Overcoming the limited bioavailability and extensive metabolism of effective in vitro drugs remains a challenge that limits the translation of promising drugs into clinical trials. Resveratrol, despite its well-reported therapeutic benefits, is not metabolically stable and thus has not been utilized as an effective clinical drug. This is because it needs to be consumed in large amounts to overcome the burdens of bioavailability and conversion into less effective metabolites. Herein, we summarize the more relevant approaches to modify resveratrol, aiming to increase its biological and therapeutic efficacy. We discuss combination therapies, derivatization, and the use of resveratrol nanoparticles. Interestingly, the combination of resveratrol with established chemotherapeutic drugs has shown promising therapeutic effects on colon cancer (with oxaliplatin), liver cancer (with cisplatin, 5-FU), and gastric cancer (with doxorubicin). On the other hand, derivatizing resveratrol, including hydroxylation, amination, amidation, imidation, methoxylation, prenylation, halogenation, glycosylation, and oligomerization, differentially modifies its bioavailability and could be used for preferential therapeutic outcomes. Moreover, the encapsulation of resveratrol allows its trapping within different forms of shells for targeted therapy. Depending on the nanoparticle used, it can enhance its solubility and absorption, increasing its bioavailability and efficacy. These include polymers, metals, solid lipids, and other nanoparticles that have shown promising preclinical results, adding more “hype” to the research on resveratrol. This review provides a platform to compare the different approaches to allow directed research into better treatment options with resveratrol.

Resveratrol (3,4,5-Trihydroxy-trans-stilbene) is a naturally occurring polyphenol that exhibits beneficial pleiotropic health effects. It is one of the most promising natural molecules in the prevention and treatment of chronic diseases and autoimmune disorders. One of the key limitations in the clinical use of resveratrol is its extensive metabolic processing to its glucuronides and sulfates. It has been estimated that around 75% of this polyphenol is excreted via feces and urine. To possibly alleviate the extensive metabolic processing and improve bioavailability, we have added segments of acetylsalicylic acid to resveratrol in an attempt to maintain the functional properties of both. We initially characterized resveratrol-aspirin derivatives as products that can inhibit cytochrome P450 Family 1 Subfamily A Member 1 (CYP1A1) activity, DNA methyltransferase (DNMT) activity, and cyclooxygenase (COX) activity. In this study, we provide a detailed analysis of how resveratrol and its aspirin derivatives can inhibit nuclear factor kappa B (NFκB) activation, cytokine production, the growth rate of cancer cells, and in vivo alleviate intestinal inflammation and tumor growth. We identified resveratrol derivatives C3 and C11 as closely preserving resveratrol bioactivities of growth inhibition of cancer cells, inhibition of NFκB activation, activation of sirtuin, and 5’ adenosine monophosphate-activated protein kinase (AMPK) activity. We speculate that the aspirin derivatives of resveratrol would be more metabolically stable, resulting in increased efficacy for treating immune disorders and as an anti-cancer agent.

Persistent inflammation can trigger altered epigenetic, inflammatory, and bioenergetic states. Inflammatory bowel disease (IBD) is an idiopathic disease characterized by chronic inflammation of the gastrointestinal tract, with evidence of subsequent metabolic syndrome disorder. Studies have demonstrated that as many as 42% of patients with ulcerative colitis (UC) who are found to have high-grade dysplasia, either already had colorectal cancer (CRC) or develop it within a short time. The presence of low-grade dysplasia is also predictive of CRC. Many signaling pathways are shared among IBD and CRC, including cell survival, cell proliferation, angiogenesis, and inflammatory signaling pathways. Current IBD therapeutics target a small subset of molecular drivers of IBD, with many focused on the inflammatory aspect of the pathways. Thus, there is a great need to identify biomarkers of both IBD and CRC, that can be predictive of therapeutic efficacy, disease severity, and predisposition to CRC. In this study, we explored the changes in biomarkers specific for inflammatory, metabolic, and proliferative pathways, to help determine the relevance to both IBD and CRC. Our analysis demonstrated, for the first time in IBD, the loss of the tumor suppressor protein Ras associated family protein 1A (RASSF1A), via epigenetic changes, the hyperactivation of the obligate kinase of the NOD2 pathogen recognition receptor (receptor interacting protein kinase 2 [RIPK2]), the loss of activation of the metabolic kinase, AMP activated protein kinase (AMPKα1), and, lastly, the activation of the transcription factor and kinase Yes associated protein (YAP) kinase, that is involved in proliferation of cells. The expression and activation status of these four elements are mirrored in IBD, CRC, and IBD-CRC patients and, importantly, in matched blood and biopsy samples. The latter would suggest that biomarker analysis can be performed non-invasively, to understand IBD and CRC, without the need for invasive and costly endoscopic analysis. This study, for the first time, illustrates the need to understand IBD or CRC beyond an inflammatory perspective and the value of therapeutics directed to reset altered proliferative and metabolic states within the colon. The use of such therapeutics may truly drive patients into remission.

Resveratrol and aspirin are known to exert potential chemopreventive effects through modulation of numerous targets. Considering that the CYP450 system is responsible for the activation of environmental procarcinogens, the aim of this study was to design a new class of hybrid resveratrol-aspirin derivatives possessing the stilbene and the salicylate scaffolds. Using HepG2 cells, we evaluated (a) the inhibition of TCDD-mediated induction of CYP1A1 exerted by resveratrol-aspirin derivatives using the EROD assay, and (b) CYP1A1 mRNA in vitro. We observed significant inhibition (84%) of CYP1A1 activity and a substantial decrease in CYP1A1 mRNA with compound 3, compared to control. Resveratrol did not exert inhibition under the same experimental conditions. This inhibitory profile was supported by docking studies using the crystal structure of human CYP1A1. The potential effect exerted by compound 3 (the most active), provide preliminary evidence supporting the design of hybrid molecules combining the chemical features of resveratrol and aspirin.

The appearance of cancer progresses through a multistep process that includes genetic, epigenetic, mutational, inflammatory and metabolic disturbances to signaling pathways within an organ. The combined influence of these changes will dictate the growth properties of the cells; the direction of further malignancy depends on the severity of these “disturbances”. The molecular mechanisms driving abnormal inflammation and metabolism are beginning to be identified and, in some cases, are quite prominent in pre-condition states of cancer and are significant drivers of the malignant phenotype. As such, utilizing signaling pathways linked to inflammation and metabolism as biomarkers of cancer is an emerging method and includes pathways beyond those well characterized to drive metabolism or inflammation. In this review, we will discuss several emerging elements influencing proliferation, inflammation and metabolism that may play a part as drivers of the cancer phenotype. These include AMPK and leptin (linked to metabolism), NOD2/RIPK2, TAK1 (linked to inflammation), lactate and pyruvate transporters (monocarboxylate transporter [MCT], linked to mitochondrial biogenesis and metabolism) and RASSF1A (linked to proliferation, cell death, cell cycle control, inflammation and epigenetics). We speculate that the aforementioned elements are important drivers of carcinogenesis that should be collectively referenced as being involved in “ImmunoMET Oncogenesis”, a new tripartite description of the role of elements in driving cancer. This term would suggest that for a better understanding of cancer, we need to understand how proliferation, inflammation and metabolic pathways are impacted and how they influence classical drivers of malignant transformation in order to drive ImmunoMET oncogenesis and the malignant state.

Objective: The function of the Ras association domain family 1 (RASSF1)/modulator of apoptosis 1 (MOAP-1) molecular tumor suppressor pathway is often perturbed in many solid and blood cancers by epigenetic loss of RASSF1A via promoter specific methylation. However, a detailed analysis of expression and stability of MOAP-1 as well as effect on cellular proliferation and cell death in blood cancers has not been explored. Materials and Methods: Expression of MOAP-1 RASSF1A was performed by immunoblotting analysis, MOAP-1 effect on biology determined by cell proliferation, cell death and tumorigenicity assays. Lastly, proteomic analysis in MOAP-1 in form 1 and 2 expressing cells reveal new interacting partners to MOAP-1. Results: The expression of MOAP-1 appears to be quite varied and exists as two forms, a p39 and p46 form in blood cancers. The higher MOAP-1 p46 form was mainly observed in acute myeloid leukemia (AML) and some acute lymphocytic leukemia (ALL) patients and cell lines. Furthermore, MOAP-1 p46 form can be reduced to the p39 form upon calf intestinal or lambda phosphatase treatment, suggesting post-translational phosphorylation likely produces the slower migrating form. Blood cancer cell lines containing the p46 form of MOAP-1 appears to be more resistant to cell death signals and have increased growth. In addition, we document in vivo protection from tumorigenesis of cells containing MOAP-1 following tail vein injection of cancer cells. Lastly, proteomic analysis revealed several interesting components of the MOAP-1 interactome in blood cancer cells that we validated. Conclusions: MOAP-1 is a bona fide tumor suppressor in blood cancers with functions beyond apoptosis.