Stem Cell-Derived Exosomes Ameliorate Doxorubicin-Induced Muscle Toxicity through Counteracting Pyroptosis.

Fatima Bianca A. Dessouki,Dinender K. Singla,Rakesh C. Kukreja

doi:10.3390/ph13120450

Fatima Bianca A. Dessouki, Dinender K. Singla + Show 1 more

Open Access

https://doi.org/10.3390/ph13120450

Copy DOI

Abstract

Doxorubicin (Dox)-induced muscle toxicity (DIMT) is a common occurrence in cancer patients; however, the cause of its development and progression is not established. We tested whether inflammation-triggered cell death, “pyroptosis” plays a role in DIMT. We also examined the potential role of exosomes derived from embryonic stem cells (ES-Exos) in attenuating DIMT. C57BL/6J mice (10 ± 2 wks age) underwent the following treatments: Control (saline), Dox, Dox+ES-Exos, and Dox+MEF-Exos (mouse-embryonic fibroblast-derived exosomes, negative control). Our results demonstrated that Dox significantly reduced muscle function in mice, which was associated with a significant increase in NLRP3 inflammasome and initiation marker TLR4 as compared with controls. Pyroptosis activator, ASC, was significantly increased compared to controls with an upregulation of specific markers (caspase-1, IL-1β, and IL-18). Treatment with ES-Exos but not MEF-Exos showed a significant reduction in inflammasome and pyroptosis along with improved muscle function. Additionally, we detected a significant increase in pro-inflammatory cytokines (TNF-α and IL-6) and inflammatory M1 macrophages in Dox-treated animals. Treatment with ES-Exos decreased M1 macrophages and upregulated anti-inflammatory M2 macrophages. Furthermore, ES-Exos showed a significant reduction in muscular atrophy and fibrosis. In conclusion, these results suggest that DIMT is mediated through inflammation and pyroptosis, which is attenuated following treatment with ES-Exos.

Highlights

Doxorubicin (Dox) is an effective chemotherapeutic drug that is used to treat a wide variety of cancers such as breast, lung, leukemia, and lymphoma through inhibition of topoisomerase II, DNA intercalation, and oxidative stress [1,2,3,4]
Our results showed a significant increase in M1 macrophages as demonstrated by the expression of specific marker, iNOS, for Dox compared to controls
M2 macrophages were significantly reduced following Dox administration in the soleus muscle. These results suggest that inflammation associated with pyroptosis may be correlated with the relative levels of M1 and M2 macrophages in the Dox chemotherapy also induces muscle toxicity (DIMT) model

Summary

Introduction

Doxorubicin (Dox) is an effective chemotherapeutic drug that is used to treat a wide variety of cancers such as breast, lung, leukemia, and lymphoma through inhibition of topoisomerase II, DNA intercalation, and oxidative stress [1,2,3,4]. Toxicity in skeletal muscle tissue can often lead to impairment of quality of life and in some severe cases, can be lethal [16]. Symptoms such as muscle weakness, myalgia, or myoglobinuria are associated with drug-induced muscle toxicity [16]. This is a significant health issue in cancer patients treated with Dox and currently there is little information about the specific causes of DIMT. Various cellular and pathophysiological changes in the soleus muscle are implicated in DIMT such as oxidative stress, fibrosis, atrophy, and apoptotic cell death [11,12,17]

Methods

Results

Discussion

Conclusion