Prevention of Mammary Tumor Development through Neuroimmunomodulation in the Spleen and Lymph Nodes of Old Female Sprague-Dawley Rats by <smlcap>L</smlcap>-Deprenyl

Abstract

Background: Development of mammary tumors is an age-associated phenomenon that is likely due to deficits in the neuroendocrine-immune interactions. Previously, we demonstrated that <smlcap>L</smlcap>-deprenyl, a monoamine oxidase-B (MAO-B) inhibitor, can enhance immune responses and restore noradrenergic (NA) innervation in the spleens of rats with carcinogen-induced and spontaneously developing mammary tumors. Objectives: To investigate whether (1) treatment of early middle-aged female rats would prevent the spontaneous development of mammary tumors accompanied by restoration of immunity in the spleen and draining lymph nodes (DLN) and sympathetic NA innervation in the spleen and (2) deprenyl can influence the proliferation of estrogen receptor (ER)-positive (MCF-7 and T47D) and ER-negative (MDA-MB-231 and Hs 578T) human breast cancer cells. Methods: Early middle-aged (8- to 9-month-old) female Sprague-Dawley rats were treated with 0, 1.0 or 2.5 mg of deprenyl/kg body weight (BW) daily i.p. for 12 months. Cells of ER-positive (ER+) and ER-negative (ER-) human breast cancer cell lines were incubated with media or 10^-3 to 10^-8<smlcap>M</smlcap> deprenyl for 1, 2, 4 or 6 days to examine the proliferation of cells. Results: Tumor incidence increased in saline-treated old female rats, while deprenyl treatment significantly reduced the incidence of mammary tumors in these rats. Saline-treated tumor-bearing rats exhibited reduced splenic NA innervation and norepinephrine (NE) content, splenic interleukin (IL)-2 and interferon (IFN)-γ levels and NK cell activity as well as DLN IL-2 and IFN-γ levels compared to young female rats without tumors. In contrast, treatment with 2.5 mg/kg of deprenyl enhanced IL-2 and IFN-γ production in both the spleen and DLN as well as splenic natural killer (NK) cell activity. Deprenyl treatment also increased concanavalin A (Con A)-induced proliferation of T lymphocytes in the DLN. Deprenyl-induced changes in immune responses were accompanied by enhanced NA innervation and NE content in the spleen. In vitro incubation of various concentrations of deprenyl with ER+ human breast cancer cell lines partly inhibited the proliferation of cells, while it had no effect on the ER- breast cancer cells. Conclusions: These results suggest that (1) development of mammary tumors is mediated through the loss of immunity and sympathetic NA nerve fibers accompanied by reduced NE levels in the spleen, (2) the prevention of mammary tumor development by deprenyl may involve the reversal of the tumor-associated decline in sympathetic NA activity and cell-mediated immune responses in the spleen and DLN and (3) the antitumor effects of deprenyl may be partially mediated through ER-dependent intracellular signaling pathways.

Enriching the Housing Environment for Mice Enhances Their NK Cell Antitumor Immunity via Sympathetic Nerve–Dependent Regulation of NKG2D and CCR5

“…The SNS has dual effects on NK cells. Sympathetic innervation may improve the function of NK cells by modulating cytokine productions in the spleen or lymph nodes (46,47). However, in the in vitro study, the primary SNS neurotransmitter norepinephrine was shown to inhibit NK activity via b-adrenoceptors (48).…”

Estrogen upregulates inflammatory signals through NF-κB, IFN-γ, and nitric oxide via Akt/mTOR pathway in the lymph node lymphocytes of middle-aged female rats

“…Further, the interaction between APCs and lymphocytes may be attenuated because of a decline in the expression of cell adhesion and homing molecules [39]. Compromised immune status with advancing age may also facilitate development of mammary tumors in which there is a reduction in IL-2 and IFN-γ production by the lymphocytes of draining lymph nodes [30]. Ovariectomy-induced suppression of immune responses was similar to those found in lymphocytes from the spleen and may involve alterations in the expression of p-ERK/Total ERK and p-CREB/Total CREB [40,28](Supplementary data S1 and S2).…”

“…Lymphocytes in the lymph nodes were isolated in HBSS by teasing the lymph nodes using pincer-tip forceps [30]. The solution containing the lymphocytes was then filtered using a nylon mesh to remove large aggregates and washed 3 times with HBSS.…”

L‑Deprenyl exerts cytotoxicity towards acute myeloid leukemia through inhibition of mitochondrial respiration

“…Previous studies have shown that high-dose L-deprenyl treatment causes toxic effects on cancer cells and mammary tumors through production of ROS (12,13,18). Since the main sites of ROS generation are mitochondrial oxidative phosphorylation complex I and III, the mitochondrial OCR was measured using an XF24 analyzer (19).…”

“…The high concentration of L-deprenyl is known to exert anticancer effects, exhibiting efficacy in reducing breast tumor size and decreasing tumor cell viability. There is also evidence that L-deprenyl decreases the activity of an estrogen-receptor (ER)-dependent intracellular signaling pathway in ER-positive human breast cancer (12). In addition to its effects on solid tumors, L-deprenyl also reduces the number of monoblastic leukemia cells by increasing production of norepinephrine, interferon-γ, cluster of differentiation 8 + lymphocytes and natural killer cells in the spleen (13).…”