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

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.

Pyrroloquinoline quinone attenuates cachexia-induced muscle atrophy via suppression of reactive oxygen species

“…Inflammatory mediators [tumor necrosis factor-α (TNF-α), interleukin-1 and interleukin -6] are key contributors to the development of cancer cachexia, which is the driving forces of skeletal muscle atrophy caused by cancer cachexia (6,7). TNF-α was often used to induce a model of muscle atrophy in cancer cachexia (8)(9)(10). Therefore, to elucidate the molecular mechanism and develop targeted therapies of cachexia associated muscle atrophy is of significant importance.…”

SiBaoChongCao exhibited anti-fatigue activities and ameliorated cancer cachexia in mice

“…Notably, up to now, there is no approved therapeutic agent for the treatment or prevention of cancer cachexia. 17 Results of the present study showed that SBCC treatment could partly ameliorate cachexia symptoms of mice bearing C26 tumor. SBCC signicantly ameliorates the decrease in body temperature in cachexia mice and slightly ameliorates the decrease in body weight.…”

“…Cancer cachexia in mice was induced as reported in our previous report. 17 Briey, a total of 24 male BALB/c mice (6-8 weeks old) were randomly divided into three groups (8 mice per group): healthy group without tumor (Health group), C26 tumor-bearing mice group (C26 model group) and C26 tumorbearing mice treated with SBCC (1.5 g kg À1 ) group (C26 + SBCC group). On day 0, mice received subcutaneous injections of C26 tumor cells (1.0 Â 10 6 cells/0.1 ml) in the right ank.…”

“…Western blotting was performed as described previously. 17 Briey, the tissues (gastrocnemius muscle or eWAT) were homogenized in RIPA buffer plus a phosphatase protease inhibitor by a tissue lyser (50 Hz, 15 min) bought from QIAGEN. The lysates were centrifuged at 13 000 rpm for 30 min at 4 C. The supernatant was quantied for protein concentration using a BCA Protein Assay Kit (Beyotime, Shanghai, China).…”

Feasibility single-arm study of a medical device containing <em>Desmodium adscendens</em> and <em>Lithothamnium calcareum</em> combined with chemotherapy in head and neck cancer patients

“… 7 In addition, the production of lipid-metabolising factor induces consequent lipolysis that results in patients’ progressive weight loss. 8 Pro-inflammatory cytokines contribute to the pathophysiology of neoplastic cachexia, such as interleukins 1 and 6, tumor necrosis factor alpha, and interferon gamma, which in turn results in an increase in C-reactive protein (CRP), haptoglobin and ceruloplasmin that are responsible for increased fatty acid turnover and muscle proteolysis. 9 Neoplastic cachexia is frequently associated with anorexia due to qualitative and quantitative alterations in hypothalamic signals, including the inhibition of the orexigenic effect of neuropeptide Y, induced by pro-inflammatory cytokines, and the increase in corticotropin-releasing factor and melanocortin.…”