Manipulation of the ubiquitin-proteasome pathway in cachexia: pentoxifylline suppresses the activation of 20S and 26S proteasomes in muscles from tumor-bearing rats

The development of pharmacological approaches for preventing the loss of mu scle proteins would be extremely valuable for cachectic patients. For examp le, severe wasting in cancer patients correlates with a reduced efficacy of chemotherapy and radiotherapy. Pentoxifylline (PTX) is a very inexpensive xanthine derivative, which is widely used in humans as a haemorheological a gent, and inhibits tumor necrosis factor transcription. We have shown here that a daily administration of PTX prevents muscle atrophy and suppresses i ncreased protein breakdown in Yoshida sarcoma-bearing rats by inhibiting th e activation of a nonlysosomal, Ca2+-independent proteolytic pathway. PTX b locked the ubiquitin pathway, apparently by suppressing the enhanced expres sion of ubiquitin, the 14-kDa ubiquitin conjugating enzyme E2, and the C2 2 0S proteasome subunit in muscle from cancer rats. The 19S complex and 11S r egulator associate with the 20S proteasome and regulate its peptidase activ ities. The mRNA levels for the ATPase subunit MSS1 of the 19S complex incre ased in cancer cachexia, in contrast with mRNAs of other regulatory subunit s. This adaptation was suppressed by PTX, suggesting that the drug inhibite d the activation of the 26S proteasome. This is the first demonstration of a pharmacological manipulation of the ubiquitin-proteasome pathway in cache xia with a drug which is well tolerated in humans. Overall, the data sugges t that PTX can prevent muscle wasting in situations where tumor necrosis fa ctor production rises, including cancer, sepsis, AIDS and trauma.