and natural killer cells in addition to therapy with doxorubicin promote the immune response and tumoricidal activities against lymphoma.

A study of vegetable oil modified QCM sensor to detect ß-pinene in Indian cardamom.

A quartz crystal microbalance (QCM) sensor was developed in this study with the vegetable oil from olive (OLV-QCM) to detect an important volatile organic compound, ß-pinene in Indian cardamom. Hydrophobic vegetable oil from olive, which contains oleic acid and omega-9, a monounsaturated fatty acid was found to be suitable for binding ß-pinene through non-covalent bonds. The fabricated QCM sensor coating was examined with the field emission scanning electron microscope (FESEM) and Fourier-transform infrared spectroscopy (FTIR) to determine its surface morphology and chemical compositions. The sensitivity, reproducibility, repeatability, and reusability were studied for the developed sensor. Notably, the sensor was observed to be highly selective towards ß-pinene as compared to the other volatile components present in cardamom. The limit of detection (LOD) and limit of quantitation (LOQ) parameters were determined as 5.57 mg L-1 and 18.57 mg L-1, respectively. Moreover, the adsorption isotherm models of the sensor were studied to validate the physical adsorption affinity towards ß-pinene applying Langmuir, Freundlich, and Langmuir-Freundlich isotherm models. The sensor showed a correlation factor of 0.99 with the peak area percentage of gas chromatography-mass spectrometry (GC-MS) analysis for ß-pinene in cardamom samples. The sensor was prepared with natural vegetable oil, unlike health hazard chemicals. In addition to this, the low-cost, easy fabrication process ensured the suitability of the sensor for practical deployment.

Arsenic level in bladder tumor of patients from an exposed population: association with progression and prognosis.

Aims: To elucidate the impact of arsenic on progression and prognosis of bladder cancer. Patients & methods: Total arsenic in 145 tumors (80 non-muscle-invasive [NMIBC] and 65 muscle-invasive bladder cancer [MIBC]) was measured and associated with Ki67 expression, tumor-clinicopathological parameters and patient outcome. Results: Tumor arsenic concentration was higher in exposed than unexposed patients (256 µg/kg vs 77 µg/kg; p < 0.0001) and positively correlated (r = 0.65; p < 0.0001) with arsenic content of patient's drinking water. Arsenic concentration showed significant association with Ki67-overexpression (p = 0.001) and advanced tumor stages (NMIBC vs MIBC; p = 0.0009). In NMIBC, high tumor arsenic (>100 µg/kg) and Ki67 overexpression was established as predictors for recurrence (hazard ratio [HR]: 4.68; p = 0.005 and HR: 3.91; p = 0.018) and progression (HR: 6.04; p = 0.023 and HR: 6.87; p = 0.013). In MIBC, association of high arsenic remained significant with increased risk of recurrence (HR: 4.58; p = 0.04). Conclusion: In NMIBC, high arsenic and Ki67 overexpression and in MIBC, only high arsenic showed prognostic importance in predicting poor patient outcome.

Lay abstract Research work suggests arsenic as risk factor for bladder cancer. In developing countries such as India, arsenic contamination of underground drinking water is a major health problem. The present study aimed to evaluate impact of arsenic on parameters of bladder cancer aggressiveness and clinical outcome of patients from West Bengal, India. Our data showed accumulation of arsenic in bladder tumor of patients exposed mainly through contaminated drinking water. Arsenic content in tumor favored aggressive phenotypes in bladder cancer (higher cell proliferation and advanced tumor stages) and was found to be a potential predictor for cases of death and disease recurrence in patients after receiving primary treatment measures. Therefore, arsenic content in bladder tumor may be used to improve existing protocols for better prediction of patient outcomes in populations with a similar type of exposure.

Development of a PAMAM Dendrimer for Sustained Release of Temozolomide against Experimental Murine Lymphoma: Assessment of Therapeutic Efficacy.

Enhanced drug localization at the tumor sites with minimal toxicity was demonstrated using dendrimer-conjugated temozolomide for treating experimental lymphoma, developed as a solid tumor. Herein, we have constructed a polyamidoamine (PAMAM) dendrimer conjugated with temozolomide to enhance the stability of the active drug metabolites, derived from the prodrug temozolomide. Our results suggest that the active drug (5-(3-methyltriazen-1-yl)imidazole-4-carboxamide) (MTIC) (derived from temozolomide) showed stable and sustained release from the dendrimer-temozolomide conjugate, suggesting the suitability of the construct for therapy. Besides growth inhibition and direct killing, the dendrimer-temozolomide construct induced extensive apoptosis not only in parental Dalton lymphoma tumor cells but also in the doxorubicin-resistant form of the tumor cells. Dendrimer-temozolomide conjugation significantly reduced the solid tumor growth and increased the lifespan with better prognosis, including improved histopathology of the treated mice, while untreated littermates developed extensive metastasis and succumbed to death.

Dendrimer-conjugated podophyllotoxin suppresses DENA-induced HCC progression by modulation of inflammatory and fibrogenic factors.

Podophyllotoxin has been explored as an anticancer, antiviral, and antibacterial agent; however, its low water solubility and toxicity limit its use. In this study, the efficacy of a more soluble and less toxic polyamidoamine (PAMAM) dendrimer-conjugated podophyllotoxin (DPODO) was evaluated against chemically induced hepatocellular carcinoma (HCC) in mice. HCC was induced by giving 0.01% diethylnitrosamine (DENA) in drinking water for 16 weeks. The HCC-induced mice were treated with 10 or 20 mg per kg body weight DPODO. The DENA administration led to HCC development, characterized by anisocytosis, karyomegaly, inflammation and degenerative changes in the liver. The DPODO treatment at 10 mg and 20 mg doses significantly reduced the histopathological changes in liver tissue. The DPODO treatment also significantly lowered the levels of inflammatory markers IL-6 and NF-κB in serum and tissue, respectively. Further, the treatment also significantly reduced fibrous tissue deposition in the liver, which was further confirmed by the reduced mRNA levels and tissue expression of fibrogenic markers TGF-ß and α-SMA in the liver. The results of the present study indicate that DPODO treatment suppresses the progression of HCC by modulating the inflammatory and fibrogenic factors, which play important roles in HCC development.

Design and synthesis of coumarin-based organoselenium as a new hit for myeloprotection and synergistic therapeutic efficacy in adjuvant therapy.

A newly designed organoselenium compound, methyl substituted umbelliferone selenocyanate (MUS), was synthesized as a primary hit against the myelotoxic activity of carboplatin. MUS was administered at 6 mg/kg b.wt, p.o. in concomitant and pretreatment schedules with carboplatin (12 mg/kg b.wt, i.p. for 10 days) in female Swiss albino mouse. MUS treatment reduced (P < 0.001) the percentage of chromosomal aberrations, micronuclei formation, DNA damage and apoptosis in murine bone marrow cells and also enhanced (P < 0.001) the bone marrow cell proliferation of the carboplatin-treated mice. These activities cumulatively restored the viable bone marrow cell count towards normalcy. Myeloprotection by MUS was achieved, in part, due to a significant reduction in the ROS/RNS formation and restoration of glutathione redox pool. Additionally, MUS synergistically enhanced the cytotoxicity of carboplatin against two human cancer cell lines (MCF-7 and Colo-205). Furthermore, MUS can effectively potentiate the antitumour activity of carboplatin against two murine cancers (Dalton's Lymphoma and Sarcoma-180) in vivo. These preclinical findings clearly indicate that MUS can improve the therapeutic index of carboplatin and ensures more effective therapeutic strategy against cancer for clinical development.

Dendrimer conjugated estramustine nanocrystalline 'Dendot': An effective inhibitor of DMBA-TPA induced papilloma formation in mouse.

Clinically approved anticancer drug estramustine mediates its function by impairing microtubule polymerization. However, the low aqueous solubility and high toxicity limit its anticancer activity via the oral route. Previously, efforts have been made to develop an enhanced water soluble form of estramustine as estramustine phosphate (EM) but acidic gastrointestinal pH breaks the phosphate derivative via oral administration. As an alternative approach, we have made an effort to enhance solubility and minimize toxicity in vivo by conjugating EM to a poly(amidoamine) (PAMAM) dendrimer, which generated the sustained release of dendrimer conjugate (DEM). To the best of our knowledge, for the first time, we report the direct proof of the nano-crystalline 'DenDot' of DEM on TEM image. The toxicity study showed that both EM and DEM were nontoxic up to 20mg/kg. A comparative anti-papilloma study was also performed with EM and dendrimer conjugates (DEM) using a two-stage mouse skin carcinogenesis model. We found that DEM was more effective in inhibiting skin tumor formation than EM. Histopathology and immunohistochemistry studies further indicated that DEM treatment increased cell apoptosis, and reduced epithelial hyperplasia, cell proliferation and inflammation in skin tissues of mice. In addition, the synthetic DEM conjugate inhibited skin tumor progression more effectively than EM.

Design, synthesis, and identification of a novel napthalamide-isoselenocyanate compound NISC-6 as a dual Topoisomerase-IIα and Akt pathway inhibitor, and evaluation of its anti-melanoma activity.

Synthesis and anti-melanoma activity of novel naphthalimide isoselenocyanate (NISC) and naphthalimide selenourea (NSU) analogs are described. The novel agents were screened for growth inhibition of different human melanoma cell lines including those having BRAFV600E mutation (UACC903, 1205Lu, and A375M) and BRAFWT (CHL-1). In general, the NISC analogs (4a-d) were more effective in inhibiting the cell viability than the NSU analogs (7a-b). Overall, NISC-6 (4d), having a six-carbon alkyl chain, was identified as the most cytotoxic compound in both BRAFV600E mutated and BRAFWT cells. NISC-6 docked strongly into the binding sites of Akt1 and human topoisomerase IIα (Topo-IIα), and the docking results were supported by experimental findings showing NISC-6 to inhibit of both Akt pathway and Topo-IIα activity in a dose dependent manner. Furthermore, NISC-6 effectively induced apoptosis in human melanoma cells, inhibited tumor growth by ∼69% in a melanoma mouse xenograft model, and showed excellent compliance with the Lipinski' rule of five, suggesting both its efficacy and drug-like behavior under physiological conditions.

Dendrimers for theranostic applications.

Recently, there have been tremendous advances in the development of various nanotechnology-based platforms for diagnosis and therapy. These nanoplatforms, which include liposomes, micelles, polymers, and dendrimers, comprise highly integrated nanoparticles that provide multiple functions, such as targeting, imaging, and therapy. This review focuses on dendrimer-based nanocarriers that have recently been developed for 'theranostics (or theragnosis)', a combination of therapy and diagnostics. We discuss the in vitro and in vivo applications of these nanocarriers in strategies against diseases including cancer. We also explore the use of dendrimers as imaging agents for fluorescence imaging, magnetic resonance imaging, X-ray computed tomography, and nuclear medical imaging.

Dual stimuli-sensitive dendrimers: Photothermogenic gold nanoparticle-loaded thermo-responsive elastin-mimetic dendrimers.

Dendrimers are synthetic macromolecules with unique structures that can work as nanoplatforms for both photothermogenic gold nanoparticles (AuNPs) and thermosensitive elastin-like peptides (ELPs) with valine-proline-glycine-valine-glycine (VPGVG) repeats. In this study, photothermogenic AuNPs were loaded into thermo-responsive elastin-mimetic dendrimers (dendrimers conjugating ELPs at their periphery) to produce dual stimuli-sensitive nanoparticles. Polyamidoamine G4 dendrimers were modified with acetylated VPGVG and (VPGVG)2, and the resulting materials were named ELP1-den and ELP2-den, respectively. The AuNPs were prepared by the reduction of Au ions using a dendrimer-nanotemplated method. The AuNP-loaded elastin-mimetic dendrimers exhibited photothermal properties. ELP1-den and ELP2-den showed similar temperature-dependent changes in their conformations. Phase transitions were observed at around 55°C and 35°C for the AuNP-loaded ELP1-den and AuNP-loaded ELP2-den, respectively, but not for the corresponding PEGylated dendrimer. In contrast to the AuNP-loaded PEGylated dendrimer, AuNP-loaded ELP2-den readily associated with cells and induced efficient photocytotoxicity at 37°C. The cell association and the photocytotoxicity properties of AuNP-loaded ELP2-den could be controlled by temperature. These results therefore suggest that dual stimuli-sensitive dendrimer nanoparticles of this type could be used for photothermal therapy.

Comparative study of microtubule inhibitors--estramustine and natural podophyllotoxin conjugated PAMAM dendrimer on glioma cell proliferation.

The synthetic estramustine (EM) and natural podophyllotoxin (PODO) anti-mitotic agents that inhibit tubulin polymerization are known anticancer agents. As low bioavailability limits their anticancer properties, we investigated whether conjugation with PAMAM dendrimer (D) could enhance the activity of D-EM and D-PODO by altering their release pattern. Release kinetics indicated synthesized conjugates to be stable against hydrolytic cleavage and showed sustained release characteristics. However, release of D-EM was slow compared to D-PODO conjugate. Antitumor effect of these conjugates on glioma cells revealed (i) increased cell death and cell cycle arrest (ii) decreased migration and (iii) increased tubulin depolymerization as compared to free drug. Importantly, the effects of natural PODO conjugate on glioma cell survival and migration is more pronounced than D-EM.

Enhancing the efficacy of Ara-C through conjugation with PAMAM dendrimer and linear PEG: a comparative study.

1ß-d-Arabinofuranosylcytosine (Cytarabine, Ara-C) is a key drug in the treatment of acute myeloid leukemia. Ara-C has a number of limitations such as a rapid deactivation by cytidine deaminase leading to the formation of a biologically inactive metabolite, Ara-U (1ß-d-arabinofuranosyluracil), a low lipophilicity, and fast clearance from the body. To address these problems, we developed a conjugate in which hydroxyl-terminated PAMAM dendrimer, G4-OH ["D"] and PEG were used as carriers for the drug (Ara-C). The conjugates were synthesized using an efficient multistep protection/deprotection method resulting in the formation of a covalent bond between the primary hydroxyl group of Ara-C and dendrimer/PEG. The structure, physicochemical properties, and drug release kinetics were characterized extensively. (1)H NMR and MALDI-TOF mass spectrometry suggested covalent attachment of 10 Ara-C molecules to the dendrimer. The release profile of Ara-C in human plasma and in PBS buffer (pH 7.4) showed that the conjugates released the drug over 14 days in PBS, with the release sped up in plasma. In PBS, while most of the drug is released from PEG-Ara-C, the dendrimer continues to release the drug in a sustained fashion. The results also suggested that the formation of the inactive form of Ara-C (Ara-U) was delayed upon conjugation of Ara-C to the polymers. The inhibition of cancer growth by the dendrimer-Ara-C and PEG-Ara-C conjugates was evaluated in A549 human adenocarcinoma epithelial cells. Both dendrimer- and PEG-Ara-C conjugates were 4-fold more effective in inhibition of A549 cells compared to free Ara-C after 72 h of treatment.

Rational incorporation of selenium into temozolomide elicits superior antitumor activity associated with both apoptotic and autophagic cell death.

BACKGROUND: The DNA alkylating agent temozolomide (TMZ) is widely used in the treatment of human malignancies such as glioma and melanoma. On the basis of previous structure-activity studies, we recently synthesized a new TMZ selenium analog by rationally introducing an N-ethylselenocyanate extension to the amide functionality in TMZ structure. PRINCIPAL FINDINGS: This TMZ-Se analog showed a superior cytotoxicity to TMZ in human glioma and melanoma cells and a more potent tumor-inhibiting activity than TMZ in mouse glioma and melanoma xenograft model. TMZ-Se was also effective against a TMZ-resistant glioma cell line. To explore the mechanism underlying the superior antitumor activity of TMZ-Se, we compared the effects of TMZ and TMZ-Se on apoptosis and autophagy. Apoptosis was significantly increased in tumor cells treated with TMZ-Se in comparison to those treated with TMZ. TMZ-Se also triggered greater autophagic response, as compared with TMZ, and suppressing autophagy partly rescued cell death induced by TMZ-Se, indicating that TMZ-Se-triggered autophagy contributed to cell death. Although mRNA level of the key autophagy gene, Beclin 1, was increased, Beclin 1 protein was down-regulated in the cells treated with TMZ-Se. The decrease in Beclin 1 following TMZ-Se treatment were rescued by the calpain inhibitors and the calpain-mediated degradation of Beclin1 had no effect on autophagy but promoted apoptosis in cells treated with TMZ-Se. CONCLUSIONS: Our study indicates that incorporation of Se into TMZ can render greater potency to this chemotherapeutic drug.

Development of novel naphthalimide derivatives and their evaluation as potential melanoma therapeutics.

Synthesis and anti-melanoma activity of various naphthalimide analogs, rationally modified by introducing isothiocyanate (ITC) and thiourea (TU) functionalities, found in well-known anti-cancer agents, is described. The structure-activity relationship comparison of the novel agents in inhibiting cancer cell growth was evaluated in various melanoma cell lines. Both ITC and TU analogs effectively inhibited cell viability and induced apoptosis in various human melanoma cells. Nitro substitution and increase in alkyl chain length, in general, enhanced the apoptotic activity of ITC derivatives. All the new compounds were well tolerated when injected intraperitoneal (i.p.) in mice at effective doses at which both the ITC and TU derivatives inhibited melanoma tumor growth in mice following i.p. xenograft. The nitro substituted naphthalimide-ITC derivative 3d was found to be the most effective in inducing apoptosis, and in inhibiting melanoma cell and tumor growth.

Amelioration of cisplatin-induced nephrotoxicity in mice by oral administration of diphenylmethyl selenocyanate.

Cisplatin is one of the most potent and active cytotoxic drug in the treatment of cancer. However, side-effects in normal tissues and organs, notably nephrotoxicity in the kidneys, limit the promising efficacy of cisplatin. The present study was designed to ascertain the possible in vivo protective potential of a synthetic organoselenium compound diphenylmethyl selenocyanate (3 mg/kg.b.w.) against the nephrotoxic damage induced by cisplatin (5 mg/kg.b.w. for 5 days) in Swiss albino mice. Treatment with diphenylmethyl selenocyanate markedly reduced cisplatin-induced lipid peroxidation, serum creatinine and blood urea nitrogen levels. Renal antioxidant defense systems, such as glutathione-S-transferase, glutathione peroxidase, superoxide dismutase, catalase, activities and reduced glutathione level, depleted by cisplatin therapy, were restored to normal by the selenium compound. The selenium compound also reduced renal tubular epithelial cell damage, nitric oxide levels and expression of COX-2, and iNOS in kidneys injured by cisplatin. These results demonstrate the protective effect of diphenylmethyl selenocyanate against cisplatin-induced nephrotoxicity in mice.

Naphthalimide based novel organoselenocyanates: finding less toxic forms of selenium that would retain protective efficacy.

A series of naphthalimide based organoselenocyanates were synthesized and screened for their toxicity as well as their ability to modulate several detoxifying/antioxidative enzyme levels at a primary screening dose of 3 mg/kg b.w. in normal Swiss albino mice for 30 days. Compound 4d showed highest activity in elevating the detoxifying/antioxidant enzymes levels.

Synthesis and bioactivity of sphingosine kinase inhibitors and their novel aspirinyl conjugated analogs.

Sphingosine kinase (SphK) is a lipid kinase with oncogenic activity, and SphK inhibitors (SKIs) are known for their anti-cancer activity. Here, we report highly efficient syntheses of SKIs and their aspirinyl (Asp) analogs. Both SKIs and their Asp analogs were highly cytotoxic towards multiple human cancer cell lines; in several cases the Asp analogs were up to three times more effective. Furthermore, they were equally potent inhibitors of SphK. The pharmacokinetic study indicated that SKI-I-Asp cleaved efficiently to form SKI-I and the half-life of SKI-I was increased from approximately 7 h in SKI-I to approximately 10 h in SKI-I-Asp injected mice, thereby prolonging its effect. In summary, the Asp-conjugated SKIs seem to be promising prodrugs of SKIs where delivery in vivo remains a problem.