Enhancement of ionizing radiation response by histamine in vitro and in vivo in human breast cancer

Abstract

The radioprotective potential of histamine on healthy tissue has been previously demonstrated. The aims of this work were to investigate the combinatorial effect of histamine or its receptor ligands and gamma radiation in vitro on the radiobiological response of 2 breast cancer cell lines (MDA-MB-231 and MCF-7), to explore the potential molecular mechanisms of the radiosensitizing action and to evaluate the histamine-induced radiosensitization in vivo in a triple negative breast cancer model. Results indicate that histamine significantly increased the radiosensitivity of MDA-MB-231 and MCF-7 cells. This effect was mimicked by the H 1 R agonist 2-(3-(trifluoromethyl)phenyl)histamine and the H 4 R agonists (Clobenpropit and VUF8430) in MDA-MB-231 and MCF-7 cells, respectively. Histamine and its agonists enhanced radiation-induced oxidative DNA damage, DNA double-strand breaks, apoptosis and senescence. These effects were associated with increased production of reactive oxygen species, which correlated with the inhibition of catalase, glutathione peroxidase and superoxide dismutase activities in MDA-MB-231 cells. Histamine was able also to potentiate in vivo the anti-tumoral effect of radiation, increasing the exponential tumor doubling time. We conclude that histamine increased radiation response of breast cancer cells, suggesting that it could be used as a potential adjuvant to enhance the efficacy of radiotherapy.

Selective cytoprotective effect of histamine on doxorubicin-induced hepatic and cardiac toxicity in animal models

“… 29 Results demonstrate that both single agents and the drug combination increased 8-OHdG formation ( Figure 5g ). In addition, single treatments alone induced phosphorylation of H2AX, a marker of DNA double-strand breaks, 24 while the combination treatment enhanced DNA damage further ( Figure 5i ).…”

“…To evaluate tumor growth the length and width of the subcutaneous tumors were measured using a caliper three times a week. 16 , 24 The tumor size was calculated as sphere volume. Tumor growth data were expressed as relative tumor volume (tumor volume measured with respect to initial tumor volume at the beginning of treatment) and analysis was carried out using GraphPad Prism version 5.00.…”

“…Furthermore, histamine was able to enhance in vivo the effect of gamma radiation, augmenting the exponential tumor doubling time of triple-negative breast cancer (TNBC) developed in nude mice. 18 , 24 …”

Histamine therapeutic efficacy in metastatic melanoma: Role of histamine H4 receptor agonists and opportunity for combination with radiation

“…The rationale behind this combination is based on the potential radiosensitization of breast cancer cells with histamine previously reported [58]. …”

Histamine: a potential cytoprotective agent to improve cancer therapy?

“…In addition, the in vivo treatment with histamine significantly reduced the size and the increased exponential doubling time of irradiated triple-negative breast tumors (TNBT) induced in nude mice with MDA-MB-231 cells. 9 …”