Development of polyvinylpyrrolidone/paclitaxel self-assemblies for breast cancer

The goal of this investigation was to develop and demonstrate a polymer/paclitaxel self-assembly (PTX-SA) formulation. Polymer/PTX-SAs were screened based on smaller size of formulation using dynamic light scattering analysis. Additionally, fluorescence microscopy and flow cytometry studies exhibited that polyvinylpyrrolidone (PVP)-based PTX-SAs (PVP/PTX-SAs) had superior cellular internalization capability in MCF7 and MDA-MB-231 breast cancer cells. The optimized PVP/PTX-SAs exhibited less toxicity to human red blood cells indicating a suitable formulation for reducing systemic toxicity. The formation of PVP and PTX self-assemblies was confirmed using fluorescence quenching and transmission electron microscopy which indicated that the PVP/PTX-SAs were spherical in shape with an average size range of 53.81 nm as detected by transmission electron microscopy (TEM). FTIR spectral analysis demonstrates incorporation of polymer and paclitaxel functional groups in PVP/PTX-SAs. Both proliferation (MTS) and clonogenic (colony formation) assays were used to validate superior anticancer activity of PVP/PTX-SAs in breast cancer cells over paclitaxel. Such superior anticancer activity was also demonstrated by downregulation of the expression of pro-survival protein (Bcl-xL), upregulation of apoptosis-associated proteins (Bid, Bax, cleaved caspase 7, and cleaved PARP) and -tubulin stabilization. These results support the hypothesis that PVP/PTX-SAs improved paclitaxel delivery to cancer cells.

APE1/Ref-1 as an emerging therapeutic target for various human diseases: phytochemical modulation of its functions

Apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional enzyme involved in the base excision repair (BER) pathway, which repairs oxidative base damage caused by endogenous and exogenous agents. APE1 acts as a reductive activator of many transcription factors (TFs) and has also been named redox effector factor 1, Ref-1. For example, APE1 activates activator protein-1, nuclear factor kappa B, hypoxia-inducible factor 1alpha, paired box gene 8, signal transducer activator of transcription 3 and p53, which are involved in apoptosis, inflammation, angiogenesis and survival pathways. APE1/Ref-1 maintains cellular homeostasis (redox) via the activation of TFs that regulate various physiological processes and that crosstalk with redox balancing agents (for example, thioredoxin, catalase and superoxide dismutase) by controlling levels of reactive oxygen and nitrogen species. The efficiency of APE1/Ref-1's function(s) depends on pairwise interaction with participant protein(s), the functions regulated by APE1/Ref-1 include the BER pathway, TFs, energy metabolism, cytoskeletal elements and stress-dependent responses. Thus, APE1/Ref-1 acts as a 'hub-protein' that controls pathways that are important for cell survival. In this review, we will discuss APE1/Ref-1's versatile nature in various human etiologies, including neurodegeneration, cancer, cardiovascular and other diseases that have been linked with alterations in the expression, subcellular localization and activities of APE/Ref-1. APE1/Ref-1 can be targeted for therapeutic intervention using natural plant products that modulate the expression and functions of APE1/Ref-1. In addition, studies focusing on translational applications based on APE1/Ref-1-mediated therapeutic interventions are discussed.

Potential molecular targeting of splice variants for cancer treatment.

Array of new targets for investigation as cancer therapeutics has great potential to grow as new splice-variants are identified and characterized in cancer cell-lines and tumor samples. Tumor-specific splice variants are being discovered at an increasing rate and their functions are also investigated in cancer progression. The tumor-specific splice variants whose expression patterns and activities are successfully characterized may become attractive targets for ablation or splicing modification. The extreme specificity of their expression suggests that a variant-specific treatment may allow for targeting of cancerous cells with minimal impact to healthy tissues. Clinical investigation of applying antisense oligonucleotides to down-regulate mRNAs that contribute to cancer cell survival and to modify splicing patterns in muscular dystrophy has shown promising results. These results show that antisense therapy may be applied effectively and safely in humans. As these treatment strategies continue to improve and novel tumor-specific splice-variants are identified, modification of splicing patterns will become an important field of investigation to develop more effective and safe cancer therapies.

Growth inhibitory, apoptotic and anti-inflammatory activities displayed by a novel modified triterpenoid, cyano enone of methyl boswellates.

Triterpenoids are pentacyclic secondary metabolites present in many terrestrial plants. Natural triterpenoids have been reported to exhibit anti-inflammatory and anti-carcinogenic activities. Here, we show that modifications of ring A of boswellic acid (2 cyano, 3 enone) resulted in a highly active growth inhibitory, anti-inflammatory, prodifferentiative and anti-tumour triterpenoid compound called cyano enone of methyl boswellates (CEMB). This compound showed cytotoxic activity on a number of cancer cell lines with IC50 ranging from 0.2 to 0.6 μM. CEMB inhibits DNA synthesis and induces apoptosis in A549 cell line at 0.25 μM and 1 μM concentrations, respectively. CEMB induces adipogenic differentiation in 3T3-L1 cells at a concentration of 0.1 μM. Finally, administration of CEMB intra-tumourally significantly inhibited the growth of C6 glioma tumour xenograft in immuno-compromised mice. Collectively, these results suggest that CEMB is a very potent anti-tumour compound.