beta-endorphin and Neoplasm-Metastasis

The objective of this study was to evaluate the effect of low-dose naltrexone (LDN) as a carboplatin chemotherapy-associated drug in female dogs with mammary carcinoma in benign mixed tumors (MC-BMT) after mastectomy and to assess its association with quality of life and survival rates. Sixty female dogs were included in this study, all of which had histopathological diagnosis of MC-BMT and were divided into three groups: G1 (control), consisting of animals submitted only to mastectomy with or without regional metastasis; G2, composed of treated animals that did not present with metastasis; and G3, treated dogs that presented with metastasis. G2 and G3 were also subdivided according to the treatment administered: chemotherapy alone (MC-BMT(-) C/MC-BMT(+) C) or LDN and chemotherapy (MC-BMT(-) C+LDN/MC-BMT(+) C+LDN). All animals were subjected to clinical evaluation, mastectomy, peripheral blood lymphocyte immunophenotyping, beta-endorphin and met-enkephalin quantification, and evaluation of survival rates and quality of life scores. The results showed higher serum concentrations of beta-endorphin and met-enkephalin, fewer chemotherapy-related side effects, and better quality of life and survival rates in the LDN-treated groups than in LDN-untreated groups (P < 0.05). Evaluation of clinical and pathological parameters indicated a significant association between the use of LDN and both prolonged survival and enhanced quality of life. These results indicate that LDN is a viable chemotherapy-associated treatment in female dogs with MC-BMT, maintaining their quality of life and prolonging survival rates.

Topics: Animals; beta-Endorphin; Carboplatin; Dogs; Drug Synergism; Enkephalin, Methionine; Female; Immunophenotyping; Lymphocytes; Mammary Neoplasms, Animal; Mastectomy; Naltrexone; Neoplasm Metastasis; Quality of Life; Survival Analysis; Treatment Outcome

β-Endorphin (BEP)-producing neuron in the hypothalamus plays a key role in bringing the stress axis to a state of homeostasis and maintaining body immune defense system. Long-term delivery of BEP to obtain beneficial effect on chemoprevention is challenging, as the peptides rapidly develop tolerance. Using rats as animal models, we show here that transplantation of BEP neurons into the hypothalamus suppressed carcinogens- and hormone-induced cancers in various tissues and prevented growth and metastasis of established tumors via activation of innate immune functions. In addition, we show that intracerebroventricular administration of nanosphere-attached dibutyryl cyclic adenosine monophosphate (dbcAMP) increased the number of BEP neurons in the hypothalamus, reduced the stress response, enhanced the innate immune function, and prevented tumor cell growth, progression, and metastasis. BEP neuronal supplementation did not produce any deleterious effects on general health but was beneficial in suppressing age-induced alterations in physical activity, metabolic, and immune functions. We conclude that the neuroimmune system has significant control over cancer growth and progression, and that activation of the neuroimmune system via BEP neuronal supplementation/induction may have therapeutic value for cancer prevention and improvement of general health.

Topics: Animals; Anticarcinogenic Agents; beta-Endorphin; Bucladesine; Carcinogens; Cell Differentiation; Disease Models, Animal; Female; Glucose Tolerance Test; Hypothalamus; Immune System; Immunohistochemistry; Killer Cells, Natural; Male; Neoplasm Metastasis; Neoplasms; Neurons; Rats; Rats, Inbred F344; Rats, Nude; Rats, Sprague-Dawley

Neurobehavioral stress has been shown to promote tumor growth and progression and dampen the immune system. In this study, we investigated whether inhibiting stress hormone production could inhibit the development of mammary carcinoma and metastasis in a rat model of breast carcinogenesis. To enhance β-endorphin (BEP), the endogenous opioid polypeptide that boosts immune activity and decreases stress, we generated BEP neurons by in vitro differentiation from fetal neuronal stem cells and transplanted them into the hypothalami of rats subjected to breast carcinogenesis. BEP-transplanted rats displayed a reduction in mammary tumor incidence, growth, malignancy rate, and metastasis compared with cortical cells-transplanted rats. BEP neuron transplants also reduced inflammation and epithelial to mesenchymal transition in the tumor tissues. In addition, BEP neuron transplants increased peripheral natural killer (NK) cell and macrophage activities, elevated plasma levels of antiinflammatory cytokines, and reduced plasma levels of inflammatory cytokines. Antimetastatic effects along with stimulation of NK cells and macrophages could be reversed by treatment with the opiate antagonist naloxone, the β-receptor agonist metaproterenol, or the nicotine acetylcholine receptor antagonist methyllycaconitine. Together, our findings establish a protective role for BEP against the growth and metastasis of mammary tumor cells by altering autonomic nervous system activities that enhance innate immune function.

Topics: Adrenal Cortex; Animals; Autonomic Nervous System; beta-Endorphin; Cell Differentiation; Cells, Cultured; Epithelial-Mesenchymal Transition; Female; Hypothalamus; Immunity, Innate; Killer Cells, Natural; Macrophage Activation; Male; Mammary Neoplasms, Experimental; Neoplasm Grading; Neoplasm Metastasis; Neural Stem Cells; Neurons; Rats; Rats, Inbred F344; Rats, Sprague-Dawley

Electrical stimulation of the periaqueductal gray of the rat's midbrain analgesia leads to an increase in the number of artificial pulmonary metastases from the Walker 256 tumor. In an effort to investigate the influence of the pain suppression system and its associated peptides on this phenomenon, we activated the pain suppression system directly from the Nucleus of the Raphe Magnus, a non-opioid subsystem. After inducing analgesia by direct injection of beta-endorphin on the Nucleus of the Raphe Magnus, we noted an increase in the number of artificial pulmonary metastases. This result could be blocked by pretreatment with naloxone. If the Nucleus of the Raphe Magnus was activated by electrical stimulation sufficient to induce analgesia, the metastatic effect was still present but markedly attenuated.

Topics: Animals; beta-Endorphin; Brain Stem; Carcinoma 256, Walker; Endorphins; Female; Lung Neoplasms; Neoplasm Metastasis; Neoplasms, Experimental; Pain; Periaqueductal Gray; Raphe Nuclei; Rats; Rats, Inbred Strains

Decapeptide ceruletide (CRL), chemically related to cholecystokinin and gastrin, proved to have remarkable analgesic properties when administered to a group of 22 burned patients, 15 patients with acute myocardial infarction, and 8 patients suffering from pain caused by malignant tumours with metastases. Its effect was such, that many of the patients required no other analgesics (opiates) even after a prolonged administration (up to 10 days) of CRL. In some of the patients a marked euphoria developed. There were no substantial changes in EEG records during CRL administration in 15 controls, among them 4 epileptics. It is probable that CRL helps to activate the internal analgesic system. In the burned patients cortisol, testosterone, renin, prolactin and tri-iodothyronine (T3) levels in serum (plasma) were measured (radio-immunoassays). CRL did not block the stress response (no drop of increased cortisol levels, no increase in low T3 levels), but it modified (influenced) it (drop of the high renin levels, and a tendency to increase the very low testosterone levels). CRL appears to act as an endorphin releaser, as evidenced by the plasma levels of beta-endorphins (quotations). CRL and similar drugs may represent a new, more physiological and probably safer approach to the management of pain.

Topics: beta-Endorphin; Burns; Ceruletide; Endorphins; Humans; Male; Myocardial Infarction; Neoplasm Metastasis; Neoplasms; Pain

The effect of large amounts of synthesized human beta-endorphin (beta-EP) administered intrathecally on pituitary-adrenocortical function was investigated by determining the plasma levels of ACTH, cortisol, growth hormone and prolactin in 8 patients with pain caused by severe disseminated cancer. They were divided into 2 groups, an Ep group of 8 patients and a control group of 5 of the same 8 patients. There were no significant effects of beta-Ep on plasma ACTH, cortisol and growth hormone levels. However, the injection of beta-Ep into human subjects resulted in a rise in plasma concentrations of prolactin.

Topics: Adrenocorticotropic Hormone; Adult; Aged; beta-Endorphin; Endorphins; Growth Hormone; Humans; Hydrocortisone; Injections, Spinal; Middle Aged; Neoplasm Metastasis; Pain, Intractable; Pituitary Hormones, Anterior; Pituitary-Adrenal System; Prolactin