The Curcuminoid EF24 in Combination with TRAIL Reduces Human Renal Cancer Cell Migration by Decreasing MMP-2/MMP-9 Activity through a Reduction in H2O2.

Cancer cells present high levels of oxidative stress, and although an increase in reactive oxygen species (ROS), such as H2O2, can lead to apoptosis, it can also induce cell invasion and metastasis. As the increase in ROS can lead to an increase in the expression of MMP-2 and MMP-9, thus causing the degradation of the extracellular matrix, an increase in the ROS H2O2 might have an impact on MMP-2/MMP-9 activity. The natural compound curcumin has shown some anticancer effects, although its bioavailability hinders its therapeutic potential. However, curcumin and its analogues were shown to resensitize kidney cancer cells to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. This study shows that the curcuminoid EF24 in combination with TRAIL increases peroxidase activity in the renal adenocarcinoma cell line ACHN, reducing the level of intracellular H2O2 and MMP-2/MMP-9 activity, a mechanism that is also observed after treatment with curcumin and TRAIL.

Effects of Curcumin Analogues DMC and EF24 in Combination with the Cytokine TRAIL against Kidney Cancer.

The natural compound curcumin has been shown to have therapeutic potential against a wide range of diseases such as cancer. Curcumin reduces cell viability of renal cell carcinoma (RCC) cells when combined with TNF-related apoptosis-inducing ligand (TRAIL), a cytokine that specifically targets cancer cells, by helping overcome TRAIL resistance. However, the therapeutic effects of curcumin are limited by its low bioavailability. Similar compounds to curcumin with higher bioavailability, such as demethoxycurcumin (DMC) and 3,5-bis(2-fluorobenzylidene)-4-piperidone (EF24), can potentially have similar anticancer effects and show a similar synergy with TRAIL, thus reducing RCC viability. This study aims to show the effects of DMC and EF24 in combination with TRAIL at reducing ACHN cell viability and ACHN cell migration. It also shows the changes in death receptor 4 (DR4) expression after treatment with these compounds individually and in combination with TRAIL, which can play a role in their mechanism of action.

Analysis of Ras-effector interaction competition in large intestine and colorectal cancer context.

Cancer is the second leading cause of death globally, and colorectal cancer (CRC) is among the five most common cancers. The small GTPase KRAS is an oncogene that is mutated in ~30% of all CRCs. Pharmacological treatments of CRC are currently unsatisfactory, but much hope rests on network-centric approaches to drug development and cancer treatment. These approaches, however, require a better understanding of how networks downstream of Ras oncoproteins are connected in a particular tissue context - here colon and CRC. Previously we have shown that competition for binding to a 'hub' protein, such as Ras, can induce a rewiring of signal transduction networks. In this study, we analysed 56 established and predicted effectors that contain a structural domain with the potential ability to bind to Ras oncoproteins and their link to pathways coordinating intestinal homoeostasis and barrier function. Using protein concentrations in colon tissue and Ras-effector binding affinities, a computational network model was generated that predicted how effectors differentially and competitively bind to Ras in colon context. The model also predicted both qualitative and quantitative changes in Ras-effector complex formations with increased levels of active Ras - to simulate its upregulation in cancer - simply as an emergent property of competition for the same binding interface on the surface of Ras. We also considered how the number of Ras-effector complexes at the membrane can be increased by additional domains present in some effectors that are recruited to the membrane in response to specific conditions (inputs/stimuli/growth factors) in colon context and CRC.