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Inflammatory cytokines and oxidative stress are two critical mediators in inflammation-associated cancer. Interleukin-6 (IL-6) is one of the most critical tumor-promoting cytokines in non-small cell lung cancer (NSCLC). In our recent study, we confirmed that NADPH oxidase 4 (NOX4), an important source of reactive oxygen species (ROS) production in NSCLC cells, promotes malignant progression of NSCLC. However, whether the crosstalk of NOX4 and IL-6 signalings exists in NSCLC remains undentified. In this study, we show that NOX4 expression is positively correlated with IL-6 expression in NSCLC tissues. Exogenous IL-6 treatment significantly enhances NOX4/ROS/Akt signaling in NSCLC cells. NOX4 also enhances IL-6 production and activates IL-6/STAT3 signaling in NSCLC cells. Specifically, NOX4 is confirmed to functionally interplay with IL-6 to promote NSCLC cell proliferation and survival. The in vivo results were similar to those obtained in vitro. These data indicate a novel NOX4-dependent link among IL-6 in the NSCLC microenvironment, oxidative stress in NSCLC cells and autocrined IL-6 in NSCLC cells. NOX4/Akt and IL-6/STAT3 signalings can reciprocally and positively regulate each other, leading to enhanced NSCLC cell proliferation and survival. Therefore, NOX4 may serve as a promising target against NSCLC alone with IL-6 signaling.

A series of new matrinic acid derivatives 5a–e was synthesized. The chemical structures of the synthesized compounds were confirmed by 1H-NMR, 13C-NMR, and electrospray ionization mass spectroscopy. The anti-tumor activities were also investigated in vitro by evaluating the effect of synthesized compounds on the proliferation of A375, A549, HeLa, and HepG2 cells. Compound 5e was found to be the most potent against A375 and HeLa cells, with IC50 values of 37 and 75.5 μg/mL, respectively. Compounds 5b, 5c, 5g, and 5h also exhibited antiproliferative activities against A549 cells, with IC50 values within the 36.2–47 μg/mL range. For HepG2 cells, 5e and 5i, with IC50 values of 78.9 and 61 μg/mL, respectively, showed higher antiproliferative activity than taxol.

Paclitaxel is a drug within one of the most promising classes of anticancer agents. Unfortunately, clinical success of this drug has been limited by the insurgence of cellular resistance. To address this, Paclitaxel resistance was modeled in an in vitro system using estrogen treated prostate cancer cells. This study demonstrates that emerging resistance to clinically relevant doses of Paclitaxel is associated with 17-β-estradiol (E2) treatment in PC-3 cells, but not in LNCaP cells. We found that small interfering RNA mediated knockdown of ERα lead to a decrease in E2 induced Paclitaxel resistance in androgen-independent cells. We also showed that ERα mediated the effects of estrogen, thereby suppressing androgen-independent cell proliferation and mediating Paclitaxel resistance. Furthermore, E2 promoted Prohibitin (PHB) mitochondrial-nucleus translocation via directly mediation of ERα, leading to an inhibition of cellular proliferation by PHB. Additionally, restoration of Paclitaxel sensitivity by ERα knockdown could be overcome by PHB overexpression and, conversely, PHB knockdown decreased E2 induced Paclitaxel resistance. These findings demonstrate that PHB lies downstream of ERα and mediates estrogen-dependent Paclitaxel resistance signaling cascades.

International audience; Herein is reported a convergent synthesis of isocombretastatins A, a novel class of potent antitubulin agents. These compounds having a 1,1-diarylethylene scaffold constitute the simplest isomers of natural Z-combretastatins A that are easy to synthesize without need to control the Z-olefin geometry. The discovery of isoCA-4 with biological activities comparable to that of CA-4 represents a major progress in this field.