Smac Mimetic Compound Treatment Induces Tumour Regression and Skeletal Muscle Wasting
Creators: name: Vineham, Jennifer
Publisher: name: Université d'Ottawa / University of Ottawa
Year: 2014
Subjects: Smac mimetic
cIAP1
cIAP2
c-FLIP
skeletal muscle
TNF-α

description: Of all of the cancer patients throughout the world, approximately 50% of them are affected to some degree by cachexia. This syndrome involves significant skeletal muscle wasting, loss of adipose tissue and overall decrease in body weight in patients, particularly those with lung, pancreatic and gastric cancers. Cancer-induced cachexia is characterized by the presence of increased cytokines, notably TNF-α, IL-1β and IL-6. Most patients suffering of cancer-induced cachexia experience increased toxicity in response to chemotherapy, leading to fewer rounds of treatment and thus impeding the patients’ chances for recovery. More research into effective treatments for cancer-induced cachexia would therefore be indispensable. The inhibitor of apoptosis proteins (IAPs) have emerged as important cancer targets, primarily because of their roles as caspase inhibitors and regulators of NF-κB signalling. Small molecule IAP antagonists known as Smac mimetic compounds (SMCs) are currently in stage I/II clinical trials. They function by targeting cIAP1 and cIAP2 (and to a lesser extent, XIAP) resulting in a cytokine mediated death response in cancer cells. SMCs induce the production of TNF-α, a cytokine with which SMCs can potently synergize. However, limited efficacy occurs in some cancer cell lines (presumably because TNF-α cannot be induced in an autocrine fashion) and an exogenous source of the cytokine, such as that induced by using an oncolytic virus, is required. Notably, TNF-α (initially known as “cachectin”) is known to play a significant role in the induction of skeletal muscle atrophy. We therefore wanted to examine the effects of TNF-α induction by SMC and oncolytic virus co-treatment on both tumour regression and skeletal muscle in tumour bearing mice. We investigated the effects of SMC treatment on Lewis Lung Carcinoma (LLC) and B16F10 melanoma cell lines, both of which have been shown to be established cachectic cancer cell lines. Our in-vitro analysis of LLC and B16F10 cells revealed that LLC cells are sensitive to SMC and TNF-α co-treatment whereas B16F10 cancer cells remain resistant. SMC treatment, in combination with an oncolytic virus, VSVΔ51, increased tumour regression and survival time in LLC tumour bearing mice. Based on findings from previous studies, we investigated the role of cellular FLICE-like inhibitory protein (c-FLIP) in the resistance of the B16F10 melanoma cell line to SMC treatment. We were able to determine that the down-regulation of c-FLIP sensitizes the B16F10 cells to SMC and TNF-α induced cell death. In extending these findings, we found that SMC treatment alone can cause skeletal muscle wasting in the tibialis anterior muscle of LLC tumour bearing mice. However, the atrophic response was observed to be minimal as documented by a slight but significant decrease (approximately 10%) in muscle fibre cross-sectional area. Moreover, no biochemical evidence of muscle atrophy, as visualized by changes in the expression of myosin heavy chain (MHC) and Muscle RING Finger protein 1 (MuRF1), was found. Regardless, we speculate that the impact of SMC treatment on muscle wasting would be transient and reversible, and propose that the benefits of such a combination immunotherapy would greatly outweigh the risks.