IL-6 mediated JAK/STAT3 signaling pathway in cancer patients with cachexia

CONCLUSION: STAT3 may be considered as a therapeutic target for cachectic patients with gastric, lung and breast cancer. Furthermore, IL-6 mediates STAT3 activation in cachectic gastric and breast cancer patients (Tab. 5, Fig. 2, Ref. 62)

Therapeutic potential of the PI3K inhibitor LY294002 and PARP inhibitor Talazoparib combination in BRCA-deficient triple negative breast cancer cells

Poly (ADP-ribose) polymerase (PARP) inhibitors provide a promising therapeutic strategy for triple-negative breast cancers (TNBCs) with BRCA1/2 mutation. However, acquire resistance mechanisms and genetic alterations limit the clinical efficacy of PARP inhibitors. The aberrant activation of phosphatidylinositol 3-kinase (PI3K) is a significant problem for cancer development and thus the inhibition of PI3K by PI3K inhibitors is a novel targeted therapy in advanced breast cancer. Here, we, for the first time, investigated that the combined inhibition of PARP by Talazoparib (TAL) and PI3K by LY294002 synergistically inhibited proliferation of BRCA1 mutant HCC1937 TNBC cells through apoptosis, G0/G1 arrest, oxidative stress and increased DNA damage compared to drug alone. Additionally, TAL and LY294002 combination could be a promising strategy for overcoming TAL resistance. Co-treatment of TAL with LY294002 considerably suppressed the activation of PI3K, Akt1 and mTOR expression and phosphorylated protein levels in TNBC cells and caused changes in the multiple kinase phosphorylation. Our findings revealed that the dual inhibition of PARP and PI3K might represent an effective therapeutic strategy for TNBC and potentially overcome TAL resistance

The Apoptotic Effects of Escin in The H-Ras Transformed 5RP7 Cell Line

Extracts of Aesculus hippocastanum L. (horse chestnut) seed have been used in the treatment of chronic venous insufficiency, edema and hemorrhoids. Most of the beneficial effects of horse chestnut are attributed to its principal component -escin or escin. We have evaluated the cytotoxic and apoptotic effects of escin in the H-Ras 5RP7 cell line by analyzing cell growth inhibition, apoptosis and caspase-3 dependent activity. We have also shown structural and ultrastructural changes in these cell using confocal and transmission electron microscopy. The results indicated that escin has significant inhibitory effects on cell growth and the percentage of apoptotic cells increased after treatment with escin, and the micrographs confirmed that escin damaged these cells and induced apoptosis. Copyright (c) 2012 John Wiley & Sons, Ltd

THE EFFECT OF SOLID LIPID NANOPARTICLES ON TAMOXIFEN-RESISTANT BREAST CANCER CELLS

To overcome the acquired Tamoxifen (Tam) resistance in Tam-resistant breast cancer cells without damaging normal cells, we have examined the therapeutic efficacy of Tam-loaded solid lipid nanoparticles (SLNs). Tam-loaded SLNs were produced by hot homogenization method. After characterization, in vitro cytotoxic and apoptotic activity of Tam-SLNs were evaluated in MCF7, MCF7-TamR (Tam-resistant breast cancer cells) and MCF10A cells. Tam-SLNs had an average size nearly 300 nm and a zeta potential of approximately-40 mV. In vitro cytotoxicity results showed that Tam-SLNs indicated the cytotoxic and apoptotic activity on MCF7 and MCF7-TamR cells. We found that MCF7-TamR cell viability was also suppressed significantly by Tam-SLNs and thus, Tam-SLNs could delay and overcome Tam-resistance (p<0.05). Furthermore, the Tam-SLNs did not induce apoptosis on MCF10A control cells. The lowest MCF10A cell viability was 83.0% whereas MCF7 and MCF7-TamR (R↔ and R↑) cells viability are reduced to 21.98%, 27.5% and 29.4% at 10 µM of Tam-SLNs, respectively (p<0.05). The obtained results were supported by apoptosis assays. SLNs-delivery system provided therapeutic efficacy to overcome Tam-resistance thanks to unique features of SLNs including small size, drug accumulation in the tumor site and controlled drug release. Therefore, Tam-SLNs may have therapeutic potential for the treatment of TAM-resistant breast cancer

Evaluation of Curcumin Therapeutic Effects on Histological Subtypes of Canine Mammary Gland Tumours

Canine mammary gland tumors (CMGTs) are the most frequent types of cancer in bitches and proposed as a model of human breast cancer. The anticancer effect of curcumin on human breast cancer has been extensively studied. The aim of this study was to evaluate the therapeutic effect of curcumin in two different histologies (simple carcinoma [SC] and squamous cell carcinoma [SCC]) of CMGTs. Primary canine mammary cells were isolated from the tumoral tissues surgically resected from two bitches (Case 1 and Case 2). Cell viability, apoptotic percentage, cell cycle progression and the changes in the cell morphology were evaluated. Curcumin inhibited the growth of both SC (Case 1) and SCC (Case 2) cells. However, Case 1 cells (43.48% +/- 3.87% at 0.5 mu M) were more sensitive to curcumin than Case 2 cells (59.36% +/- 2.09% at 0.5 mu M). Curcumin induced total apoptotic cell death through G0/G1 arrest, and this effect was more profound in Case 1 cells. Furthermore, cytoplasmic vacuolization, apoptotic bodies and membrane blebbing were observed in both cells following curcumin treatment. Our findings provide a novel approach for the effects of curcumin as a natural compound on CMGTs. Further investigations should be performed to investigate the molecular mechanisms of the differences in curcumin efficacy for different histological subtypes

Anti-inflammatory effects of nobiletin on TLR4/TRIF/IRF3 and TLR9/IRF7 signaling pathways in prostate cancer cells

Background: Toll-like receptors (TLRs) are often expressed in natural immune cells as well as in tumor cells. TLR4 exhibits both tumor promoting and tumor-suppressing roles and higher TLR9 expression is an important marker of poor prognosis in prostate cancer (PCa). Nobiletin (NOB) is an O-methylated flavonoid and NOB has been proven to have anti-cancer effect in PCa cells. However, there is no study in the literature investigating the potential anti-inflammatory effects of NOB on the TLR signaling pathways in cancer. Therefore, we aimed to explore the potential anti-inflammatory effects of NOB on the TLR4/TRIF/IRF3 and TLR9/IRF7 signaling pathways in different types of PCa cell lines, for the first time. Material and methods: In the current study, the cytotoxic effect of NOB PC-3 (hormone-independent and metastatic) and LNCaP cells (hormone-dependent) was evaluated by WST-1 assay. Furthermore, the inhibitory effects of NOB on TLR4/TRIF/IRF3 and TLR9/IRF7signaling pathway were determined by RT-PCR, western blotting and ELISA analysis. Results: NOB demonstrated an inhibitory effect on PCa cell growth and LNCaP cells were more sensitive to NOB than PC-3 cells due to androjen receptor status. Furthermore, NOB alone could suppress TLR4/TRIF/IRF3 and TLR9/IRF7 signaling pathways through the downregulation of their associated pathways (mRNA and related protein levels) and the release of IFN-alpha and IFN-beta compared to LPS or CpG-ODN stimulated PCa cells. Conclusions: NOB potentially inhibited TLR4 and TL9-dependent signaling pathway in PCa cells. However, the efficacy of NOB was different in PCa cells due to the hormone status and aggressive features

Comparison of the anti-cancer activity of 5-aminolevulinic acid-mediated photodynamic therapy after continuous wave and pulse irradiation in different histological types of canine mammary sarcoma tumors

Canine mammary sarcoma tumors (CMST) are the most aggressive tumors with poor prognosis in dogs. Due to inadequate treatment options for CMST, recent studies have focused on alternative treatment strategies. We previously determined the optimized protocol of 5-ALA-based photodynamic therapy (PDT) in canine liposarcoma. However, its molecular mechanisms in the treatment of different histological types of CMST remain unclear.In this context, we, for the first time, assessed 5-aminolevulinic acid (5-ALA)-PDT-mediated anti-cancer activity and its molecular mechanism after continuous wave (CW) and pulse radiation (PR) on three different histological types (liposarcoma, chondrosarcoma, and osteosarcoma) of CMST cells by WST-1, Annexin V, ROS, acridine orange/propidium iodide staining, RT-PCR, and western blot analysis.Our findings showed that 5-ALA/PDT significantly suppressed the proliferation of CMST cells (p < 0.01) and induced apoptosis via increased ROS level and overexpression of Caspase-9 and Caspase-3 mRNA and cleaved protein levels in especially liposarcoma and chondrosarcoma cells following CW and PR irradiation at 9 J/cm(2). However, the response of CMST cells to 5-ALA was different upon CW and PR irradiation due to differences in their origin.Collectively, our findings provided the first evidence that 5-ALA-based PDT could be used as an alternative treatment strategy, especially liposarcoma and chondrosarcoma. However, further in vitro and in vivo studies are required to elucidate the underlying molecular mechanism of the efficacy of 5-ALA in CMST cells at the molecular level