Melatonin and erastin emerge synergistic anti-tumor effects on oral squamous cell carcinoma by inducing apoptosis, ferroptosis, and inhibiting autophagy through promoting ROS

Abstract

Background Oral squamous cell carcinomas are one of the most common cancers worldwide with aggressive behavior and poor prognosis. Reactive oxygen species (ROS) are associated with cancer and cause various types of regulated cell death (RCD). Inducing the RCD pathway by modulating ROS levels is imperative to conquer cancers. The aim of this study is to investigate the synergistic anticancer effects of melatonin and erastin on ROS modulation and subsequent RCD induction. Methods Human tongue squamous cell carcinoma cell lines (SCC-15 cells) were treated with melatonin, erastin, or their combination. Cell viability, ROS levels, autophagy, apoptosis, and ferroptosis levels were tested according to the results of the PCR array, which were verified with/without the induction and inhibition of ROS by H2O2 and N-acetyl-L-cysteine, respectively. In addition, a mouse-based subcutaneous oral cancer xenograft model was constructed to identify the effects of melatonin, erastin, and their combination on the autophagy, apoptosis, and ferroptosis levels in isolated tumor tissues. Results ROS levels were increased by the administration of melatonin at high concentrations (mM), and the combination of melatonin with erastin enhanced the levels of malonic dialdehyde, ROS, and lipid ROS, and reduced the levels of glutamate and glutathione. SQSTM1/p62, LC3A/B, cleaved caspase-3, and PARP1 protein levels in SCC-15 cells were also increased by melatonin plus erastin treatment, which further increased as ROS accumulated, and decreased as ROS levels were suppressed. Combined treatment of melatonin and erastin markedly reduced the tumor size in vivo, demonstrated no obvious systemic side effects, and significantly enhanced the apoptosis and ferroptosis levels in the tumor tissues, in parallel with decreased autophagy levels. Conclusions Melatonin combined with erastin exhibits synergistic anticancer effects without adverse reactions. Herein, this combination might become a promising alternative strategy for oral cancer treatment. Graphical Abstract

Melatonin ameliorates 10‐hydroxycamptothecin‐induced oxidative stress and apoptosis via autophagy‐regulated p62/Keap1/Nrf2 pathway in mouse testicular cells

“…However, HCPT therapy has some adverse clinical effects 36 . It has been reported that HCPT exposure damages mouse oocyte development and quality 37 . In the present study, HCPT exposure caused spermatogenesis damage and poor fecundity in males from juvenile to adult mice.…”

“…36 It has been reported that HCPT exposure damages mouse oocyte development and quality. 37 In the present study, HCPT exposure caused spermatogenesis damage and poor fecundity in males from juvenile to adult mice. Melatonin is a well-known powerful antioxidant that could promote spermatogonia stem cell proliferation and protect mouse spermatocytes against some medical drugs-induced apoptosis.…”

“…19,21,30,32 Cancer cells usually exhibit more enhanced metabolism and produce higher ROS levels than normal cells, making tumor cells strategically modulate multiple antioxidant enzymes to maintain redox balance. 37 Thus, melatonin may play a proapoptotic and prooxidant role in cancer cells but has an antiapoptotic and antioxidant effect in normal cells depending on its dose and cell type. 51,54,55 The possible mechanism of melatonininduced ROS production and cell apoptosis has been explored and reviewed, 51,54,55 but the exact mechanism remains incompletely understood and needs further investigation.…”

Baicalin induces ferroptosis in oral squamous cell carcinoma by suppressing the activity of FTH1

“…Increasingly, studies have been focusing on discovering novel approaches to treat OSCC patients by inducing ferroptosis. For instance, a combinatorial strategy of melatonin and erastin has significant antitumor effects on OSCC cells in vivo by enhancing apoptosis and ferroptosis and suppressing autophagy, 33 providing a new approach to fighting OSCC. In addition, several ferroptosis‐mediated new drug designing systems may be promising in the management of OSCC 34…”

Exploring beyond Common Cell Death Pathways in Oral Cancer: A Systematic Review

“…This has been evaluated both in vitro and in vivo by tampering with the signaling cascades that trigger ferroptosis or silencing of ferroptosis inhibitors, which can be achieved through direct genetic modifications or chemical compounds. Some of the compounds used to achieve such effects are erastin [21,42,57], carnosic acid [34], piperlongumine [58] and Disulfiram [63].…”