Basic cell physiological activities (cell adhesion, chemotaxis and proliferation) induced by selegiline and its derivatives in Mono Mac 6 human monocytes

Abstract

Selegiline (R-deprenyl), a monoamine oxidase-B (MAO-B) inhibitor, has complex pharmacological effect that contributes to treatment of neurodegenerative diseases such as Parkinson's and presumably Alzheimer's disease and might work as an inhibitor of tumor growth. In respect of tumorigenesis and metastasis formation, the controlled modifications of adhesion and migration have high therapeutic significance. In the present study, our purpose was to investigate cell physiological responses (adhesion, chemotaxis and proliferation) induced by selegiline, its metabolites and synthetic derivatives and to find some correlations between the molecular structure and the reported antitumor behavior of the derivatives. Our results demonstrated that both R- and S-deprenyls have the potency to elicit increased adhesion and a chemorepellent activity in monocyte model (Mono Mac 6 cell line derived from monoblastic leukemia); however, only the R-enantiomer proved to be cytotoxic. Among the metabolites R-amphetamine has retained the adhesion inducer and the chemorepellent effect of the parent drug on the most significant level. In contrast, a reversed chemotactic effect and an improved cytotoxic character were detected in the presence of fluoro group (p-fluoro-S-deprenyl). In summary, the adhesion inducer activity, chemorepellent and advantageous cytotoxic effects of selegiline and some derivatives indicate that these drug molecules might have inhibitory effects in metastasis formation in primary tumors.

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

“…It has been reported that treatment with high-dose L-deprenyl induces toxicity against monoblastic leukemia and pituitary and mammary cancer (13,(27)(28)(29). In addition, treatment of mono-mac-6 cells with a high concentration of L-deprenyl reduces cell proliferation and metastasis (13).…”

“…It has been reported that treatment with high-dose L-deprenyl induces toxicity against monoblastic leukemia and pituitary and mammary cancer (13,(27)(28)(29). In addition, treatment of mono-mac-6 cells with a high concentration of L-deprenyl reduces cell proliferation and metastasis (13). It has also been shown that decreasing norepinephrine and dopamine, metabolites of MAO, by treatment with L-deprenyl reduces tumor size in vivo (27)(28)(29).…”

“…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).…”

“…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). However, whether an intracellular organelle-based mechanism underlies the antitumor effect of L-deprenyl, and whether this action is dependent on MAO-B inhibition, remains uncertain.…”

HPLC analysis of blood–brain barrier penetration of 4-fluorodeprenyl

“…Knoll and Miklya [14] found that treatment with (-)-4-fluorodeprenyl enhanced the release of dopamine (from corpus striatum, substantia nigra and tuberculum olfactorium) and noradrenaline (from locus coeruleus), however, the (+)-enantiomer was more active than the (-)-fo rm . Lajko et al [15] investigated the effect of derivatization of deprenyl in 4-position with fluoride. This change did not only result in cell adhesion, but the chemotactic effect was also reversed.…”