Therapeutic potential of histamine H₄ receptor agonists in triple‐negative human breast cancer experimental model

Abstract

BACKGROUND AND PURPOSEThe presence of the histamine H4 receptor (H4R) was previously reported in benign and malignant lesions and cell lines derived from the human mammary gland. The aim of this work was to evaluate the effects of H4R ligands on the survival, tumour growth rate and metastatic capacity of breast cancer in an experimental model. EXPERIMENTAL APPROACHXenograft tumours of the highly invasive human breast cancer cell line MDA-MB-231 were established in immune deficient nude mice. The following H4R agonists were employed: histamine (5 mg kg RESULTSData indicate that developed tumours were highly undifferentiated, expressed H4R and exhibited high levels of histamine content and proliferation marker (PCNA) while displaying low apoptosis. Mice of the untreated group displayed a median survival of 60 days and a tumour doubling time of 7.4 Ϯ 0.6 days. A significant decrease in tumour growth evidenced by an augment of the tumour doubling time was observed in the H4R agonist groups (13.1 Ϯ 1.2, P < 0.01 in histamine group; 15.1 Ϯ 1.1, P < 0.001 in clozapine group; 10.8 Ϯ 0.7, P < 0.01 in JNJ28610244 group). This effect was associated with a decrease in the PCNA expression levels, and also reduced intratumoural vessels in histamine and clozapine treated mice. Histamine significantly increased median survival (78 days; Log rank Mantel-Cox Test, P = 0.0025; Gehan-Breslow-Wilcoxon Test, P = 0.0158) and tumoural apoptosis. CONCLUSIONS AND IMPLICATIONSHistamine through the H4R exhibits a crucial role in tumour progression. Therefore, H4R ligands offer a novel therapeutic potential as adjuvants for breast cancer treatment. LINKED ARTICLESThis article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue-1 AbbreviationsBrdU, 5-bromo-2′-deoxyuridine; ER, oestrogen receptor; H1R, histamine receptor 1; H2R, histamine receptor 2; H3R, histamine receptor 3; H4R, histamine receptor 4; siRNA, small interfering RNA

Clozapine Induces Autophagic Cell Death in Non-Small Cell Lung Cancer Cells

“…Finally, in this study, we assessed the short-term effect of clozapine (over 2 to 3 days), but not the long-term effect. Although the dose of clozapine that we used was rational and has been implemented in many studies [22,42,43], we also demonstrated that even at a lower concentration, clozapine continued to impair NSCLC cell growth during treatment for a longer period. Not only is this finding consistent with the clinical observation that patients with schizophrenia require prolonged antipsychotic administration [24], but the dose that we used for long-term treatment was also closer to the actual dose used in the clinic [44,45].…”

“…In vitro studies using liquid culture systems and immunofluorocytometry have revealed that clozapine specifically exhibits toxic effects against myeloid maturation [21]. However, only few studies have been conducted to study the drug's potential anticancer effects [22], and the possible mechanisms underlying the induction of autophagy have not been explored. In the present study, we hypothesized that clozapine could inhibit the proliferation of NSCLC cells.…”

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

“…In this regard, we have recently reported that in vivo H 4 R ligands' administration produced a significant decrease in tumor growth rate in a triple negative breast cancer experimental model. 16 Interestingly, histamine was able to potentiate in vivo the anti-tumoral effect of gamma radiation, increasing the exponential tumor doubling time, suggesting that histamine could also be investigated as a potential adjuvant to cancer radiotherapy.…”

“…Tumors of MDA-MB-231 cells were developed as previously described. 16 When the tumor volumes reached 8 mm in diameter (on day 22 after surgery) xenografted mice were separated into 3 groups, the Untreated group received a subcutaneous (sc) daily injection of saline solution (n D 6), Untreated 2 Gy group received a sc daily injection of saline solution (untreated and irradiated animals, n D 6) or Histamine 2 Gy group received a sc daily injection of histamine 5 mg/kg (treated and irradiated, n D 6). One day after treatment began, animals were irradiated with a 2 Gy dose per day for 3 consecutive days.…”

“…Histamine also significantly increased median survival of tumor-bearing animals and tumoral apoptosis. 16 In the light of the above mentioned evidences, the aims of this work were: (1) 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 with different malignant characteristics, (2) to explore the potential molecular mechanisms of the radiosensitizing action by evaluating the effects of histamine receptor ligands on breast cancer cell proliferation, apoptosis and senescence and also the regulation of reactive oxygen species (ROS) production, antioxidant enzyme modulation and DNA damage, and (3) to evaluate the histamineinduced radiosensitization in vivo in a triple negative breast cancer model.…”