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PI3Kδ Inhibition Modulates the Innate Inflammatory Response in Pancreatic Ductal Adenocarcinoma and Normalizes Aberrant Metabolism Associated with Cachexia

ABSTRACT: PDAC is an inflammatory disease in urgent need of effective therapeutic intervention. The PI3K p110δ isform inhibition resulted in sustained survival rarely seen in KPC mouse model of pancreatic cancer. The single agent therapy significantly decreased tumor burden, differentially regulated tumour inflammatory and metabolic transcirptome profile and normalized muscle metabolic response associated with cachexia.

ORGANISM(S): Mus musculus

PROVIDER: GSE59757 | GEO | 2022/05/01

REPOSITORIES: GEO

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Project description:Background: Cancer cachexia (CAC) reduces patient survival and quality of life. Developments of efficient therapeutic strategies are required for the CAC treatments. This long-term process could be shortened by the drug-repositioning approach which exploits old drugs approved for non-cachexia disease. Amiloride, a diuretic drug, is clinically used for treatments of hypertension and edema due to heart failure. Here, we explored the effects of amiloride for ameliorating muscle wasting in murine models of cancer cachexia. Methods: CT26 and LLC tumor cells were subcutaneously injected into mice to induce cancer cachexia. Amiloride was intraperitoneally injected daily once tumors were formed. Cachexia features of the CT26 and LLC models, respectively, were characterized by phenotypic, histopathologic and biochemical analyses. Plasma exosomes and muscle atrophy-related proteins were quantitatively analyzed. Integrative NMR-based metabolomic and transcriptomic analyses were conducted to identify significantly altered metabolic pathways and distinctly changed metabolism-related biological processes in gastrocnemius. Results: The CT26 and LLC models displayed prominent cachexia features including decreases in body weight, skeletal muscle, adipose tissue and muscle strength. The amiloride treatment in tumor-bearing mice distinctly alleviated muscle atrophy and relieved cachexia-related features without affecting tumor growth. The CT26 and LLC cachexia mice showed increased particle density of plasma exosomes which were largely derived from tumors. Significantly, the amiloride treatment inhibited tumor-derived exosome release, which did not obviously affect exosome secretion from non-neoplastic tissues or induce observable systemic toxicities in normal healthy mice. Integrative-omics revealed significant metabolic impairments in cachectic gastrocnemius, including promoted muscular catabolism, inhibited muscular protein synthesis, blocked glycolysis and impeded ketone body oxidation. The amiloride treatment evidently improved the metabolic impairments in cachectic gastrocnemius. Conclusions: Our results demonstrated the efficacy of amiloride in ameliorating cachectic muscle wasting and elucidated the underlying mechanistic rationale for its use as an alternative strategy to improve CAC treatments.

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PI3Kδ Inhibition Modulates the Innate Inflammatory Response in Pancreatic Ductal Adenocarcinoma and Normalizes Aberrant Metabolism Associated with Cachexia

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