The development of new pharmacological approaches for preventing muscle wasting in
cancer is an important goal because cachectic patients display a reduced response to
chemotherapy and
radiotherapy.
Xanthine derivatives such as
pentoxifylline inhibit tumour
necrosis factor-alpha (TNF) production, which has been implicated in the signalling of muscle wasting. However, the effect of
pentoxifylline has been inconclusive in clinical trials. We report here the first direct evidence that daily
injections of
torbafylline (also known as
HWA 448), another
xanthine derivative, had no effect by itself on muscle proteolysis in control healthy rats. In
cancer rats, the
drug blocked the
lipopolysaccharide-induced hyperproduction of TNF and prevented muscle wasting. In these animals
HWA 448 suppressed the enhanced
proteasome-dependent proteolysis, which is sensitive to the
proteasome inhibitor MG132, and the accumulation of high-molecular-mass
ubiquitin (Ub) conjugates in the myofibrillar fraction. The
drug also normalized the enhanced muscle expression of Ub, which prevails in the atrophying muscles from
cancer rats. In contrast,
HWA 448 did not reduce the increased expression of either the 14 kDa Ub conjugating
enzyme E2 or the
ATPase and non-
ATPase subunits of the 19 S regulatory complex of the 26 S
proteasome, including the non-
ATPase subunit S5a, which recognizes polyUb degradation signals. Finally, the
drug also prevented muscle wasting in septic rats (which exhibit increased TNF production), and was much more potent than
pentoxifylline or other
xanthine derivatives. Taken together, the data indicate that
HWA 448 is a powerful inhibitor of muscle wasting that blocks enhanced Ub-
proteasome-dependent proteolysis in situations where TNF production rises, including
cancer and
sepsis.