Anticancer therapeutic potential of multimodal targeting agent- "phosphorylated galactosylated chitosan coated magnetic nanoparticles" against N-nitrosodiethylamine-induced hepatocellular carcinoma.

Superparamagnetic iron oxide nanoparticles (SPIONs) are extensively used as carriers in targeted drug delivery and has several advantages in the field of magnetic hyperthermia, chemodynamic therapy and magnet assisted radionuclide therapy. The characteristics of SPIONs can be tailored to deliver drugs into tumor via "passive targeting" and they can also be coated with tissue-specific agents to enhance tumor uptake via "active targeting". In our earlier studies, we developed HCC specific targeting agent- "phosphorylated galactosylated chitosan"(PGC) for targeting asialoglycoprotein receptors. Considering their encouraging results, in this study we developed a multifunctional targeting system- "phosphorylated galactosylated chitosan-coated magnetic nanoparticles"(PGCMNPs) for targeting HCC. PGCMNPs were synthesized by co-precipitation method and characterized by DLS, XRD, TEM, VSM, elemental analysis and FT-IR spectroscopy. PGCMNPs were evaluated for in vitro antioxidant properties, uptake in HepG2 cells, biodistribution, in vivo toxicity and were also evaluated for anticancer therapeutic potential against NDEA-induced HCC in mice model in terms of tumor status, electrical properties, antioxidant defense status and apoptosis. The characterization studies confirmed successful formation of PGCMNPs with superparamagnetic properties. The internalization studies demonstrated (99-100)% uptake of PGCMNPs in HepG2 cells. These results were also supported by biodistribution studies in which increased iron content (296%) was noted inside the hepatocytes. Further, PGCMNPs exhibited no in vivo toxicity. The anticancer therapeutic potential was evident from observation that PGCMNPs treatment decreased tumor bearing animals (41.6%) and significantly (p ≤ 0.05) lowered tumor multiplicity. Overall, this study indicated that PGCMNPs with improved properties are efficiently taken-up by hepatoma cells and has therapeutic potential against HCC. Further, this agent can be tagged with 32P and hence can offer multimodal cancer treatment options via radiation ablation as well as magnetic hyperthermia.

Advances in Understanding and Management of Erdheim-Chester Disease.

Erdheim Chester Disease (ECD) is a rare histiocytic disorder marked by infiltration of organs with CD68+ histiocytes. ECD stems from mutations of BRAF and MAP2K1 in hematopoietic stem and progenitor cells (HSPCs), which further differentiate into monocytes and histiocytes. Histopathology reveals lipid-containing histiocytes, which test positive for CD68 and CD133 in immunohistochemistry. Signs and symptoms vary and depend on the organ/s of manifestation. Definitive radiological results associated with ECD include hairy kidney, coated aorta, and cardiac pseudotumor. Treatment options primarily include anti-cytokine therapy and inhibitors of BRAF and MEK signaling.

Beyond cyclopamine: Targeting Hedgehog signaling for cancer intervention.

Hedgehog (Hh) signaling plays a significant role in embryogenesis and several physiological processes, such as wound healing and organ homeostasis. In a pathological setting, it is associated with oncogenesis and is responsible for disease progression and poor clinical outcomes. Hedgehog signaling mediates downstream actions via Glioma Associated Oncogene Homolog (GLI) transcription factors. Inhibiting Hh signaling is an important oncological strategy in which inhibitors of the ligands SMO or GLI have been looked at. This review briefly narrates the Hh ligands, signal transduction, the target genes involved and comprehensively describes the numerous inhibitors that have been evaluated for use in various neoplastic settings.

Targeting oncogenic transcription factors by polyphenols: A novel approach for cancer therapy.

Inflammation is one of the major causative factor of cancer and chronic inflammation is involved in all the major steps of cancer initiation, progression metastasis and drug resistance. The molecular mechanism of inflammation driven cancer is the complex interplay between oncogenic and tumor suppressive transcription factors which include FOXM1, NF-kB, STAT3, Wnt/ß- Catenin, HIF-1α, NRF2, androgen and estrogen receptors. Several products derived from natural sources modulate the expression and activity of multiple transcription factors in various tumor models as evident from studies conducted in cell lines, pre-clinical models and clinical samples. Further combination of these natural products along with currently approved cancer therapies added an additional advantage and they considered as promising targets for prevention and treatment of inflammation and cancer. In this review we discuss the application of multi-targeting natural products by analyzing the literature and future directions for their plausible applications in drug discovery.

Promising anticancer activities of Justicia simplex D. Don. in cellular and animal models.

ETHNOPHARMACOLOGICAL RELEVANCE: Justicia simplex D. Don. belonging to the family of Acanthaceae has been traditionally used for treatment of rheumatism, inflammation and bronchitis. The plant is traditionally considered as an anticancer medicine and is used by healers of Karnataka to treat various types of cancers. AIM OF THE STUDY: The present study aims at the elucidation of anticancer activity of various extracts of J. simplex, isolation of its active constituents and assessment of the role in growth inhibition and angiogenesis both in vitro and in vivo. MATERIALS AND METHODS: Extracts of J. simplex was evaluated for the in vitro cytotoxic effect by Brine Shrimp Lethality assay, Trypan Blue dye exclusion assay and antiproliferative assay. In vivo cytotoxicity of the extracts were determined by liquid tumor model in Swiss albino mice. Tumor prognosis, metastasis and angiogenesis were assessed by VEGF expression of the solid tumor. Phytochemical analysis afforded the isolation of a compound, the chemical structure of which was established using IR, NMR and TOF-MS spectral method. The compound was also evaluated for the growth inhibitory and angiogenic effects. RESULTS AND CONCLUSION: The petroleum ether extract revealed potent anticancer activity in in vitro and in vivo studies. The anti-angiogenic effect is due to the down regulation of VEGF expression. The growth inhibitory assay revealed that the isolated compound namely triacontanoic ester of 5''-hydroxyjustisolin is responsible for the anticancer activity.

Pro-apoptotic and cytotoxic effects of enriched fraction of Elytranthe parasitica (L.) Danser against HepG2 Hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC), the most common type of liver cancer accounts for more than one million deaths worldwide. Current treatment modality for HCC is marginally effective. Plants belonging to Mistletoe family (Loranthaceae) have been used in chemotherapy for many years. The present study was aimed at exploring the anti-proliferative, pro-oxidant and pro-apoptotic potential of stem of Elytranthe parasitica (L.) Danser (EP), a parasitic shrub belonging to Loranthaceae. METHODS: Elytranthe parasitica (L.) Danser, a climbing parasitic shrub was investigated for its cytotoxic activity against HepG2, a hepatocellular carcinoma cell line by Sulforhodamine B (SRB) assay. Further, pro-oxidant activity of EP extract/fractions was studied using copper phenanthroline assay. To understand the mechanism of cell death, the pro-apoptotic effects of Hep-G2 cells treated with EP extract/fractions were visualized by dual staining using acridine orange and ethidium bromide, a morphological marker of apoptosis. Phytochemical profiling of EP was explored by estimating the phenol, flavonoid and tannin content in its various fractions and extract. The occurrence of gallic acid, a principal polyphenol in EP extract and fractions was detected and further quantified using HPTLC (High Performance Thin Layer Chromatography) fingerprinting. RESULT: Active fraction of Elytranthe parasitica, EP.DEE exhibited potent cytotoxic activity in a dose dependent manner against HepG2 hepatocellular carcinoma cell line with an IC50 of 56.7 ± 7.8 µg/mL. Dual staining with acridine orange and ethidium bromide revealed that HepG2 cells treated with EP active fractions underwent cell death chiefly by apoptosis. Highest phenol, flavonoid and tannin content were observed in active fractions, EP.EA (Ethyl acetate fraction) and EP.DEE (Diethyl ether fraction). Gallic acid was identified and quantified in EP extract and active fractions, EP.DEE and EP.EA. CONCLUSION: Our findings indicate EP active fraction could be a promising contender in the treatment of hepatocellular carcinoma.

Synthesis of methoxy-substituted chalcones and in vitro evaluation of their anticancer potential.

Methoxy-substituted chalcones, 3 were obtained using simple, efficient method from 2-naphtylethanone, 1 and aromatic aldehydes, 2. The in vitro cytotoxicity activities of the chalcones against a panel of three human cancer cell lines were explored. The tested compounds were found to possess significant cytotoxic activity. The DNA strand break and damage was quantified through alkaline comet assay, flow cytometric analysis, and chromatin condensation studies, which revealed the apoptotic nature of the compounds. Compound 3c, (3-(3,4,5-trimethoxyphenyl)-1-(2-naphthyl) prop-2-en-1-one) showed highest cytotoxicity of 0.019 µm against HeLa, 0.020 µm against HCT15 and 0.022 µm against A549. Compound 3e, (3-(3,5-dimethoxyphenyl)-1-(2-naphthyl) prop-2-en-1-one) showed better IC50 values against all the three cell lines employed for the study.

Preliminary evaluation of in vitro cytotoxicity and in vivo antitumor activity of Xanthium strumarium in transplantable tumors in mice.

In the present study, active fractions of the methanolic extract of Xanthium strumarium (XS) showing potent cytotoxicity were determined using microculture tetrazolium (MTT) and sulforhodamine B (SRB) assays in selected cancer cell lines. The active fractions viz., chloroform soluble fraction of root (CEXSR), hexane soluble fraction of leaf (HEXSL), hexane soluble fraction of fruits (HEXSF) and chloroform soluble fraction of fruits (CEXSF) of XS were tested in transplantable animal tumor models for their antitumor potential. Dalton's ascitic lymphoma (DLA) cells were used to induce solid and liquid (ascites) tumor in mice. The tumor bearing animals were treated with active fractions at two dose levels (100 and 200 mg/kg). The antitumor activities of the active fractions in tumor bearing animals were monitored with parameters such as body weight and increase in life-span as well as biochemical and hematological modalities (in the case of liquid tumor). Tumor incidence and tumor volume were the parameters monitored in the case of the solid tumor model. The results were analyzed by one-way ANOVA followed by Tukey's post hoc test. The extracts were found to increase the life-span of tumor bearing animals and restore the altered hematological and biochemical parameters significantly.