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

Summary

This is preclinical work in cell culture and mice — there is no human data in it. Cancer-mediated activation of the ActRIIB-ALK4/5 heterodimer by myostatin is strongly associated with muscle wasting, and the investigators tested the ALK4/5 receptor blockers SB431542 and GW788388 for their ability to prevent that wasting, while also exploring possible synergy with the IGF-I analogue LONG R3 (LR3) IGF-I. In vitro, C2C12 skeletal muscle cells were treated with vehicle, SB431542, GW788388 or LR3 IGF-I; differentiation index and mean nuclei count increased with SB431542, GW788388 and LR3 IGF-I. In vivo, a C26-CD2F1 model was used to induce cachexia, with mice allocated as non-tumour-bearing (NTB) or C26 tumour-bearing (C26 TB) vehicle controls, or treated with SB431542, LR3 IGF-I, SB431542 combined with LR3 IGF-I, or GW788388 given intraperitoneally or orally. GW788388 outperformed SB431542 at limiting loss of bodyweight, grip strength and gastrocnemius weight, and downregulated Atrogin-1 expression to a level comparable with non-tumour-bearing mice. LR3 IGF-I treatment did limit loss of muscle mass — but the authors state plainly that this came at the expense of accelerated tumour growth. Their conclusion selects GW788388, not the IGF analogue: treatment with GW788388 prevented cancer cachexia and downregulated the associated ubiquitin ligase Atrogin-1.

Key Findings

• LR3 IGF-I limited loss of muscle mass in cachectic C26 tumour-bearing mice, but at the expense of accelerated tumour growth — the anabolic benefit and the tumour effect were observed in the same animals
• In vitro in C2C12 skeletal muscle cells, differentiation index and mean nuclei count increased with SB431542, GW788388 and LR3 IGF-I
• The in vivo model was C26-CD2F1-induced cachexia, with arms for non-tumour-bearing and tumour-bearing vehicle controls, SB431542, LR3 IGF-I, SB431542 plus LR3 IGF-I, and GW788388 given intraperitoneally or orally
• GW788388 was superior to SB431542 at limiting loss of bodyweight, grip strength and gastrocnemius weight, and downregulated Atrogin-1 comparably to non-tumour-bearing mice
• The authors’ stated conclusion endorses GW788388 as preventing cancer cachexia; LR3 IGF-I is not put forward as the answer despite its muscle-sparing effect

Relevance to IGF-1-LR3

The muscle-sparing result here is the kind of finding vendors would quote, and the sentence immediately following it is the one that matters: LR3 IGF-I limited loss of muscle mass but at the expense of accelerated tumour growth. IGF-1-LR3 is sold to healthy people who want to grow muscle, and IGF-1 signalling is mitogenic by design — a compound engineered to evade IGF binding proteins and deliver unbuffered growth signal does not distinguish between muscle tissue and tumour tissue. In a model where the investigators could measure both, the tumours grew faster. That is an oncologic safety signal, not a footnote, and it belongs in any honest discussion of the compound’s risk profile. Two limits should travel with it. First, this is mice and cell culture; there are no human trials of IGF-1 LR3 in this evidence set, so the magnitude of any human risk is unquantified. Second, this was a cancer model by construction — the animals already had tumours — so it demonstrates that LR3 IGF-I accelerated growth of existing malignancy rather than that it initiates cancer. Neither limit makes the finding reassuring for a user with an undiagnosed lesion.

Citation

Levolger S, Wiemer EAC, van Vugt JLA, et al. Inhibition of activin-like kinase 4/5 attenuates cancer cachexia associated muscle wasting. Scientific reports. 2019;9(1):9826. doi:10.1038/s41598-019-46178-9.

See Also

• Parent compound: IGF-1-LR3