The MEK-Inhibitor Selumetinib Attenuates Tumor Growth and Reduces IL-6 Expression but Does Not Protect against Muscle Wasting in Lewis Lung Cancer Cachexia

Abstract

Cachexia, or wasting of skeletal muscle and fat, afflicts many patients with chronic diseases including cancer, organ failure, and AIDS. Muscle wasting reduces quality of life and decreases response to therapy. Cachexia is caused partly by elevated inflammatory cytokines, including interleukin-6 (IL-6). Others and we have shown that IL-6 alone is sufficient to induce cachexia both in vitro and in vivo. The mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitor Selumetinib has been tested in clinical trials for various cancers. Moreover, Selumetinib has also been shown to inhibit the production of IL-6. In a retrospective analysis of a phase II clinical trial in advanced cholangiocarcinoma, patients treated with Selumetinib experienced significant gains in skeletal muscle vs. patients receiving standard therapy. However, the use of Selumetinib as a treatment for cachexia has yet to be investigated mechanistically. We sought to determine whether MEK inhibition could protect against cancer-induced cachexia in mice. In vitro, Selumetinib induced C2C12 myotube hypertrophy and nuclear accretion. Next we tested Selumetinib in the Lewis lung carcinoma (LLC) model of cancer cachexia. Treatment with Selumetinib reduced tumor mass and reduced circulating and tumor IL-6; however MEK inhibition did not preserve muscle mass. Similar wasting was seen in limb muscles of Selumetinib and vehicle-treated LLC mice, while greater fat and carcass weight loss was observed with Selumetinib treatment. As well, Selumetinib did not block wasting in C2C12 myotubes treated with LLC serum. Taken together, out results suggest that this MEK inhibitor is not protective in LLC cancer cachexia despite lowering IL-6 levels, and further that it might exacerbate tumor-induced weight loss. Differences from other studies might be disease, species or model-specific.

Luteolin reduces cancer‑induced skeletal and cardiac muscle atrophy in a Lewis lung cancer mouse model

“…In the present study, we successfully replicated a cachexia model by subcutaneously injecting LLW cells into C57BL/6 mice according to procedures outlined in the literature (14)(15)(16). As muscle loss is the main characteristic of cachexia, which leads to insufficient muscle function, we first observed variation in muscle weight.…”

Inflammatory signalling regulates eccentric contraction‐induced protein synthesis in cachectic skeletal muscle

“…We extend these findings by demonstrating a single PDTC dose improved basal protein synthesis. It has recently been suggested that intermittent cycles of pathway inhibition/activation may be required to combat muscle wasting during cancer cachexia . Indeed, many cytokine‐related signalling pathways have established roles in myogenesis and load‐induced muscle growth and remodelling .…”

Tumor-Derived Ligands Trigger Tumor Growth and Host Wasting via Differential MEK Activation

“…These results indicate that MEK signaling is associated with loss of muscle and adipose tissues, the main features of cancer cachexia, and suggest that MEK activation may be involved in tumor-induced host wasting. However, administration of MEK inhibitors in tumorbearing mice and patients are associated with inconsistent results (Au et al, 2016;Prado et al, 2012;Quan-Jun et al, 2017).…”