TNF-α sensitizes chemotherapy and radiotherapy against breast cancer cells

Abstract

PurposeDespite new developments in cancer therapy, chemotherapy and radiotherapy remain the cornerstone of breast cancer treatment. Therefore, finding ways to reduce the toxicity and increase sensitivity is particularly important. Tumor necrosis factor alpha (TNF-α) exerts multiple functions in cell proliferation, differentiation and apoptosis. In the present study, we investigated whether TNF-α could enhance the effect of chemotherapy and radiotherapy against breast cancer cells.MethodsCell growth was determined by MTT assay in vitro, and by using nude mouse tumor xenograft model in vivo. Cell cycle and apoptosis/necrosis were evaluated by flow cytometry. DNA damage was visualized by phospho-Histone H2A.X staining. mRNA expression was assessed by using real-time PCR. Protein expression was tested by Western blot assay.ResultsTNF-α strengthened the cytotoxicity of docetaxel, 5-FU and cisplatin against breast cancer cells both in vitro and in vivo. TNF-α activated NF-κB pathway and dependently up-regulated expressions of CyclinD1, CyclinD2, CyclinE, CDK2, CDK4 and CDK6, the key regulators participating in G1→S phase transition. As a result, TNF-α drove cells out of quiescent G0/G1 phase, entering vulnerable proliferating phases. Treatment of TNF-α brought more DNA damage after Cs137-irradiation and strengthened G2/M and S phase cell cycle arrest induced by docetaxel and cisplatin respectively. Moreover, the up-regulation of RIP3 (a necroptosis marker) by 5-FU, and the activation of RIP3 by TNF-α, synergistically triggered necroptosis (programmed necrosis). Knockdown of RIP3 attenuated the synergetic effect of TNF-α and 5-FU.ConclusionTNF-α presented radiotherapy- and chemotherapy-sensitizing effects against breast cancer cells.

Tumor necrosis factor: An inflammatory microenvironment marker in primary breast cancer patients

“…[8,23] When low doses of TNF-α derivative was supplemented with chemotherapy and radiotherapy, a synergistic activity was observed by sensitizing chemotherapy drugs in in vitro and in vivo experiments. [24] In conclusion, the present study showed that pre-operative plasma concentration of TNF α and TNF β increased significantly with ER and PR negativity. Plasma TNF α levels TNF β HER-2/neu positivity 0.14 0.22 # P < 0.05 is significant.…”

RIP3 mediates TCN-induced necroptosis through activating mitochondrial metabolism and ROS production in apoptosis-resistant cancer cells

“…Necroptosis might act as an alternative pathway to initiate cell death when apoptosis is restrained. Since RIP3 serves as a critical regulator of necroptosis, silencing RIP3 causes cancer cells to develop resistance to 5-FU [59,60], cisplatin [61][62][63], camptothecin and etoposide and the activation of key regulators in necroptotic pathway can increase the sensitivity of cells to chemotherapy drugs [5]. Here, we demonstrated that administration of TCN combination with cisplatin signi cantly increased the chemotherapeutic sensitivity of cancer cells in vivo.…”

Arctigenin inhibits the activation of the mTOR pathway, resulting in autophagic cell death and decreased ER expression in ER-positive human breast cancer cells

“…Hence, in this study, we analyzed whether arctigenin induced the necroptosis of the MCF-7 cells. Untreated MDA-MB-231 human breast cancer cells were used as a positive control, since they have previously been shown to express RIPK3 (27). Our results from western blot analysis ( Fig.…”

“…Its fragmentation is a marker of apoptosis. (27) to express detectable levels of RIPK3, were used as the positive control. Graphs represent the means ± SD of at least 3 independent experiments.…”