Redox dysregulation in cancer cells represents a chemical vulnerability that can be targeted by prooxidant redox intervention. Dietary constituents that contain an electrophilic Michael acceptor pharmacophore may therefore display promising chemopreventive and chemotherapeutic anti-cancer activity. Here, we demonstrate that the cinnamon-derived dietary Michael acceptor trans-cinnamic aldehyde (CA) impairs melanoma cell proliferation and tumor growth. Feasibility of therapeutic intervention using high doses of CA (120 mg/kg, p.o., q.d., 10 days) was demonstrated in a human A375 melanoma SCID-mouse xenograft model. Low micromolar concentrations (IC 50 < 10 μM) of CA, but not closely related CA-derivatives devoid of Michael acceptor activity, suppressed proliferation of human metastatic melanoma cell lines (A375, G361, LOX) with G1 cell cycle arrest, elevated intracellular ROS, and impaired invasiveness. Expression array analysis revealed that CA induced an oxidative stress response in A375 cells, up-regulating heme oxygenase-1 (HMOX1), sulfiredoxin 1 homolog (SRXN1), thioredoxin reductase 1 (TXNRD1), and other genes including the cell cycle regulator and stress-responsive tumor suppressor gene cyclin-dependent kinase inhibitor 1A (CDKN1A), a key mediator of G1 phase arrest. CA, but not Michael-inactive derivatives, inhibited NFκB transcriptional activity and TNFα-induced IL-8 production in A375 cells. These findings support a previously unrecognized role of CA as a dietary Michael acceptor with potential anticancer activity.
Cytokinins and cytokinin nucleosides are purine derivatives with potential anticancer activity. N 6 -furfuryladenosine (FAdo, kinetin-riboside) displays antiproliferative and apoptogenic activity against various human cancer cell lines, and FAdo has recently been shown to suppress tumor growth in murine xenograft models of human leukemia and melanoma. In this study, FAdo-induced genotoxicity, stress response gene expression, and cellular ATP depletion were examined as early molecular consequences of FAdo-exposure in MiaPaCa-2 pancreas carcinoma, A375 melanoma, and other human cancer cell lines. FAdo, but not adenosine or N 6 -furfuryladenine, displayed potent antiproliferative activity that was also observed in human primary fibroblasts and keratinocytes. Remarkably, massive ATP depletion and induction of genotoxic stress as assessed by the alkaline comet assay occurred within 60 to 180 minutes of exposure to low micromolar concentrations of FAdo. This was followed by rapid upregulation of CDKN1A and other DNA damage/stress response genes (HMOX1, DDIT3, GADD45A) as revealed by expression array and Western analysis. Pharmacological and siRNA-based genetic inhibition of adenosine kinase suppressed FAdo cytotoxicity and also prevented ATP-depletion and p21-upregulation suggesting the importance of bioconversion of FAdo into the nucleotide form required for drug action. Taken together our data suggest that early induction of genotoxicity and energy crisis are important causative factors involved in FAdo cytotoxicity.
Strong experimental evidence suggests the involvement of photo-oxidative stress mediated by reactive oxygen species as a crucial mechanism of solar damage relevant to human skin photoaging and photocarcinogenesis. Based on the established role of antioxidant response element (ARE)-mediated gene expression in cancer chemoprevention, we tested the hypothesis that small molecule Nrf2-activators may serve a photo-chemopreventive role by targeting skin cell photo-oxidative stress. A luciferase-based reporter gene assay was used as a primary screen for the identification of novel agents that modulate the Nrf2-Keap1 signaling pathway. A series of cinnamoyl-based electrophilic Michael acceptors including cinnamic aldehyde and methyl-1-cinnamoyl-5-oxo-2-pyrrolidine-carboxylate was identified as potent Nrf2-activators. Hit confirmation was performed in a secondary screen, based on immunodetection of Nrf2 protein upregulation in human Hs27 skin fibroblasts, HaCaT keratinocytes, and primary skin keratinocytes. Bioefficacy profiling of positive test compounds in skin cells demonstrated compound-induced upregulation of hemeoxygenase I and NAD(P)H-quinone oxidoreductase, two Nrf2 target genes involved in the cellular antioxidant response. Pretreatment with cinnamoylbased Nrf2-activators suppressed intracellular oxidative stress and protected against photooxidative induction of apoptosis in skin cells exposed to high doses of singlet oxygen. Our pilot studies suggest feasibility of developing cinnamoyl-based Nrf2-activators as novel photochemopreventive agents targeting skin cell photo-oxidative stress.
A challenging task of the immune system is to fight cancer cells. However, a variety of human cancers educate immune cells to become tumor supportive. This is exemplified for tumor-associated macrophages (TAMs), which are polarized towards an antiinflammatory and cancer promoting phenotype. Mechanistic explanations, how cancer cells influence the macrophage phenotype are urgently needed to address potential anti-cancer strategies along this line. One potential immune modulating compound, sphingosine-1-phosphate (S1P), was recently highlighted in both tumor growth and immune modulation. Using a xenograft model in nude mice, we demonstrate a supportive role of sphingosine kinase 2 (SphK2), one of the S1P-producing enzymes for tumor progression. The growth of SphK2-deficient MCF-7 breast tumor xenografts was markedly delayed when compared with controls. Infiltration of macrophages in SphK2-deficient and control tumors was comparable. However, TAMs from SphK2-deficient tumors displayed a pronounced anti-tumor phenotype, showing an increased expression of pro-inflammatory markers/mediators such as NO, TNF-a, IL-12 and MHCII and a low expression of anti-inflammatory IL-10 and CD206. These data suggest a role for S1P, generated by SphK2, in early tumor development by affecting macrophage polarization. ' 2009 UICC
Tumor-associated macrophages (TAMs) are a major supportive component within neoplasms. Mechanisms of macrophage (MΦ) attraction and differentiation to a tumor-promoting phenotype, which is characterized by pronounced interleukin (IL)-10 production, are under investigation. We report that supernatants of dying cancer cells induced substantial IL-10 release from primary human MΦs, dependent on signaling through tyrosine kinase receptor A (TRKA or neurotrophic tyrosine kinase receptor type 1 (NTRK1)). Mechanistically, sphingosine-1-phosphate (S1P) release from apoptotic cancer cells triggered src-dependent shuttling of cytosolic TRKA to the plasma membrane via S1P receptor signaling. Plasma membrane-associated TRKA, which was activated by constitutively autocrine secreted nerve growth factor, used phosphatidylinositol 3-kinase (PI3K)/AKT and p38 mitogen-activated protein kinase (MAPK) signaling to induce IL-10. Interestingly, TRKA-dependent signaling was required for cytokine production by TAMs isolated from primary murine breast cancer tissue. Besides IL-10, this pathway initiated secretion of IL-6, tumor necrosis factor-α (TNF-α) and monocyte chemotactic protein-1 (MCP-1), indicating relevance in cancer-associated inflammation. Our findings highlight a fine-tuned regulatory system including S1P-dependent TRKA trafficking for executing TAM-like cell function in vitro as well as in vivo.
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