Melatonin as a Therapeutic Agent for the Inhibition of Hypoxia-Induced Tumor Progression: A Description of Possible Mechanisms Involved

Abstract

Hypoxia has an important role in tumor progression via the up-regulation of growth factors and cellular adaptation genes. These changes promote cell survival, proliferation, invasion, metastasis, angiogenesis, and energy metabolism in favor of cancer development. Hypoxia also plays a central role in determining the resistance of tumors to chemotherapy. Hypoxia of the tumor microenvironment provides an opportunity to develop new therapeutic strategies that may selectively induce apoptosis of the hypoxic cancer cells. Melatonin is well known for its role in the regulation of circadian rhythms and seasonal reproduction. Numerous studies have also documented the anti-cancer properties of melatonin, including anti-proliferation, anti-angiogenesis, and apoptosis promotion. In this paper, we hypothesized that melatonin exerts anti-cancer effects by inhibiting hypoxia-induced pathways. Considering this action, co-administration of melatonin in combination with other therapeutic medications might increase the effectiveness of anti-cancer drugs. In this review, we discussed the possible signaling pathways by which melatonin inhibits hypoxia-induced cancer cell survival, invasion, migration, and metabolism, as well as tumor angiogenesis.

Keywords: angiogenesis; antioxidant; apoptosis; cancer; melatonin; metastasis.

Figure 1

The mechanisms of hypoxia in cancer progression. Hypoxia enhances cancer cell survival by inducing autophagy via hypoxia-inducible factor-1 alpha (HIF-1α) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Subsequently, it causes (1) the down-regulation of caveolin-1 (Cav-1), leading to the up-regulation of TP53-inducible glycolysis and apoptosis regulator (TIGAR) and protects cells against oxidative stress and apoptosis, and (2) protection of the cells from apoptosis via BCL2 interacting protein 3 (BNIP3) and BCL2 interacting protein 3-like (BNIP3L). Hypoxia can induce tumor angiogenesis by (1) increasing proangiogenic factors such as vascular endothelial growth factor (VEGF), angiopoietin-2 (Ang-2), platelet-derived growth factor (PDGF), and basic fibroblast growth factor (bFGF), (2) decreasing angiogenesis inhibitors such as thrombospondin, (3) up-regulation of extracellular matrix (ECM) proteins, such as lysyl oxidase (LOX) and matrix metalloproteinases (MMPs), and (4) activating Notch and Wnt signaling pathways. Hypoxia increases cancer cell invasion and migration by the down-regulation of cell adhesion molecules and the up-regulation of ECM degradation molecules such as MMP-9 and urokinase-type plasminogen activator receptor (uPAR). Hypoxia affects the metabolic pathways to provide high energy for cancer cells by (1) enhancing the transcription of glucose transporters genes (GLUT1 and GLUT3), VEGF, and glycolytic enzymes (e.g., lactate dehydrogenase, LDHA), (2) inducing the expression of glycogenesis enzymes including phosphoglucomutase-1 (PGM1), glycogen synthase-1 (GYS1), UDP-glucose pyrophosphorylase 2 (UGP2) and 1,4-alpha-glucan branching enzyme 1 (GBE1), (3) reducing glycogen phosphorylase (GP) activity, and (4) diverting pyruvate from the citric acid cycle into lactate by pyruvate dehydrogenase kinases-1 and -3 (PDK-1 and -3).

Figure 2

The mechanisms through which melatonin inhibits hypoxia-induced tumor progression. Melatonin inhibits the survival of hypoxic cancer cells by (1) up-regulating and activating the apoptotic factors, (2) down-regulating and inactivating anti-apoptotic factors [B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xL)], (3) blocking the cell cycle by up-regulating p21/WAF1 and p53, and (4) inhibiting carbonic anhydrase IX (CA IX) expression and activity and cAMP-related pathways to make an unsuitable environmental pH. Melatonin inhibits hypoxia-induced angiogenesis by (1) suppressing the activity of vascular endothelial growth factor (VEGF), angiopoietin-2 (Ang-2), stromal-derived factor 1 (SDF-1), matrix metalloproteinase-2 and -9 (MMP-2 and -9), angiopoietin-1 and -2 (ANGPT-1 and -2), (2) inhibiting the expression of lipoxygenase (LOX) via interacting with RZR/RORα nuclear receptor, and (3) blocking the hypoxia-induced tumor-associated macrophages (TAMs) and membrane-type 1 matrix metalloproteinase (MT1-MMP) activity and subsequently reducing Semaphorin-4D (Sema4D). Melatonin inhibits the hypoxia-induced invasion and migration of cancer cells by (1) decreasing levels of proteases including Cathepsin C (CTSC), MMP-2, MMP-9, MT1-MMP, and urokinase-type plasminogen activator (uPA), (2) up-regulating the adhesion proteins, such as integrin and E-cadherin, (3) suppressing oxidative-stress-induced detachment of cancer cells via overexpression of the β1 integrin and down-regulation of ROS-αvβ3 integrin-FAK/Pyk2 (focal adhesion kinase/proline-rich tyrosine kinase 2) signaling pathway, and (4) blocking hypoxia-induced microtubule organization and rearrangement via blocking the Rho-kinase 1 (ROCK1) signaling pathway. Melatonin disturbs hypoxia-induced cancer cell metabolism by (1) reducing reactive oxygen species (ROS) and down-regulating hypoxia-inducible factor-1 (HIF-1), VEGF and glycolysis-related enzymes such as glucose transporter 1 (GLUT1) and progestins activate 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), and (2) competing with glucose in binding to GLUT1, and 3) inhibition of 3-phosphoinositide-dependent protein kinase 1 (PDK-1) signaling pathway.