Trabectedin (
ET743) and
lurbinectedin (
PM01183) limit the production of inflammatory
cytokines that are elevated during
cancer cachexia. Mice carrying C26
colon adenocarcinoma display
cachexia (i.e., premature death and body wasting with muscle, fat and cardiac tissue depletion), high levels of inflammatory
cytokines and subsequent
splenomegaly. We tested whether such drugs protected these mice from
cachexia. Ten-week-old mice were inoculated with C26 cells and three days later randomized to receive intravenously vehicle or 0.05 mg/kg
ET743 or 0.07 mg/kg
PM01183, three times a week for three weeks.
ET743 or
PM01183 extended the lifespan of C26-mice by 30% or 85%, respectively, without affecting
tumor growth or food intake. Within 13 days from C26 implant, both drugs did not protect fat, muscle and heart from
cachexia. Since
PM01183 extended the animal survival more than
ET743, we analyzed
PM01183 further. In tibialis anterior of C26-mice, but not in atrophying myotubes,
PM01183 restrained the NF-κB/PAX7/
myogenin axis, possibly reducing the pro-inflammatory milieu, and failed to limit the C/EBPβ/atrogin-1 axis.
Inflammation-mediated
splenomegaly of C26-mice was inhibited by
PM01183 for as long as the treatment lasted, without reducing
IL-6,
M-CSF or IL-1β in plasma.
ET743 and
PM01183 extend the survival of C26-bearing mice unchanging
tumor growth or
cachexia but possibly restrain muscle-related
inflammation and C26-induced
splenomegaly.