Pyrrolidine Dithiocarbamate (PDTC) Attenuates Cancer Cachexia by Affecting Muscle Atrophy and Fat Lipolysis.

Chunxiao Miao,Yanfen Fang,Yuanyuan Lv,Xiaoping Chai,Wanli Zhang,Xiongwen Zhang,Xuan Liu,Lixing Feng

doi:10.3389/fphar.2017.00915

Abstract

Cancer cachexia is a kind of whole body metabolic disorder syndrome accompanied with severe wasting of muscle and adipose tissue. NF-κB signaling plays an important role during skeletal muscle atrophy and fat lipolysis. As an inhibitor of NF-κB signaling, Pyrrolidine dithiocarbamate (PDTC) was reported to relieve cancer cachexia; however, its mechanism remains largely unknown. In our study, we showed that PDTC attenuated cancer cachexia symptom in C26 tumor bearing mice models in vivo without influencing tumor volume. What’s more, PDTC inhibited muscle atrophy and lipolysis in cells models in vitro induced by TNFα and C26 tumor medium. PDTC suppressed atrophy of myotubes differentiated from C2C12 by reducing MyoD and upregulating MuRF1, and preserving the expression of perilipin as well as blocking the activation of HSL in 3T3-L1 mature adipocytes. Meaningfully, we observed that PDTC also inhibited p38 MAPK signaling besides the NF-κB signaling in cancer cachexia in vitro models. In addition, PDTC also influenced the protein synthesis of skeletal muscle by activating AKT signaling and regulated fat energy metabolism by inhibiting AMPK signaling. Therefore, PDTC primarily influenced different pathways in different tissues. The study not only established a simple and reliable screening drugs model of cancer cachexia in vitro but also provided new theoretical basis for future treatment of cancer cachexia.

Highlights

Cachexia is a severe wasting syndrome accompanied with serious loss of body weight during a lot of chronic diseases such as cancer, AIDS, tuberculosis (Tisdale, 2009)
Pyrrolidine dithiocarbamate (PDTC) didn’t influence C26 tumor growth in mice (Figures 2E,F). These results demonstrated that PDTC effectively attenuated C26 tumor-induced body weight loss, and did not affect C26 tumor growth
The concentration of PDTC and TNFα used in these experiments had no effect on 3T3-L1 mature adipocytes viability. These results demonstrated that PDTC inhibited the lipolysis process in 3T3-L1 mature adipocytes in cancer cachexia condition

Summary

Introduction

Cachexia is a severe wasting syndrome accompanied with serious loss of body weight during a lot of chronic diseases such as cancer, AIDS, tuberculosis (Tisdale, 2009). Infliximab, anti-TNFα monoclonal antibody, was applied to treat cancer-related cachexia in subjects with pancreatic cancer in clinical phase II (Wiedenmann et al, 2008; Arruda et al, 2010; Gueta et al, 2010; Miksza et al, 2013). These agents have entered into clinical evaluation, it is increasingly evident that a single therapy may not be sufficient to prevent or ameliorate cancer cachexia due to the complexity of this syndrome. Better understanding the molecular mechanisms of cancer cachexia will allow the identification of potential therapeutic targets and the development of promising drugs

Methods

Results

Conclusion