Combination of melatonin and rapamycin for head and neck cancer therapy: Suppression of AKT/mTOR pathway activation, and activation of mitophagy and apoptosis via mitochondrial function regulation

Abstract

Head and neck squamous cell carcinoma (HNSCC) clearly involves activation of the Akt mammalian target of rapamycin (mTOR) signalling pathway. However, the effectiveness of treatment with the mTOR inhibitor rapamycin is often limited by chemoresistance. Melatonin suppresses neoplastic growth via different mechanisms in a variety of tumours. In this study, we aimed to elucidate the effects of melatonin on rapamycin-induced HNSCC cell death and to identify potential cross-talk pathways. We analysed the dose-dependent effects of melatonin in rapamycin-treated HNSCC cell lines (Cal-27 and SCC-9). These cells were treated with 0.1, 0.5 or 1 mmol/L melatonin combined with 20 nM rapamycin. We further examined the potential synergistic effects of melatonin with rapamycin in Cal-27 xenograft mice. Relationships between inhibition of the mTOR pathway, reactive oxygen species (ROS), and apoptosis and mitophagy reportedly increased the cytotoxic effects of rapamycin in HNSCC. Our results demonstrated that combined treatment with rapamycin and melatonin blocked the negative feedback loop from the specific downstream effector of mTOR activation S6K1 to Akt signalling, which decreased cell viability, proliferation and clonogenic capacity. Interestingly, combined treatment with rapamycin and melatonin-induced changes in mitochondrial function, which were associated with increased ROS production, increasing apoptosis and mitophagy. This led to increase cell death and cellular differentiation. Our data further indicated that melatonin administration reduced rapamycin-associated toxicity to healthy cells. Overall, our findings suggested that melatonin could be used as an adjuvant agent with rapamycin, improving effectiveness while minimizing its side effects.

Mammalian STE20-Like Kinase 1 Deletion Alleviates Renal Ischaemia-Reperfusion Injury via Modulating Mitophagy and the AMPK-YAP Signalling Pathway

“…Additionally, the kidney has high mitochondrial oxidative metabolism and is exquisitely sensitive to hypoxic injury [49]. The function of renal tubular epithelial cells is primarily modulated by mitochondrial metabolism, making them more vulnerability to mitochondrial damage [50]. Accumulative evidence has established the critical role of mitochondrial injury in renal I/R injury.…”

Hyperglycaemia Stress-Induced Renal Injury is Caused by Extensive Mitochondrial Fragmentation, Attenuated MKP1 Signalling, and Activated JNK-CaMKII-Fis1 Biological Axis

“…For example, mitochondrial respiration is repressed in hyperglycaemia-cultured renal mesangial and tubular cells [6]. Damaged mitochondria release the mitochondrial DNA into blood, which has been acknowledged as a potential noninvasive biomarker of the severity of diabetic nephropathy [7]. Dysregulated mitochondrial bioenergetics also participates into the development of hyperglycaemiaassociated renal damage [8].…”

Reduced delivery of epididymal adipocyte‐derived exosomal resistin is essential for melatonin ameliorating hepatic steatosis in mice

“…Previous studies demonstrate that the overload of energy substrate‐mediated MAMs reorganization results in mitochondrial Ca 2+ dysbolism and oxidative stress in hepatocytes, indicating that ER‐mitochondrial coupling is a significant regulatory pathway during the development of obesity. Although, in this investigation, we do not deeply study the role of mitochondria in this regulatory circuit, previous reports indicate that melatonin can alleviate diabetes‐induced hepatic mitochondrial dysfunction, suggesting that the reversion of overload of energy substrates‐induced mitochondrial imbalance may be another research interest.…”

“…Recently, gastrointestinal tract has also been shown to secrete melatonin during night and daytime . However, intense investigations have gradually overthrew traditional standpoints and recognized melatonin as a broad‐spectrum regulatory molecule in multiple physiological activities, including improvements of reproduction, remissions of intestinal dysbacteriosis, anti‐inflammation, and anti‐cancer efforts . In obese individuals and mice models, melatonin has also been identified to control the development of obesity, improve lipid metabolism, ameliorate hepatic oxidative stress and mitochondrial dysfunction, and alleviate local/systematical inflammation in different tissues and organs .…”