Inhibition of Mammary Cancer Progression in Fetal Alcohol Exposed Rats by β‐Endorphin Neurons

Abstract

Background Fetal alcohol exposure (FAE) increases the susceptibility to carcinogen-induced mammary cancer progression in rodent models. Fetal alcohol exposer also have decreased β-endorphin (β-EP) level and caused hyperstress response, which leads to inhibition of immune function against cancer. Previous studies have shown that injection of nanosphere-attached dibutyryl cyclic adenosine monophosphate (dbcAMP) into the 3rd ventricle increases the number of BEP neurons in the hypothalamus. In this study, we assessed the therapeutic potential of stress regulation using methods to increase hypothalamic levels of β-EP, a neuropeptide that inhibits stress axis activity, in treatment of carcinogen-induced mammary cancer in fetal alcohol exposed rats. Methods Fetal alcohol-exposed and control Sprague Dawley rats were given a dose of N-Nitroso-N-methylurea (MNU) at postnatal day 50 to induce mammary cancer growth. Upon detection of mammary tumors, the animals were either transplanted with β-EP neurons or injected with dbcAMP-delivering nanospheres into the hypothalamus to increase β-EP peptide production. Spleen cytokines were detected using RT-PCR assays. Metastasis study was done by injecting mammary cancer cells MADB106 into jugular vein of β-EP-activated or control fetal alcohol exposed animals. Results Both transplantation of β-EP neurons and injection of dbcAMP-delivering nanospheres inhibited MNU-induced mammary cancer growth in control rats, and reversed the effect of fetal alcohol exposure on the susceptibility to mammary cancer. Similar to the previously reported immune-enhancing and stress-suppressive effects of β-EP transplantation, injection of dbcAMP-delivering nanospheres increased the levels of interferon-γ and granzyme B and decreased the levels of epinephrine and norepinephrine in fetal alcohol exposed rats. Mammary cancer cell metastasis study also showed that fetal alcohol exposure increased incidence of lung tumor retention, while β-EP transplantation inhibited lung tumor growth in both normal and fetal alcohol exposed rats. Conclusions Our results suggest that increase of β-EP production in the hypothalamus may serve as a potential therapeutic strategy for treating the cancer growth in patients with chronic stress and compromised immune function, such as the patients with fetal alcohol exposure.

The Genetics of Fetal Alcohol Spectrum Disorders

“…It is unclear if this complex interaction is involved in human FASD. However, it is interesting to note that individuals with Fanconi Anemia are predisposed to cancer due to DNA damage, predominantly due to reactive aldehydes, (Duxin and Walter, 2015) and rat models suggest that embryonic alcohol exposure may speed the acquisition of tumors (Polanco et al, 2010; Zhang et al, 2016). We know virtually nothing about the long-term health issues faced by individuals with FASD (Moore and Riley, 2015) and these findings may provide insight into these life long issues.…”

Opioid Receptor-Mediated and Non-Opioid Receptor-Mediated Roles of Opioids in Tumour Growth and Metastasis

“…This set of studies underlines the importance of opioid antagonists pharmacokinetics and pharmacodynamics in their anti-cancer effects, and somewhat reconciles the previous findings that both agonists and antagonists offered protection, by suggesting that the antagonists increase the sensitivity to endogenous agonists that are actually protective. This is supported by the antineoplastic activity of β-endorphin shown in vivo in models of breast carcinogenesis ( 64 , 65 ), and antagonised by naloxone ( 64 ). Similarly, low dose naltrexone enhanced serum concentrations of beta-endorphin and met-enkephalin and survival rates in dogs with mammary carcinoma ( 66 ).…”

Different Processed Products of Curcumae Radix Regulate Pain-Related Substances in a Rat Model of Qi Stagnation and Blood Stasis

“…The elevated level of 5-HT in model rats is consistent with the TCM theory that "the pain is caused by obstruction." β-EP, as one of the main bodies of endogenous opioid peptides, is produced by the hypothalamus and pituitary in vertebrates during exercise, excitement, pain, consumption of spicy food, and orgasm, and it resembles opiates in its ability to produce analgesia and a feeling of well-being (Chang-Hui and Shi- Jia, 2012;Zhang et al, 2016). Many studies have confirmed its analgesic effect, and it has become recognized as an inhibitory neurotransmitter to adjust pain (Qun et al, 2012;Du et al, 2016).…”