The current study is to develop a natural drug carrier with seaweed derived polymers namely κ-Carrageenan (κ-Car) for drug delivery applications. κ-Car is a natural polysaccharide which derived from edible red seaweeds, they are easily available, non-toxic, cost effective, biodegradable and biocompatible nature. Curcumin (Cur) is a yellow-orange polyphenol existing in turmeric, which is predominantly used as spice and food coloring agent. The ultimate use of polymeric composites, especially those composed of natural polymers, has become a very interesting approach in recent drug delivery applications, due to their non-toxicity and biological origin. In this study the primary approach which depends on the loading of Curcumin into κ-Carrageenan was accomplished, and which (κ-Car-Cur) an active drug carrier was developed for drug delivery against selected lung cancer cells (A549). Thus, the κ-Car-Cur was synthesized by solvent evaporation method followed by freeze drying, and it was further characterized. From this study, it has been reported that the high encapsulation efficiency, good stability, and successful release of Cur from the carrier (κ-Car) was achieved. The drug release was more active at acidic pH 5.0 with the cumulative release of 78%, which is the favorable condition present in tumor microenvironments. The in vitro cellular applications studies of κ-Car-Cur demonstrated that, κ-Car-Cur composites induced higher cytotoxicity against selected cancer cells than free Cur and effectively involved to trigger cellular apoptosis in A549 cancer cells. Further, it was also possessed that inhibition of cell growth and changes in metabolic activity of cancer cells are the unique characteristic features of cellular apoptosis, through reactive oxygen species (ROS) generation. It also observed that there was a decrease in mitochondrial membrane potential (ΔψmΔψm) which leads to a cellular apoptosis during treatment with κ-Car-Cur. Hence, the study outcomes may provide the potential outline for the use of κ-Car-Cur as a promising tool to deliver drugs at intracellular level.

Polysaccharides are substances that modify the biological response to several stressors. The present study investigated the antitumor activity of the soluble fraction of polysaccharides (SFP), extracted from cabernet franc red wine, in Walker-256 tumor-bearing rats. The monosaccharide composition had a complex mixture, suggesting the presence of arabinoglactans, mannans, and pectins. Treatment with SFP (30 and 60mg/kg, oral) for 14days significantly reduced the tumor weight and volume compared with controls. Treatment with 60mg/kg SFP reduced blood monocytes and neutrophils, reduced the tumor activity of N-acetylglucosaminidase, myeloperoxidase, and nitric oxide, increased blood lymphocytes, and increased the levels of tumor necrosis factor α (TNF-α) in tumor tissue. Treatment with SFP also induced the expression of the cell necroptosis-related genes Rip1 and Rip3. The antineoplastic effect of SFP appears to be attributable to its action on the immune system by controlling the tumor microenvironment and stimulating TNF-α production, which may trigger the necroptosis pathway.

Hypoxia is a consequence of the decrease in the oxygen reaching the tissues of the body. It is a prominent feature of most solid tumors and is known to promote malignant progression, metastatic capacity, resistance to chemotherapy, and leads to poor patient prognosis. When a cell is under hypoxic stress, a cascade of cell signals is initiated through a family of transcription factors named as hypoxia inducible factors (HIFs). During hypoxia, HIF stabilizes and enters the nucleus and binds to the DNA via the hypoxia response element (HRE) and leads to the translation of downstream genes. The decision of adaptation or cell death depends on the extent of hypoxic stress faced by the cells. Proper understanding of hypoxic stress response is critical for understanding the mechanism of tumor cell adaptation to hypoxia and to develop efficient therapeutic interventions. In this paper, we develop a Boolean network model with targeted drug intervention in a cell that mimics persistent hypoxia. This hypoxic pathway is combined with pathways that help the cell adapt to the situation or undergo cell death. It is linked to apoptosis, cell survival, and energy production via the p53/Mdm2, PI3k/Akt/mTOR, and Glycolysis/TCA cycle pathways, respectively. In this model, we have incorporated eight known anticancer drugs that target these pathways. Through simulations, we have identified drug combinations that provided overall benefits to the cell in comparison to the no intervention case. Where applicable, the behavior predicted by this model is in agreement with experimental observations from the published literature.

Six dinuclear platinum(II) complexes with a chiral tetradentate ligand, (1R,1'R,2R,2'R)-N1,N1'-(1,4-phenylenebis(methylene))dicyclohexane-1,2-diamine, have been designed, synthesized and characterized. In vitro cytotoxicity evaluation of these metal complexes against human A549, HCT-116, MCF-7 and HepG-2 cell lines have been carried out. All compounds showed antitumor activity to HepG-2, HCT-116 and A549. Particularly, compounds A1 and A2 exhibited significant better activity than other four compounds and A2 even showed comparable cytotoxicity to cisplatin against HepG-2 cell line.

Clinacanthus nutans is widely grown in tropical Asia and locally known "belalai gajah" or Sabah snake grass. It has been used as a natural product to treat skin rashes, snake bites, lesion caused by herpes, diabetes, fever, and cancer. Therefore, the objectives of this research are to determine the maximum yield and time of exhaustive flavonoids extraction using Peleg's model and to evaluate potential of antiproliferative activity on human lung cancer cell (A549). The extraction process was carried out on fresh and dried leaves at 28 to 30°C with liquid-to-solid ratio of 10 mL/g for 72 hrs. The extracts were collected intermittently analysed using mathematical Peleg's model and RP-HPLC. The highest amount of flavonoids was used to evaluate the inhibitory concentration (IC50) via 2D cell culture of A549. Based on the results obtained, the predicted maximum extract density was observed at 29.20 ± 14.54 hrs of extraction (texhaustive). However, the exhaustive time of extraction to acquire maximum flavonoids content exhibited approximately 10 hrs earlier. Therefore, 18 hrs of extraction time was chosen to acquire high content of flavonoids. The best antiproliferative effect (IC50) on A549 cell line was observed at 138.82 ± 0.60 µg/mL. In conclusion, the flavonoids content in Clinacanthus nutans water extract possesses potential antiproliferative properties against A549, suggesting an alternative approach for cancer treatment.

The cardiovascular risk of angiogenesis inhibitors is not well-quantified. We hypothesized that, compared to direct vascular endothelial growth factor (VEGF) inhibitors (anti-VEGF antibodies or decoy receptors), small molecule agents have higher risk due to their less specific mechanism.

Important links exist between the process of pre-mRNA splicing and cancer, as illustrated by the frequent mutation of splicing factors in tumors and the emergence of various families of antitumor drugs that target components of the splicing machinery, notably SF3B1, a protein subunit of spliceosomal U2 small nuclear ribonucleoprotein particle (snRNP). Sudemycins are synthetic compounds that harbor a pharmacophore common to various classes of splicing inhibitors. Here, we describe the synthesis and functional characterization of novel sudemycin analogues that functionally probe key chemical groups within this pharmacophore. Our results confirm the importance of a conjugated diene group and in addition reveal significant spatial flexibility in this region of the molecule. Sudemycin K, a derivative that replaces the pharmacophore's oxycarbonyl by an amide group, displays improved potency as an inhibitor of cancer cell proliferation, as a regulator of alternative splicing in cultured cells and as an inhibitor of in vitro spliceosome assembly. Sudemycin K displays higher stability, likely related to the replacement of the oxycarbonyl group, which can be a substrate of esterases, by an amide group. The activity and special reactivity of sudemycin K can pave the way to the synthesis and evaluation of a variety of novel sudemycin derivatives.

The antifungal drug itraconazole was recently found to exhibit potent antiangiogenic activity and has since been repurposed as an investigational anticancer agent. Itraconazole has been shown to exert its antiangiogenic activity through inhibition of the mTOR signaling pathway, but the molecular mechanism of action was unknown. We recently identified the mitochondrial protein VDAC1 as a target of itraconazole and a mediator of its activation of AMPK, an upstream regulator of mTOR. However, VDAC1 could not account for the previously reported inhibition of cholesterol trafficking by itraconazole, which was also demonstrated to lead to mTOR inhibition. In this study, we demonstrate that cholesterol trafficking inhibition by itraconazole is due to direct inhibition of the lysosomal protein NPC1. We further map the binding site of itraconazole to the sterol-sensing domain of NPC1 using mutagenesis, competition with U18666A, and molecular docking. Finally, we demonstrate that simultaneous AMPK activation and cholesterol trafficking inhibition leads to synergistic inhibition of mTOR, endothelial cell proliferation, and angiogenesis.

We investigated the effect of Dalbergioidin (DAL), a well-known natural product extracted from Uraria crinita, on doxorubicin- (DXR-) induced renal fibrosis in mice. The mice were pretreated for 7 days with DAL followed by a single injection of DXR (10 mg/kg) via the tail vein. Renal function was analyzed 5 weeks after DXR treatment. DXR caused nephrotoxicity. The symptoms of nephrotic syndrome were greatly improved after DAL treatment. The indices of renal fibrosis, the phosphorylation of Smad3, and the expression of alpha-smooth muscle actin (α-SMA), fibronectin, collagen III (Col III), E-cadherin, TGF-β, and Smad7 in response to DXR were all similarly modified by DAL. The present findings suggest that DAL improved the markers for kidney damage investigated in this model of DXR-induced experimental nephrotoxicity.

A relatively new approach in treatment of malignant melanoma is the use of betulin and its synthetic derivatives that have anticancer properties. The aim of the study was to determine the effect of an acetylenic derivative of betulin, 28-O-propynoylbetulin, on cell growth and apoptosis induction in human melanotic and amelanotic melanoma cells.

Therapy that directly targets apoptosis and/or inflammation could be highly effective for the treatment of cancer. Murraya koenigii is an edible herb that has been traditionally used for cancer treatment as well as inflammation. Here, we describe that girinimbine, a carbazole alkaloid isolated from M. koenigii, induced apoptosis and inhibited inflammation in vitro as well as in vivo. Induction of apoptosis in human colon cancer cells (HT-29) by girinimbine revealed decreased cell viability in HT-29, whereas there was no cytotoxic effect on normal colon cells. Changes in mitochondrial membrane potential, nuclear condensation, cell permeability, and cytochrome c translocation in girinimbine-treated HT-29 cells demonstrated involvement of mitochondria in apoptosis. Early-phase apoptosis was shown in both acridine orange/propidium iodide and annexin V results. Girinimbine treatment also resulted in an induction of G0/G1 phase arrest which was further corroborated with the upregulation of two cyclin-dependent kinase proteins, p21 and p27. Girinimbine treatment activated apoptosis through the intrinsic pathway by activation of caspases 3 and 9 as well as cleaved caspases 3 and 9 which ended by triggering the execution pathway. Moreover, apoptosis was confirmed by downregulation of Bcl-2 and upregulation of Bax in girinimbine-treated cells. In addition, the key tumor suppressor protein, p53, was seen to be considerably upregulated upon girinimbine treatment. Induction of apoptosis by girinimbine was also evidenced in vivo in zebrafish embryos, with results demonstrating significant distribution of apoptotic cells in embryos after a 24-hour treatment period. Meanwhile, anti-inflammatory action was evidenced by the significant dose-dependent girinimbine inhibition of nitric oxide production in lipopolysaccharide/interferon-gamma-induced cells along with significant inhibition of nuclear factor-kappa B translocation from the cytoplasm to nucleus in stimulated RAW 264.7 cells. Girinimbine was also shown to have considerable antioxidant activity whereby 20 μg/mL of girinimbine was equivalent to 82.17±1.88 μM of Trolox. In mice with carrageenan-induced peritonitis, oral pretreatment with girinimbine helped limit total leukocyte migration (mainly of neutrophils), and reduced pro-inflammatory cytokine levels (interleukin-1beta and tumor necrosis factor-alpha) in the peritoneal fluid. These findings strongly suggest that girinimbine could act as a chemopreventive and/or chemotherapeutic agent by inducing apoptosis while suppressing inflammation. There is a potential for girinimbine to be further investigated for its applicability in treating early stages of cancer.

Purpose Imatinib (IM) can safely be discontinued in patients with chronic myeloid leukemia (CML) who have had undetectable minimal residual disease (UMRD) for at least 2 years. We report the final results of the Stop Imatinib (STIM1) study with a long follow-up. Patients and Methods IM was prospectively discontinued in 100 patients with CML with UMRD sustained for at least 2 years. Molecular recurrence (MR) was defined as positivity of BCR-ABL transcript in a quantitative reverse transcriptase polymerase chain reaction assay confirmed by a second analysis point that indicated an increase of one log in relation to the first analysis point at two successive assessments or loss of major molecular response at one point. Results The median molecular follow-up after treatment discontinuation was 77 months (range, 9 to 95 months). Sixty-one patients lost UMRD after a median of 2.5 months (range, 1 to 22 months), and one patient died with UMRD at 10 months. Molecular recurrence-free survival was 43% (95% CI, 33% to 52%) at 6 months and 38% (95% CI, 29% to 47%) at 60 months. Treatment was restarted in 57 of 61 patients with MR, and 55 patients achieved a second UMRD with a median time of 4 months (range, 1 to 16 months). None of the patients experienced a CML progression. Analyses of the characteristics of the study population identified that the Sokal risk score and duration of IM treatment were significantly associated with the probability of MR. Conclusion With a median follow-up of more than 6 years after treatment discontinuation, the STIM1 study demonstrates that IM can safely be discontinued in patients with a sustained deep molecular response with no late MR.

Phenotypic cell-based high-throughput screenings play a central role in drug discovery and toxicology. The main tendency in cell screenings is the increase of the throughput and decrease of reaction volume in order to accelerate the experiments, reduce the costs, and enable screenings of rare cells. Conventionally, cell-based assays are performed in microtiter plates, which exist in 96- to 1536-wells formats and cannot be further miniaturized. In addition, performing screenings of suspension cells is associated with risk of losing cell content during the staining procedures and incompatibility with high-content microscopy. Here, we evaluate the Droplet-Microarray screening platform for culturing, screening, and imaging of suspension cells. We demonstrate pipetting-free cell seeding and proliferation of cells in individual droplets of 3-80 nL in volume. We developed a methodology to perform parallel treatment, staining, and fixation of suspension cells in individual droplets. Automated imaging of live suspension cells directly in the droplets combined with algorithms for pattern recognition for image analysis is demonstrated. We evaluated the developed methodology by performing a dose-response study with antineoplastic drugs. We believe that the DMA screening platform carries great potential to be adopted for broad spectrum of screenings of suspension cells.

Naphthoquinones are naturally occurring biologically active entities. Practical de novo syntheses of three naphthoquinones i.e. lawsone (1), lapachol (2), and β-lapachone (3b) have been achieved from commercially available starting materials. The conversion of lapachol (2) to β-lapachone (3b) was achieved through p-TSA/Iodine/BF3-etherate mediated regioselective cyclisation. Further, 2-alkyl and 2-benzyllawsone derivatives have been prepared as possible anticancer agents. Four derivatives exhibited significant anticancer activity and the best analogue i.e. compound 21a exhibited potential anticancer activity (IC50=5.2μM) against FaDu cell line. Compound 21a induced apoptosis through activation of caspase pathway and exerted cell cycle arrest at S phase in FaDU cells. It also exhibited significant topoisomerase-II inhibition activity. Compound 21a was found to be safe in Swiss albino mice up to 1000mg/kg oral dose.

This two-stage Phase II study assessed the activity of single agent alisertib in patients with recurrent/persistent uterine leiomyosarcoma (uLMS).

The critical role of βTrCP1 in cancer development makes it a discerning target for the development of small drug like molecules. Currently, no inhibitor exists that is able to target its substrate binding site. Through molecular docking and dynamics simulation assays, we explored the comparative binding pattern of βTrCP1-WD40 domain with ACV and its phospho-derivatives (ACVMP, ACVDP and ACVTP). Consequently, through principal component analysis, βTrCP1-ACVTP was found to be more stable complex by obscuring a reduced conformational space than other systems. Thus based on the residual contribution and hydrogen bonding pattern, ACVTP was considered as a noteworthy inhibitor which demarcated binding in the cleft formed by βTrCP1-WD40 specific β-propeller. The outcomes of this study may provide a platform for rational design of specific and potent inhibitor against βTrCP1, with special emphasis on anticancer activity.

To investigate the effect of cerebrolysin on the growth and metastasis of malignant tumors in mice (a model of lung carcinoma Lewis).

A 64-year-old man with recurrent multiple myeloma (BJP-κ type) was treated with 15 mg of lenalidomide (LEN) and dexamethasone. He developed Quincke's edema on his eyelid on day 4. Since the edema improved after withdrawal of LEN, the drug was subsequently re-administered at a decreased dose. However, the edema developed again on day 4. After withdrawal of LEN, the drug was administered again with gradually dose escalation, while confirming the absence of eyelid edema. Although edema did not develop, eosinophils and basophils were increased, and the CRP level was elevated. During the third course of LEN administration, his chest CT showed bilateral ground-glass opacity, and LEN-induced hypersensitivity pneumonitis was diagnosed. The pneumonitis resolved after LEN withdrawal and prednisolone administration. These observations suggested that Quincke's edema, eosinophilia and basophilia, CRP elevation, and hypersensitivity pneumonitis might occur due to the immunological effects of LEN, which is classified as an immunomodulatory drug.

To investigate the relationship between tamoxifen-associated nonalcoholic fatty liver disease (NAFLD) and survival outcomes in patients with breast cancer.

Breast cancer is the most common cancer in women worldwide. Triple-negative breast cancer (TNBC) is an aggressive type that can be treated using platinum-based chemotherapy such as cisplatin (cis-diamminedichloroplatinum II). Although the calpain protein is essential in many cellular processes, including apoptosis, cell signaling, and proliferation, its role in cisplatin-induced apoptosis in TNBC cells is not fully understood. The present study assessed calpain 1-dependent, cisplatin-induced apoptosis in TNBC cells.