Melatonin overcomes gemcitabine resistance in pancreatic ductal adenocarcinoma by abrogating nuclear factor‐κB activation

Abstract

Constitutive activation and gemcitabine induction of nuclear factor-κB (NF-κB) contribute to the aggressive behavior and chemotherapeutic resistance of pancreatic ductal adenocarcinoma (PDAC). Thus, targeting the NF-κB pathway has proven an insurmountable challenge for PDAC therapy. In this study, we investigated whether the inhibition of NF-κB signaling pathway by melatonin might lead to tumor suppression and overcome gemcitabine resistance in pancreatic tumors. Our results showed that melatonin inhibited activities of NF-κB by suppressing IκBα phosphorylation and decreased the expression of NF-κB response genes in MiaPaCa-2, AsPc-1, Panc-28 cells and gemcitabine resistance MiaPaCa-2/GR cells. Moreover, melatonin not only inhibited cell proliferation and invasion in a receptor-independent manner, but also enhanced gemcitabine cytotoxicity at pharmacologic concentrations in these PDAC cells. In vivo, the mice treated with both agents experienced a larger reduction in tumor burden than the single drug-treated groups in an orthotopic xenograft mouse model. Taken together, these results indicate that melatonin inhibits proliferation and invasion of PDAC cells and overcomes gemcitabine resistance of pancreatic tumors through NF-κB inhibition. Our findings therefore provide novel preclinical knowledge about melatonin inhibition of NF-κB in PDAC and suggest that melatonin should be investigated clinically, alone or in combination with gemcitabine for PDAC treatment.

Inhibition of the NF-κB pathway by nafamostat mesilate suppresses colorectal cancer growth and metastasis

“…CCK-8 (Dojindo, Japan) and colonic assays were used to detect cell viability and proliferation, as described previously [20].…”

“…Nuclear and cytoplasmic extracts were obtained with a nuclear protein kit (KeyGEN, Nanjing, China) according to the manufacturer's instructions. Immunofluorescence of p65 was detected using a standard protocol [20].…”

Effects of Melatonin and Its Analogues on Pancreatic Inflammation, Enzyme Secretion, and Tumorigenesis

“…In addition, recent studies have shown that high doses (mM) of melatonin decreased pancreatic tumor cells proliferation and invasion by inhibition of NF-κB signaling pathway, but also enhanced gemcitabine cytotoxicity in these cells [100]. A supporting action of melatonin in antitumor therapy has also been demonstrated by Uguz et al [101], who observed that melatonin enhances the antiproliferative effects of cytostatics such as 5-fluorouracil or cisplatin on pancreatic rat carcinoma.…”

What is known about melatonin, chemotherapy and altered gene expression in breast cancer

“…In summary, in our opinion, melatonin is an endogenous produced hormone with a high potential of being included as an effective anticancer molecule in the prevention and treatment of, not only hormone-dependent cancers, but also, other types of cancer, since its inhibitory effects have been demonstrated in gastric, lung, pancreatic and hematopoietic cancers (145,148,151,153). However, in the next years, additional research must be conducted to clarify if melatonin administration in combination with chemotherapeutic agents may constitute a novel anticancer treatment.…”

“…In ER + breast cancer rat models treated with Adriamycin ® , melatonin co-treatment results in lighter tumor weights, increased tumor cell apoptosis, higher expression of E-cadherin and higher survival rate (147). In combination with the nucleoside analogue gemcitabine, recent reports demonstrate that melatonin inhibits both proliferation and invasion of pancreatic ductal adenocarcinoma cells through nuclear factor-κB inhibition (148). Melatonin supports the effects of doxorubicin by activating transient receptor potential vanilloid 1 and apoptosis, thus inducing MCF-7 cell death (149).…”