Inhibition of activin-like kinase 4/5 attenuates cancer cachexia associated muscle wasting.

Abstract

Cancer mediated activation of the ActRIIB-ALK4/5 heterodimer by myostatin is strongly associated with muscle wasting. We investigated in vitro and in vivo the efficacy of ALK4/5 receptor blockers SB431542 and GW788388 in preventing muscle wasting, and explored synergy with IGF-I analogue LONG R3 (LR3) IGF-I. In vitro, C2C12 skeletal muscle cells were treated with vehicle, SB431542, GW788388 and LR3 IGF-I. A C26-CD2F1 cachexia model was used to induce cachexia in vivo. Mice were allocated as non-tumour bearing (NTB) or C26 tumour-bearing (C26 TB) vehicle control, treated with SB431542, LR3 IGF-I, SB431542 and LR3 IGF-I, or GW788388 (intraperitoneally or orally). In vitro, differentiation index and mean nuclei count increased using SB431542, GW788388, LR3 IGF-I. In vivo, GW788388 was superior to SB431542 in limiting loss of bodyweight, grip-strength and gastrocnemius weight. and downregulated Atrogin-1 expression comparable to NTB mice. LR3 IGF-I treatment limited loss of muscle mass, but at the expense of accelerated tumour growth. In conclusion, treatment with GW788388 prevented cancer cachexia, and downregulated associated ubiquitin ligase Atrogin-1.

• Authors: S Levolger, E A C Wiemer, J L A van Vugt, S A Huisman, M G van Vledder, S van Damme-van Engel, G Ambagtsheer, J N M IJzermans, R W F de Bruin
• Journal: Scientific reports (Sci Rep) Vol. 9 Issue 1 Pg. 9826 (07 08 2019) ISSN: 2045-2322 [Electronic] England
• PMID: 31285507 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-(4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)benzamide
• 4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide
• Benzamides
• Dioxoles
• LR(3)IGF-I
• Pyrazoles
• Insulin-Like Growth Factor I
• Activin Receptors, Type I
• Acvr1b protein, mouse
• Receptor, Transforming Growth Factor-beta Type I
• Tgfbr1 protein, mouse

Topics

• Activin Receptors, Type I (antagonists & inhibitors)
• Administration, Oral
• Animals
• Benzamides (administration & dosage, pharmacology)
• Body Weight (drug effects)
• Cachexia (etiology, metabolism, prevention & control)
• Cell Differentiation (drug effects)
• Cell Line
• Colonic Neoplasms (complications, metabolism, pathology)
• Dioxoles (administration & dosage, pharmacology)
• Gene Expression Regulation (drug effects)
• Injections, Intraperitoneal
• Insulin-Like Growth Factor I (administration & dosage, analogs & derivatives, pharmacology)
• Male
• Mice
• Neoplasm Transplantation
• Pyrazoles (administration & dosage, pharmacology)
• Receptor, Transforming Growth Factor-beta Type I (antagonists & inhibitors)