HSP90 inhibitors ameliorated cachexia in different cachectic
mice models.
To investigate the protective effect of the HSP90 inhibitor in
vivo , C26 tumor-bearing cachectic mice were given two HSP90 inhibitors:
17DMAG (15 mg/kg, daily) or PU-H71 (50 mg/kg, daily), respectively. Both
drugs were well tolerated by the mice. We observed that the body weights
of the mice in the 17DMAG and PU-H71 groups were consistently higher
than those in the corresponding vehicle solvent group (Figure 4a, left).
And in an additional surviving test, the 17DMAG treatment significantly
prolongs the overall survival time compared to its vehicle (shift in the
median survival time from 15.5 to 20 days) (Figure 4a, right). However,
PU-H71 had only a moderate effect on the survival time, not as
significant as that of 17DMAG (Figure 4a, right). 17DMAG or PU-H71
treatment significantly increased the tumor-free body mass compared with
the vehicles (Figure 4d, left). Notably, neither 17DMAG nor PU-H71
treatment inhibited C26 tumor growth, excluding the possibility that the
protective effects of 17DMAG or PU-H71 on body weight were based on its
antitumor effect (Figure S2c). Since 17DMAG showed greater potential for
cachexia treatment than PU-H71, it was chosen for further investigation
in our work.
In C26 tumor-bearing mice, the 17DMAG treatment significantly restored
grip strength, increased lean body mass, and the mass of four major
groups of skeletal muscle tibialis anterior (TA), gastrocnemius
(Gastroc), soleus, and extensor digitalis longus (EDL) (Figure 4b-d). In
addition, inguinal white adipose tissue (iWAT), which was almost
completely absent in C26 tumor-bearing mice, was significantly restored
by 17DMAG treatment (Figure S2d). 17DMAG treatment also normalized the
downregulated serum triglycerides (TG) levels compared with those in the
mock treatment vehicle control. However, 17DMAG did not affect the
elevated serum IL-6 level of C26 tumor-bearing mice (Figure S2e).
To validate whether 17DMAG has a universal efficiency in different
cancer cachexia models, another cancer cachexia model of Xenograft of
LLC (Lewis lung cancer), was applied on C57BL6 mice. As previously
reported, the body mass and gastrocnemius muscle mass were decreased in
tumor-bearing mice (Gallot et al., 2014). 17DMAG administration
significantly attenuated the decrease in body mass and muscle mass
(Figure S3a-e), but final tumor weights of 17DMAG treated tumor-bearing
mice were significantly reduced compared with tumor-bearing control
(Figure S3b), which indicated that 17DMAG not only had a protective
effect on cachexia but also inhibited tumor growth in LLC cachectic mice
model.