Histamine receptors as potential therapeutic targets for cancer drug development

VANINA A MEDINA; DIEGO MARTINEL LAMAS; PABLO BRENZONI; NOELIA A MASSARI; ELIANA CARABAJAL; ELENA S RIVERA

DRUG DEVELOPMENT – A CASE STUDY BASED INSIGHT INTO MODERN STRATEGIES

Published by InTech

Año: 2011; p. 75 - 100

Since histamine discovery in 1910, it has been recognized as a major mediator in gastric acid secretion and inflammation that is a main pathophysiological characteristic of allergy. For many years, drug development and therapeutic application of histamine antagonists were mainly focused on the allergic and gastrointestinal diseases. At present, it is one of the monoamines (2-(imidazol-4-yl)ethylamine) with the broadest spectrum of activities in various physiological and pathological situations. Thus, it has been shown to be involved in aminergic neurotransmission and numerous brain functions including learning, memory, sleep/wakefulness, locomotor activity, nociception, food intake, secretion of pituitary hormones, and regulation of gastrointestinal and circulatory functions, as well as modulation of immunity and hematopoiesis. A significant body of research has contributed to the elucidation of the functional capacities of histamine in tumor cell growth and development. Evidences for multiple cellular sources of histamine, the recent description of functional histamine H3 receptor (H3R) in peripheral tissues, the discovery of a novel histamine receptor (H4R) and the demonstration of a histamine–cytokine cross-talk have modified the perspective which suggests new potential therapeutic uses of histamine and its receptor ligands. Currently, attention in the pharmaceutical industry is directed towards the therapeutic use of the newest members of the histamine receptor family. Despite the progress made in the understanding of the biology and properties of the H3R, to date no clinical proof of concept for an H3R antagonist has been reported. This could be due to the great complexity associated with the H3R, including the heterogeneity of isoforms and their differential tissue localization, constitutive activity, pharmacological and signalling characteristics and also the occurrence of H3R isoform dimerization that can make drug discovery efforts difficult. The H3R has been representing a promising target for drug discovery for numerous disorders, including obesity, epilepsy, Alzheimer’s disease, among others. Nevertheless, it was recently reported the expression of the H3R in benign and malignant lesions and cell lines derived from human mammary gland, and also in McA-RH7777 rat hepatoma cells and PANC-1 pancreatic carcinoma cells, indicating that it also could represent an attractive drug target for cancer, especially considering that H3R was associated to the modulation of cell proliferation. Recent findings indicate that H4R is expressed in human breast tissues and cell lines exhibiting a key role in histamine-mediated biological processes such as cell proliferation, senescence, apoptosis and metastatic potential in malignant cells. Similar responses were observed in the human cell lines of pancreatic carcinoma and melanoma where histamine, via H4R inhibits proliferation and modulates cell differentiation and migration. In addition, H4R was detected in both colorectal cancer and adjacent normal colonic specimens, and in human colon cancer cell lines in which histamine exerts both a proproliferative and a proangiogenic effect via H2R/H4R activation. Though these reports make unquestionably the presence of functional H4R in human cancer tissues, the precise role of H4R in cell proliferation seems to be cancer type dependent and must be further investigated. The presented data suggest a novel and complex role of H4R in carcinogenesis that might represent a new molecular target and avenue potentially useful for the design of more specific and effective therapies for cancer. In addition, radiation therapy is a well recognized treatment modality for cancer. Although effective, adverse effects due to radiotherapy are unavoidable, even with localized delivery techniques. Regardless of many years of research, there are surprisingly few radiation protectors in use today, whose clinical use is limited due to their toxicity; thus, the development of effective and nontoxic agents is yet a challenge for oncologists and radiobiologists. We have recently reported that histamine significantly protects two of the most radiosensitive tissues, small intestine and bone marrow, from high doses of radiation. In addition, histamine has the ability to prevent functional and histological alterations of salivary glands exerted by ionizing radiation. These features make histamine a suitable candidate for its use as a selective radioprotector for patients undergoing radiotherapy. In the present review we aimed to briefly summarize current knowledge on histamine and histamine receptor involvement in cancer before focusing on some recent evidence supporting the novel role of H3R and H4R in cancer progression representing a promising molecular target and avenue for cancer drug development. Furthermore, we described novel findings, suggesting the potential application of histamine and its ligands as an adjuvant to tumor radiotherapy.