Synergistic antitumor effect of melatonin with several chemotherapeutic drugs on human Ewing sarcoma cancer cells: potentiation of the extrinsic apoptotic pathway

Abstract

Ewing sarcoma, the second most frequent bone cancer type, affects mainly adolescents, who have a survival of 50% 5 yr after diagnosis. Current treatments include a combination of surgery, radiotherapy and chemotherapy, which present potential serious side effects. Melatonin, a natural molecule without relevant side effects, has been previously shown to induce cytotoxicity in SK-N-MC cells, a Ewing sarcoma cell line. Here, we found that there is a synergy in the antitumor effect when melatonin (50 mum-1 mm) is combined with vincristine at the concentration of 5-10 nm or with ifosfamide at the range of 100 mum-1 mm. This synergism is due to the potentiation of cell death, particularly to the potentiation of apoptosis, i.e., mainly the extrinsic apoptotic pathway. There is a significant increase in the activation of caspase-3, -8, -9 and Bid when melatonin is combined with vincristine or ifosfamide compared to the individual treatments. Finally, there is also a potentiation of the early free radical production, likely dependent on the extrinsic apoptosis pathway activation, when the drugs are combined with melatonin. Other proteins which are related to this pathway including mitogen-activated protein kinase or protein kinase B/Akt are not involved in apoptosis induced by these agents separately or when combined. The results shown here together with the facts that: (i) no relevant side effects have been reported for melatonin and (ii) melatonin has a cytoprotective effect on noncancer cells, opens the door for a new approach in the treatment of the Ewing sarcoma family of tumors.

Combining Doublecortin-Like Kinase Silencing and Vinca Alkaloids Results in a Synergistic Apoptotic Effect in Neuroblastoma Cells

“…In line with this notion are the findings that microtubule-destabilizing agents, such as VAs, cause the activation of caspase-3 (Fan et al, 2001), and silencing of DCLK leads to the activation of caspase-3 as well (Verissimo et al, 2010). Previous studies have shown that VAs induce caspase-8 activation (Bayless and Davis, 2004;Casado-Zapico et al, 2010). We have detected an increase in caspase-8 activity in NB cells treated with the combination of VAs and DCLK knockdown compared with cells treated with VAs alone.…”

Involvement of melatonin in autophagy-mediated mouse hepatoma H22 cell survival

“…Furthermore, melatonin acts to prevent many of the H 2 O 2 -induced alterations in the MAPK and mTOR signaling pathways in H4IIE hepatoma cells [15]. Melatonin down-regulates Akt leading to TGFβ-1-dependent growth inhibition of breast cancer cells [16,17]. Yet the exact roles of melatonin on autophagic pathway in the process of cancer progression still need to be further elucidated.…”

Protective Effect of Melatonine Against Radiation Induced Nephrotoxicity in Rats

“…At both physiological and pharmacological concentrations, melatonin acts as a differentiating agent in some cancer cells and lowers their invasive and metastatic status through alterations in adhesion molecules and maintenance of gap junctional intercellular communication. In other cancer cell types, melatonin, either alone or in combination with other agents, induces apoptotic cell death (Blask et al, 2002;Casado et al, 2010;Rodringuez-Garcia et al, 2012). Melatonin reduces tumor growth in experimental models in vivo and proliferation and invasive properties of cancer cells in culture (Cos et al, 2002;Manda and Bhatia, 2003).…”