Parthenolide regulates oxidative stress‐induced mitophagy and suppresses apoptosis through p53 signaling pathway in C2C12 myoblasts

Abstract

Muscle redox disturbances and oxidative stress have emerged as a common pathogenetic mechanism and potential therapeutic intervention in some muscle diseases. Parthenolide (PTL), a sesquiterpene lactone found in large amounts in the leaves of feverfew, possesses anti‐inflammatory, anti‐migraine, and anticancer properties. Although PTL was reported to alleviate cancer cachexia and improve skeletal muscle characteristics in a cancer cachexia model, its actions on oxidative stress‐induced damage in C2C12 myoblasts have not been reported and the regulatory mechanisms have not yet been defined. In our study, PTL attenuated H2O2‐induced growth inhibition and morphological changes. Furthermore, PTL exhibited scavenging activity against reactive oxygen species and protected C2C12 cells from apoptosis in response to H2O2. Meanwhile, PTL suppressed collapse of the mitochondrial membrane potential, thereby contributing to normalizing H2O2‐induced autophagy flux and mitophagy, correlating with inhibiting degradation of mitochondrial marker protein TIM23, the increase in LC3‐II expression and the reduction of mitochondria DNA. Besides its protective effect on mitochondria, PTL also prevented H2O2‐induced lysosomes damage in C2C12 cells. In addition, the phosphorylation of p53, cathepsin B, and Bax/Bcl‐2 protein levels, and the translocation of Bax from the cytosol to mitochondria induced by H2O2 in C2C12 cells was significantly reduced by PTL. In conclusion, PTL modulates oxidative stress‐induced mitophagy and protects C2C12 myoblasts against apoptosis, suggesting a potential protective effect against oxidative stress‐associated skeletal muscle diseases.

Parthenolide and Its Soluble Analogues: Multitasking Compounds with Antitumor Properties

“…In this regard, Gopal et al have reported that PN can stimulate the ubiquitination of MDM2 thereby activating p53 cellular functions [ 83 ]. More recently, activation or stabilization of p53 by PN in tumor cells has also been found by other authors [ 17 , 84 , 85 ].…”

“…Indeed, patients often develop a wasting syndrome characterized by systemic inflammation and involuntary loss of body mass that cannot be reversed by normal nutritional support [ 15 ]. NF-κB inhibitors could also be used as anticancer therapy to treat cachexia [ 16 , 17 ].…”

Identification of a synergistic combination of dimethylaminoparthenolide and shikonin alters metabolism and inhibits proliferation of pediatric precursor‐B cell acute lymphoblastic leukemia

“…The net effect of these pathways is both energy generation and biosynthesis of macromolecules for proliferation. DMAPT has been shown to directly inhibit cell survival and proliferative signals from nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB), 34,40 signal transducer and activator of transcription (STAT), 44 and mitogen‐activated protein kinases (MAPK) 45 . At the same time, DMAPT activates proapoptotic signaling through c‐Jun N‐terminal kinases (JNK) and p53 33,34,46 .…”

Curcumin Protects Human Umbilical Vein Endothelial Cells against H2O2-Induced Cell Injury

“…To the best of our knowledge, there is no widely accepted in vitro model for migraine. Both C2C12 myoblasts and meningeal mast cells [35] have been used as model for migraine research [36]. Harriott et al also suggested the spreading depression model to be used as a preclinical model of migraine [37].…”