BGP-15 is a novel cytoprotective compound with potential HSP72 co-inducing and PARP inhibiting properties. We have previously found that oxaliplatin treatment results in intestinal dysfunction, oxidative stress and loss of enteric neurons. Gastrointestinal side-effects of chemotherapy are under-recognised clinical hurdle leading to dose reduction, delays and cessation of treatment, presenting a constant challenge for efficient and tolerable anti-cancer treatment. This study indicates that XELOX therapy does not affect plasma AA levels or worsen oxidative stress. Plasma levels of MOS did not change significantly. The results showed that during XELOX therapy (from phase B to phase D), in comparison to baseline (phase A), the branched chain amino acid/essential amino acid ratio, branched chain amino acids expressed as a percentage of total AAs, and arginine expressed as a percentage of total AAs significantly decreased (p = 0.017, p = 0.028, p = 0.028, respectively). Venous blood samples for AA and MOS (malondialdehyde, MDA 8-hydroxy-2’-deoxyguanosine, 8-OHdG) measurements were drawn in fasting patients before each oxaliplatin infusion at initiation (A), 1 month (B) and 3 months (C) of the therapy, and after XELOX had finished (6 months, D). Fourteen normal-weight CRC patients were enrolled one month after surgery and scheduled for oxaliplatin-fluoropyrimidine combination (XELOX) therapy.
Therefore, this study aimed to document plasma AAs and MOS before, during and after chemotherapy in colorectal cancer (CRC) surgery patients. We hypothesize that chemotherapy may worsen plasma amino acids (AAs) and markers of oxidative stress (MOS). Our study highlights BGP-15 as a potential adjunct therapy to address chemotherapy-induced skeletal muscle and mitochondrial pathology.Ĭhemotherapy for colorectal cancer may lower muscle protein synthesis and increase oxidative stress.
BGP-15 adjunct therapy protected against increased ROS production, improved mitochondrial viability 4-fold and preserved fibre diameter and number. There was a tendency for reduction in intramuscular protein content, albeit apparently not via Murf1 (atrophy)- or p62 (autophagy)- dependent pathways. These data correspond with reduced diameter of isolated FDB fibres and shift in the fibre size distribution frequency of TA to the left. Here, we are the first to show that OXA penetrates the mitochondria, and, as a possible consequence of this, increases mtROS production.
OXA treatment also altered the muscle architecture, increasing collagen deposition, neutral lipid and Ca2+ accumulation all of which were ameliorated with BGP-15 adjunct therapy. OXA induced a 15% (p<0.05) reduction in lean tissue mass without significant changes in food consumption or energy expenditure. To do so, we investigated the effects of two weeks of OXA (3mg/kg) treatment with and without BGP-15 (15mg/kg). Here we investigate the effects of oxaliplatin (OXA) treatment in mice on the skeletal muscle and mitochondria, and the capacity for the Poly ADP-ribose polymerase (PARP) inhibitor, BGP-15, to ameliorate any pathological side-effects induced by OXA. As such, a defence against chemotherapy-induced skeletal muscle dysfunction is required. Albeit highly effective, chemotherapy has a multitude of deleterious side-effects including skeletal muscle wasting and fatigue, which considerably reduces patient quality of life and survivability. Skeletal muscle mass is strongly associated with the nutritional status of the organism (Jeejeebhoy et al., 1990 Mithal et al., 2013 Moon, 2014), whereby in times of nutrient deprivation (i.e., starvation), skeletal muscle protein synthesis pathways are inhibited and degradation pathways are activated to liberate nutritionals stores (particularly glucose and amino acids) for key physiological functions (Thissen et al., 1994 Levine and Kroemer, 2008).Ĭhemotherapy is a leading intervention against cancer. It is interesting to speculate that the loss of lean mass (and tendency for the loss of fat mass) might be strongly correlated with OXA-induced enteric neuropathy and gastrointestinal dysfunction which has been reported previously (Stojanovska et al., 2015 McQuade et al., 2016a) and which likely limits the capacity for nutrient absorption in the small intestine. Further analysis of body composition elucidated that OXA treatment depressed total lean tissue mass with a tendency for fat mass to follow the same declination when indexed against absolute body weight (Figures 2A-C).