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.