Sweet Cherries as Anti-Cancer Agents: From Bioactive Compounds to Function

Abstract

Sweet cherries (Prunus avium L.) are among the most appreciated fruits worldwide because of their organoleptic properties and nutritional value. The accurate phytochemical composition and nutritional value of sweet cherries depends on the climatic region, cultivar, and bioaccessibility and bioavailability of specific compounds. Nevertheless, sweet cherry extracts are highly enriched in several phenolic compounds with relevant bioactivity. Over the years, technological advances in chemical analysis and fields as varied as proteomics, genomics and bioinformatics, have allowed the detailed characterization of the sweet cherry bioactive phytonutrients and their biological function. In this context, the effect of sweet cherries on suppressing important events in the carcinogenic process, such as oxidative stress and inflammation, was widely documented. Interestingly, results from our research group and others have widened the action of sweet cherries to many hallmarks of cancer, namely metabolic reprogramming. The present review discusses the anticarcinogenic potential of sweet cherries by addressing their phytochemical composition, the bioaccessibility and bioavailability of specific bioactive compounds, and the existing knowledge concerning the effects against oxidative stress, chronic inflammation, deregulated cell proliferation and apoptosis, invasion and metastization, and metabolic alterations. Globally, this review highlights the prospective use of sweet cherries as a dietary supplement or in cancer treatment.

Keywords: anthocyanins; anti-cancer agents; apoptosis; inflammation; invasion; metabolic reprogramming; metastization; oxidative stress; proliferation; sweet cherries.

Figure 1

Sweet cherry modulation of oxidative stress and inflammation. Sweet cherry extracts reduce oxidative stress by decreasing the production of reactive oxygen species (ROS), namely nitric oxide (NO) and lipid peroxidation. This was accompanied by the decreased activity of nitric oxide (NO) synthase, up-regulation of glutathione (GSH), and altered expression of several enzymes involved in the antioxidant defense, such as glutathione reductase (GR), glutathione peroxidase (GPx), NAD(P)H quinone oxidoreductase (NQO1), catalase, and superoxide dismutase (SOD). The anti-inflammatory effect of sweet cherries is achieved by both inducing anti-inflammatory markers whereas inhibiting the pro-inflammatory ones. Identified targets include the anti-inflammatory (interleukin (IL)-2, -4 and -10) and pro-inflammatory (IL-6, -1β and -18) cytokines tumor necrosis factor (TNF)-α, cyclooxygenase (COX) 1 and COX2, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), C-reactive protein (CRP), epidermal growth factor (EGF), endothelin-1 (ET-1), extracellular newly identified receptor for advanced glycation end-products binding protein (EN-RAGE), ferritin and plasminogen activator inhibitor-1 (PAI-1). Green and red circle sections mean activation and inhibition, respectively.

Figure 2

Sweet cherries effects in modulating the intracellular signaling that governs cancer cell proliferation and apoptosis. Regardless of anthocyanins or proanthocyanins enrichment, sweet cherry extracts reduced cell proliferation and induced apoptosis with altered expression and/or activity of several molecular targets. However, extracts enriched in anthocyanins or proanthocyanins can influence specific molecular targets (see text for details). Overall, mechanistically, the phosphoinositide 3-kinase (PI3K) pathway was inhibited with the mechanistic target of rapamycin (mTOR) and AKT as targets. Cytokine receptors signaling could also be influenced by sweet cherry extract, namely by the modulation of signal transducer and activator of transcription (STAT) 3 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB or RelA/p50). In the mitogen-activated protein kinase (MAPK) pathway, altered activity of p38-MAPK, extracellular signal-regulated kinase (ERK) 1/2, and c-Jun N-terminal kinase (JNK) was reported. Concerning apoptosis, the sweet cherry extract enriched in anthocyanins influenced both the extrinsic (caspase-8) and intrinsic (B-cell lymphoma 2-associated X protein (Bax), apoptosis-inducing factor (AIF), cytochrome c release, caspase-9) pathways, culminating in the activation of caspase-3. Whole sweet cherry extract or extract enriched in proanthocyanins activated only the intrinsic pathway (Bax, AIF, caspase-9 and -3, and cytochrome c release). Green and red arrows mean up- and down-regulation of expression and/or activity, respectively. Legend: FADD, Fas-associated protein with death domain; FasL, Fas ligand; FasR, Fas receptor; IκBα, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, α; IKK, IκB kinase; JAK, Janus Kinase; RAP, Ras proximate; RTK, Receptor tyrosine kinase; TFs, Transcription factors.

Figure 3

Sweet cherry actions in the regulation of glucose metabolism. Sweet cherry extract modulated glucose uptake in both neoplastic and non-neoplastic cancer cells, which was linked with the decreased expression of glucose transporters (GLUTs), GLUT1 and GLUT3. After entering the cell, glucose undergoes glycolysis with the production of pyruvate that can be converted to lactate by lactate dehydrogenase (LDH) or to acetyl-coenzyme A (Acetyl-CoA), which enters the tricarboxylic acid (TCA) cycle. In prostate cancer cells, the presence of sweet cherry extract also reduced lactate production, which was underpinned by the decreased activity of LDH and a reduced expression of the lactate exporter, monocarboxylate transporter (MCT) 4. In addition, sweet cherry extract downregulated phosphofructokinase-1 (PFK-1) expression in non-neoplastic cells, whereas increasing LDH activity. Green and red arrows mean up- and down-regulation of expression and/or activity, respectively.