Rosiglitazone synergizes anticancer activity of cisplatin and reduces its nephrotoxicity in 7, 12-dimethyl benz{a}anthracene (DMBA) induced breast cancer rats

<p>Abstract</p> <p>Background</p> <p>Antineoplastic drug cisplatin remains the drug of choice for various solid tumours including breast cancer. But dose dependent nephrotoxicity is the major drawback in majority of platinum based chemotherapy regimens. Recent reports have shown that inflammatory pathways are the main offender for cisplatin induced nephrotoxicity. The present study was undertaken to assess the effect of rosiglitazone, a PPARγ agonist and an anti-inflammatory agent, on cisplatin induced nephrotoxicity, and its anticancer activity in DMBA induced breast cancer rats.</p> <p>Methods</p> <p>Mammary tumours were induced in female Sprague-Dawley rats by feeding orally with dimethylbenz [a]anthracene (DMBA) (60 mg/kg). Cisplatin induced nephropathy was assessed by measurements of blood urea nitrogen, albumin and creatinine levels. Posttranslational modifications of histone H3, mitogen-activated protein (MAP) kinase p38 expression and PPAR-γ expression were examined by western blotting.</p> <p>Results</p> <p>Our data shows involvement of TNF-α in preventing cisplatin induced nephrotoxicity by rosiglitazone. Rosiglitazone pre-treatment to cisplatin increases the expression of p38, PPAR-γ in mammary tumours and shows maximum tumour reduction. Furthermore, cisplatin induced changes in histone acetylation, phosphorylation and methylation of histone H3 in mammary tumours was ameliorated by pre-treatment of rosiglitazone. Suggesting, PPAR-γ directly or indirectly alters aberrant gene expression in mammary tumours by changing histone modifications.</p> <p>Conclusion</p> <p>To best of our knowledge this is the first report which shows that pre-treatment of rosiglitazone synergizes the anticancer activity of cisplatin and minimizes cisplatin induced nephrotoxicity in DMBA induced breast cancer.</p

Styrene maleic acid recovers proteins from mammalian cells and tissues while avoiding significant cell death.

Detection of protein biomarkers is an important tool for medical diagnostics, typically exploiting concentration of particular biomarkers or biomarker release from tissues. We sought to establish whether proteins not normally released by living cells can be extracted without harming cells, with a view to extending this into biomarker harvest for medical diagnosis and other applications. Styrene maleic acid (SMA) is a polymer that extracts nanodiscs of biological membranes (containing membrane proteins) from cells. Hitherto it has been used to harvest SMA-lipid-membrane protein particles (SMALP) for biochemical study, by destroying the living cellular specimen. In this study, we applied SMA at low concentration to human primary cardiovascular cells and rat vascular tissue, to 'biopsy' cell proteins while avoiding significant reductions in cell viability. SMA at 6.25 parts per million harvested proteins from cells and tissues without causing significant release of cytosolic dye (calcein) or reduction in cell viability at 24 and 72 hours post-SMA (MTT assay). A wide range of proteins were recovered (20-200 kDa) and a number identified by mass spectrometry: this confirmed protein recovery from plasma membrane, intracellular membranes and cell cytosol without associated cell death. These data demonstrate the feasibility of non-lethally sampling proteins from cells, greatly extending our sampling capability, which could yield new physiological and/or pathological biomarkers

Individual and combined soy isoflavones exert differential effects on metastatic cancer progression

To investigate the effects soy isoflavones in established cancers, the role of genistein, daidzein, and combined soy isoflavones was studied on progression of subcutaneous tumors in nude mice created from green fluorescent protein (GFP) tagged-MDA-MB-435 cells. Following tumor establishment, mice were gavaged with vehicle or genistein or daidzein at 10 mg/kg body weight (BW) or a combination of genistein (10 mg/kg BW), daidzein (9 mg/kg BW), and glycitein (1 mg/kg BW) three times per week. Tumor progression was quantified by whole body fluorescence image analysis followed by microscopic image analysis of excised organs for metastases. Results show that daidzein increased while genistein decreased mammary tumor growth by 38 and 33% respectively, compared to vehicle. Daidzein increased lung and heart metastases while genistein decreased bone and liver metastases. Combined soy isoflavones did not affect primary tumor growth but increased metastasis to all organs tested, which include lung, liver, heart, kidney, and bones. Phosphoinositide-3-kinase (PI3-K) pathway real time PCR array analysis and western blotting of excised tumors demonstrate that genistein significantly downregulated 10/84 genes, including the Rho GTPases RHOA, RAC1, and CDC42 and their effector PAK1. Daidzein significantly upregulated 9/84 genes that regulate proliferation and protein synthesis including EIF4G1, eIF4E, and survivin protein levels. Combined soy treatment significantly increased gene and protein levels of EIF4E and decreased TIRAP gene expression. Differential regulation of Rho GTPases, initiation factors, and survivin may account for the disparate responses of breast cancers to genistein and daidzein diets. This study indicates that consumption of soy foods may increase metastasis

What Is New for an Old Molecule? Systematic Review and Recommendations on the Use of Resveratrol

Stilbenes are naturally occurring phytoalexins that generally exist as their more stable E isomers. The most well known natural stilbene is resveratrol (Res), firstly isolated in 1939 from roots of Veratrum grandiflorum (white hellebore) (1) and since then found in various edible plants, notably in Vitis vinifera L. (Vitaceae) (2). The therapeutic potential of Res covers a wide range of diseases, and multiple beneficial effects on human health such as antioxidant, anti-inflammatory and anti-cancer activities have been suggested based on several in vitro and animal studies (3). In particular, Res has been reported to be an inhibitor of carcinogenesis at multiple stages via its ability to inhibit cyclooxygenase, and is an anticancer agent with a role in antiangiogenesis (4). Moreover, both in vitro and in vivo studies showed that Res induces cell cycle arrest and apoptosis in tumor cells (4). However, clinical studies in humans evidenced that Res is rapidly absorbed after oral intake, and that the low level observed in the blood stream is caused by a fast conversion into metabolites that are readily excreted from the body (5). Thus, considerable efforts have gone in the design and synthesis of Res analogues with enhanced metabolic stability. Considering that reduced Res (dihydro- resveratrol, D-Res) conjugates may account for as much as 50% of an oral Res dose (5), and that D-Res has a strong proliferative effect on hormone-sensitive cancer cell lines such as breast cancer cell line MCF7 (6), we recently devoted our synthetic efforts to the preparation of trans-restricted analogues of Res in which the E carbon-carbon double bond is embedded into an imidazole nucleus. To keep the trans geometry, the two aryl rings were linked to the heteroaromatic core in a 1,3 fashion. Based on this design, we successfully prepared a variety of 1,4-, 2,4- and 2,5-diaryl substituted imidazoles including Res analogues 1, 2 and 3, respectively, by procedures that involve transition metal-catalyzed Suzuki-Miyaura cross-coupling reactions and highly selective N-H or C-H direct arylation reactions as key synthetic steps. The anticancer activity of compounds 1–3 was evaluated against the 60 human cancer cell lines panel of the National Cancer Institute (NCI, USA). The obtained results, that will be showed and discussed along with the protocols developed for the preparation of imidazoles 1–3, confirmed that a structural optimization of Res may provide analogues with improved potency in inhibiting the growth of human cancer cell lines in vitro when compared to their natural lead. (1) Takaoka,M.J.Chem.Soc.Jpn.1939,60,1090-1100. (2) Langcake, P.; Pryce, R. J. Physiological. Plant Patology 1976, 9, 77-86. (3) Vang, O.; et al. PLoS ONE 2011, 6, e19881. doi:10.1371/journal.pone.0019881 (4) Kraft, T. E.; et al. Critical Reviews in Food Science and Nutrition 2009, 49, 782-799. (5) Walle, T. Ann. N.Y. Acad. Sci. 2011, 1215, 9-15. doi: 10.1111/j.1749-6632.2010.05842.x (6) Gakh,A.A.;etal.Bioorg.Med.Chem.Lett.2010,20,6149-6151

Genomic profiling toward precision medicine in non-small cell lung cancer: getting beyond EGFR

Amanda L Richer,1 Jacqueline M Friel,1 Vashti M Carson,2 Landon J Inge,1 Timothy G Whitsett2 1Norton Thoracic Institute, St Joseph&rsquo;s Hospital and Medical Center, 2Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA Abstract: Lung cancer remains the leading cause of cancer-related mortality worldwide. The application of next-generation genomic technologies has offered a more comprehensive look at the mutational landscape across the different subtypes of non-small cell lung cancer (NSCLC). A number of recurrent mutations such as TP53, KRAS, and epidermal growth factor receptor (EGFR) have been identified in NSCLC. While targeted therapeutic successes have been demonstrated in the therapeutic targeting of EGFR and ALK, the majority of NSCLC tumors do not harbor these genomic events. This review looks at the current treatment paradigms for lung adenocarcinomas and squamous cell carcinomas, examining genomic aberrations that dictate therapy selection, as well as novel therapeutic strategies for tumors harboring mutations in KRAS, TP53, and LKB1 which, to date, have been considered &ldquo;undruggable&rdquo;. A more thorough understanding of the molecular alterations that govern NSCLC tumorigenesis, aided by next-generation sequencing, will lead to targeted therapeutic options expected to dramatically reduce the high mortality rate observed in lung cancer. Keywords: non-small cell lung cancer, precision medicine, epidermal growth factor receptor, Kirsten rat sarcoma viral oncogene homolog, serine/threonine kinase 11, tumor protein p5