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

摘要: The development of pharmacological approaches for preventing the loss muscle proteins would be extremely valuable cachectic patients. For example, severe wasting in cancer patients correlates with a reduced efficacy chemotherapy and radiotherapy. Pentoxifylline (PTX) is very inexpensive xanthine derivative, which widely used humans as haemorheological agent, inhibits tumor necrosis factor transcription. We have shown here that daily administration PTX prevents atrophy suppresses increased protein breakdown Yoshida sarcoma-bearing rats by inhibiting activation nonlysosomal, Ca2+-independent proteolytic pathway. blocked ubiquitin pathway, apparently suppressing enhanced expression ubiquitin, 14-kDa conjugating enzyme E2, C2 20S proteasome subunit from rats. 19S complex 11S regulator associate regulate its peptidase activities. mRNA levels ATPase MSS1 cachexia, contrast mRNAs other regulatory subunits. This adaptation was suppressed PTX, suggesting drug inhibited 26S proteasome. first demonstration manipulation ubiquitin-proteasome pathway cachexia well tolerated humans. Overall, data suggest can prevent situations where production rises, including cancer, sepsis, AIDS trauma.