TY - JOUR
T1 - Senotherapeutic drug treatment ameliorates chemotherapy-induced cachexia
AU - Englund, Davis A.
AU - Jolliffe, Alyssa M.
AU - Hanson, Gabriel J.
AU - Aversa, Zaira
AU - Zhang, Xu
AU - Jiang, Xinyi
AU - White, Thomas A.
AU - Zhang, Lei
AU - Monroe, David G.
AU - Robbins, Paul D.
AU - Niedernhofer, Laura J.
AU - Kamenecka, Theodore M.
AU - Khosla, Sundeep
AU - LeBrasseur, Nathan K.
N1 - Publisher Copyright:
© 2024, Englund et al.
PY - 2024/1
Y1 - 2024/1
N2 - Cachexia is a debilitating skeletal muscle wasting condition for which we currently lack effective treatments. In the context of cancer, certain chemotherapeutics cause DNA damage and cellular senescence. Senescent cells exhibit chronic activation of the transcription factor NF-κB, a known mediator of the proinflammatory senescence-associated secretory phenotype (SASP) and skeletal muscle atrophy. Thus, targeting NF-κB represents a logical therapeutic strategy to alleviate unintended consequences of genotoxic drugs. Herein, we show that treatment with the IKK/NF-κB inhibitor SR12343 during a course of chemotherapy reduces markers of cellular senescence and the SASP in liver, skeletal muscle, and circulation and, correspondingly, attenuates features of skeletal muscle pathology. Lastly, we demonstrate that SR12343 mitigates chemotherapy-induced reductions in body weight, lean mass, fat mass, and muscle strength. These findings support senescent cells as a promising druggable target to counteract the SASP and skeletal muscle wasting in the context of chemotherapy.
AB - Cachexia is a debilitating skeletal muscle wasting condition for which we currently lack effective treatments. In the context of cancer, certain chemotherapeutics cause DNA damage and cellular senescence. Senescent cells exhibit chronic activation of the transcription factor NF-κB, a known mediator of the proinflammatory senescence-associated secretory phenotype (SASP) and skeletal muscle atrophy. Thus, targeting NF-κB represents a logical therapeutic strategy to alleviate unintended consequences of genotoxic drugs. Herein, we show that treatment with the IKK/NF-κB inhibitor SR12343 during a course of chemotherapy reduces markers of cellular senescence and the SASP in liver, skeletal muscle, and circulation and, correspondingly, attenuates features of skeletal muscle pathology. Lastly, we demonstrate that SR12343 mitigates chemotherapy-induced reductions in body weight, lean mass, fat mass, and muscle strength. These findings support senescent cells as a promising druggable target to counteract the SASP and skeletal muscle wasting in the context of chemotherapy.
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U2 - 10.1172/jci.insight.169512
DO - 10.1172/jci.insight.169512
M3 - Article
C2 - 38051584
AN - SCOPUS:85183312440
SN - 2379-3708
VL - 9
JO - JCI Insight
JF - JCI Insight
IS - 2
M1 - e169512
ER -