New treatment developed for cancer-induced weight loss [PreClinical]
1. In mouse models of cancer-induced fat and muscle wasting (cachexia), lower levels of the protein Ampk were accompanied by higher levels of the Ampk-interacting protein Cidea.
2. Treatment with a peptide designed to inhibit the interaction between Ampk and Cidea resulted in reduced cachexia.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Many patients with cancer lose a significant amount of their fat and muscle. Due to the fatality of cachexia along with data showing the protective nature of higher amounts of body fat in cancer patients, this study aimed to determine molecular processes involved in the rapid depletion of adipose tissue and to develop a means for its inhibition.
Mice implanted with mouse or human colon cancer cells served as models of cachexia. In both models, there was a lower expression of Ampk, a protein kinase involved in ATP-producing catabolic processes. Correspondingly, ATP levels were lower in these mice. Cidea, a protein known to interact with and destabilize the Amp-associated complex, was found to be highly expressed in adipose tissue biopsies from cachexic patients as well as the mice, potentially explaining the low levels of Ampk. A peptide was then designed to inhibit the interaction between Cidea and the Ampk complex, allowing for the stabilization and continued expression of Ampk. Treatment with this peptide led to a greater percentage of white adipose tissue in both mouse models.
There was no dose response testing to determine the potential toxicity or minimal effective dose of this treatment. In addition, potential side effects of the treatment were not reported and the function of Ampk in other cell lines was also not included. Although these can be goals for future studies, this research demonstrates a potential strategy for treatment of cachexia that could extend the lives of cancer patients.
Click to read the study in Nature Medicine
Relevant Reading: Mechanisms of metabolic dysfunction in cancer-associated cachexia
In-Depth [animal study]: C26 cells, a mouse colon cancer cell line, were implanted in mice. A Western blot of their white adipose tissue showed a lower expression of Ampk. It was also noted that these mice had a significantly lower amount of ATP production (p<0.001). Similar results were obtained following the implantation of human SW480 colon cancer cells into mice. The expression of Cidea, a protein known to inhibit Ampk, was overexpressed in each mouse model as well as in abdominal and subcutaneous adipose tissue biopsies from over 60 patients with cachexia (p<0.05).
The demonstration of the potentially crucial role of the Ampk pathway led to the production of a peptide coding for Ampk-β1 that would act as a competitive inhibitor to prevent the interaction between Cidea and Ampk-β. First, this peptide was co-transfected with Cidea into mouse embryonic fibroblasts and was found to restore the stability and interaction between Ampk associated proteins. This peptide was then encoded within an adeno-associated virus in order to deliver this peptide to adipose tissue. Follow microinjection of 3 x 109 infectious units of this virus, a 30% increase in adipose tissue weight was noted with no major effects seen in the healthy control mice, demonstrating the potential safety of this drug. The injection of this drug also significantly reduced the adipose tissue loss typically seen in these mice (p<0.05).
Image: PD
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