Cisplatin-Induced Skeletal Muscle Dysfunction: Mechanisms and Counteracting Therapeutic Strategies

Abstract

Among the severe side effects induced by cisplatin chemotherapy, muscle wasting is the most relevant one. This effect is a major cause for a clinical decline of cancer patients, since it is a negative predictor of treatment outcome and associated to increased mortality. However, despite its toxicity even at low doses, cisplatin remains the first-line therapy for several types of solid tumors. Thus, effective pharmacological treatments counteracting or minimizing cisplatin-induced muscle wasting are urgently needed. The dissection of the molecular pathways responsible for cisplatin-induced muscle dysfunction gives the possibility to identify novel promising therapeutic targets. In this context, the use of animal model of cisplatin-induced cachexia is very useful. Here, we report an update of the most relevant researches on the mechanisms underlying cisplatin-induced muscle wasting and on the most promising potential therapeutic options to preserve muscle mass and function.

Keywords: cisplatin; ghrelin; growth hormone secretagogues (GHS); muscle atrophy; skeletal muscle.

Figure 1

Molecular mechanism underlying cisplatin-induced muscle wasting. AMPK: 5’-adenosine monophosphate-activated protein kinase; Akt: Protein kinase B; Atgs: Autophagy-specific genes; Bnip3: BCL2 interacting protein 3; FoxO3: Forkhead boxO, Gabaralp1: GABA type A receptor-associated protein-like 1; IGF-1: Insulin-like growth factor-1; IL-1: Interleukin-1; IL-6: Interleukin-6; LC3B: Lipidated microtubule-associated protein 1 light chain 3 alpha; mTOR: Mammalian target of rapamycin; MuRF-1: Muscle ring-finger-1; NFκB: Prototypical nuclear factor kappa light-chain-enhancer of activated B cells; NRF1/2: Nuclear respiratory factor 1/2; p62: Sequestosome-1; PGC-1α: Peroxisome proliferator-activated receptor γ coactivator-1α; PI3K: Phosphoinositide 3-kinases; Smad2/3: Small mother against decapentaplegic.