olvanil and Breast-Neoplasms

Inactivation of sensory neurons expressing transient receptor potential vanilloid 1 (TRPV1) enhances breast cancer metastasis. Sensory neurons have profound effects on immune response to a wide range of diseases including cancer. Hence, activation of sensory nerves using feasible approaches such as specific TRPV1 agonists may inhibit breast cancer metastasis through neuroimmune pathways. TRPV1 agonists are considered for the treatment of pain and inflammatory diseases.. We here first determined the effects of four different TRPV1 agonists on proliferation of three different metastatic breast carcinoma cells since TRPV1 is also expressed in cancer cells. Based on the results obtained under in-vitro conditions, brain metastatic breast carcinoma cells (4TBM) implanted orthotopically into the mammary-pad of Balb-c mice followed by olvanil treatment (i.p.). Changes in tumor growth, metastasis and immune response to cancer cells were determined.. Olvanil dose-dependently activated sensory nerve fibers and markedly suppressed lung and liver metastasis without altering the growth of primary tumors. Olvanil (5 mg/kg) systemically increased T cell count, enhanced intra-tumoral recruitment of CD8+ T cells and increased IFN-γ response to irradiated cancer cells and Con-A. Anti-inflammatory changes such as increased IL-10 and decrease IL-6 as well as S100A8+ cells were observed following olvanil treatment.. Our results show that anti-metastatic effects of olvanil is mainly due to activation of neuro-immune pathways since olvanil dose used here is not high enough to directly activate immune cells. Furthermore, olvanil effectively depletes sensory neuropeptides; hence, olvanil is a good non-pungent alternative to capsaicin.

Topics: Animals; Breast Neoplasms; Capsaicin; Cell Line, Tumor; Cell Proliferation; Female; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Nerve Fibers; Pain; Sensory Receptor Cells; TRPV Cation Channels

Palmitoylethanolamide (PEA) is a bioactive fatty acid amide belonging to the class of N-acyl-ethanolamines (NAEs). This compound has been known since the 1950s for its anti-inflammatory effects, but was re-discovered only after the finding that another NAE, arachidonoyl-ethanolamide (anandamide, AEA), could act as an endogenous ligand of cannabinoid receptors. Although a similar function for PEA has also been proposed, this compound does not activate the two cannabinoid receptor subtypes described to date. PEA and AEA are co-synthesized by cells, and PEA might act as an 'entourage' compound for AEA, i.e. as an endogenous enhancer of AEA biological actions. Indeed, long-term treatment of human breast cancer cells (HBCCs) with PEA downregulates the expression of the enzyme responsible for AEA degradation, the fatty acid amide hydrolase, thereby leading to an enhancement of AEA-induced, and cannabinoid CB1 receptor-mediated, cytostatic effect on HBCCs. AEA is also a full agonist for the receptors of another class of bioactive fatty acid amides, the N-acyl-vanillyl-amines (e.g. capsaicin and olvanil). These sites of action are known as vanilloid receptors of type 1 (VR1). PEA enhances the VR1-mediated effects of AEA and capsaicin on calcium influx into cells. These 'entourage' effects of PEA might be attributable to modulation of VR1 activity, and could underlie the enhancement by PEA, described here for the first time, of the antiproliferative effects of VR1 receptor agonists.

Topics: Amides; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Breast Neoplasms; Cannabinoids; Capsaicin; Cell Division; Dose-Response Relationship, Drug; Drug Synergism; Endocannabinoids; Ethanolamines; Female; Humans; Palmitic Acids; Receptors, Cannabinoid; Receptors, Drug; Signal Transduction; Tumor Cells, Cultured