How Cisplatin Destroys Muscle and What Can Stop It
A comprehensive review maps the molecular pathways behind cisplatin-induced muscle wasting and evaluates promising natural and hormonal interventions.
Summary
Cisplatin, a widely used platinum-based chemotherapy drug, causes severe muscle wasting that worsens cancer outcomes and quality of life. This 2025 review from Taipei Medical University systematically examines the molecular mechanisms driving cisplatin-induced muscle atrophy—including the ubiquitin-proteasome pathway, caspase activation, autophagy-lysosome pathway, myostatin signaling, and IGF-1/PI3K/Akt/mTOR suppression—alongside oxidative stress and pro-inflammatory cytokine cascades. The authors then evaluate both molecular-based therapies (ghrelin, growth hormone secretagogues, testosterone) and plant-derived natural compounds (capsaicin, naringenin, and others) for their ability to counteract these pathways in preclinical models.
Detailed Summary
Muscle wasting (cachexia) affects a large proportion of cancer patients and accounts for over 20% of cancer-related deaths. Cisplatin, one of the most widely prescribed chemotherapy agents for head, neck, lung, bladder, ovarian, and testicular cancers, is a major driver of this problem. Understanding and targeting the molecular basis of cisplatin-induced muscle atrophy is therefore a pressing clinical priority.
This review from Taipei Medical University provides a comprehensive mechanistic map of how cisplatin dismantles skeletal muscle. Cisplatin activates the ubiquitin-proteasome pathway (UPP) by upregulating the muscle-specific E3 ligases MuRF-1 and MAFbx (atrogin-1), which degrade myofibrillar proteins including myosin heavy chain and troponin I. Simultaneously, cisplatin triggers the intrinsic caspase pathway—shifting the Bax/Bcl-2 balance toward apoptosis, releasing cytochrome c, and activating caspase-3, a key enzyme in actomyosin breakdown. The autophagy-lysosome pathway (ALP) is also dysregulated, with cisplatin promoting excessive autophagic flux through FoxO-mediated upregulation of autophagy-related genes and markers such as LC3 and Bnip3.
On the anabolic side, cisplatin suppresses the IGF-1/PI3K/Akt/mTOR pathway, reducing phosphorylation of p70S6K and releasing inhibition of 4E-BP1, thereby blunting protein synthesis. Myostatin (GDF-8) and GDF-15 signaling through the ActRIIB receptor and SMAD2/3/4 complex further amplifies atrophic gene expression. Pro-inflammatory cytokines TNF-α, IL-1, and IL-6—elevated by cisplatin—activate NF-κB and JAK/STAT pathways, compounding protein degradation. Reactive oxygen species (ROS) generated by cisplatin act as an additional upstream driver linking oxidative stress to all these catabolic cascades.
Therapeutically, the review evaluates molecular agents and natural compounds in in vivo and in vitro models. Ghrelin and growth hormone secretagogues stimulate anabolic IGF-1/Akt signaling and suppress MuRF-1/MAFbx. Testosterone restores anabolic tone and reduces inflammatory signaling. Among plant-derived compounds, capsaicin (TRPV1 agonist) reduces ROS and NF-κB activation, preserving muscle fiber diameter in cisplatin-treated models. Naringenin, a citrus flavonoid, attenuates oxidative stress and suppresses atrophic gene expression. Other candidates reviewed include curcumin, resveratrol, and beta-hydroxy-beta-methylbutyrate (HMB), each targeting overlapping nodes in the atrophy network.
The authors note important caveats: most evidence derives from rodent models and cell lines, clinical translation remains limited, and bioavailability of natural compounds in humans is often poor. One study also found that cisplatin may induce atrophy independent of the UPP in tumor-bearing mice, suggesting mechanistic heterogeneity that complicates single-target strategies. Future work should prioritize well-designed clinical trials, optimized delivery systems for natural compounds, and combination approaches addressing multiple atrophy pathways simultaneously.
Key Findings
- Cisplatin upregulates MuRF-1 and MAFbx E3 ligases, accelerating myofibrillar protein degradation via the ubiquitin-proteasome pathway.
- Cisplatin suppresses IGF-1/PI3K/Akt/mTOR signaling, reducing muscle protein synthesis and enabling FoxO-driven atrophic gene expression.
- Caspase-3 activation and elevated ROS are central mediators linking cisplatin-induced oxidative stress to muscle apoptosis and actomyosin breakdown.
- Ghrelin, testosterone, and growth hormone secretagogues restore anabolic signaling and reduce atrophic marker expression in preclinical models.
- Natural compounds capsaicin and naringenin attenuate NF-κB activation, oxidative stress, and atrophic gene expression in cisplatin-exposed muscle.
Methodology
This is a systematic narrative review synthesizing published in vitro, in vivo (rodent), and limited clinical evidence on cisplatin-induced muscle wasting mechanisms and therapeutic interventions. The authors organized findings by molecular pathway and by therapeutic category (molecular agents vs. plant-derived compounds), drawing on studies across multiple cancer-relevant cisplatin models.
Study Limitations
Nearly all mechanistic and therapeutic evidence is preclinical (cell lines and rodent models), limiting direct clinical applicability. Bioavailability of plant-derived compounds in humans is often insufficient without specialized delivery formulations. At least one study found cisplatin-induced atrophy occurring independently of the UPP in tumor-bearing mice, indicating mechanistic heterogeneity that may reduce the efficacy of single-target interventions.
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