Target For Chemoprevention Research Articles

The Aryl Hydrocarbon Receptor and Its Crosstalk: A Chemopreventive Target of Naturally Occurring and Modified Phytochemicals.

The aryl hydrocarbon receptor (AhR) is an environmentally sensitive transcription factor (TF) historically associated with carcinogenesis initiation via the activation of numerous carcinogens. Nowadays, the AhR has been attributed to multiple endogenous functions to maintain cellular homeostasis. Moreover, crosstalk, often reciprocal, has been found between the AhR and several other TFs, particularly estrogen receptors (ERs) and nuclear factor erythroid 2-related factor-2 (Nrf2). Adequate modulation of these signaling pathways seems to be an attractive strategy for cancer chemoprevention. Several naturally occurring and synthetically modified AhR or ER ligands and Nrf2 modulators have been described. Sulfur-containing derivatives of glucosinolates, such as indole-3-carbinol (I3C), and stilbene derivatives are particularly interesting in this context. I3C and its condensation product, 3,3'-diindolylmethane (DIM), are classic examples of blocking agents that increase drug-metabolizing enzyme activity through activation of the AhR. Still, they also affect multiple essential signaling pathways in preventing hormone-dependent cancer. Resveratrol is a competitive antagonist of several classic AhR ligands. Its analogs, with ortho-methoxy substituents, exert stronger antiproliferative and proapoptotic activity. In addition, they modulate AhR activity and estrogen metabolism. Their activity seems related to a number of methoxy groups introduced into the stilbene structure. This review summarizes the data on the chemopreventive potential of these classes of phytochemicals, in the context of AhR and its crosstalk modulation.

Evaluation of EGFR and COX pathway inhibition in human colon organoids of serrated polyposis and other hereditary cancer syndromes.

Serrated polyposis syndrome (SPS) presents with multiple sessile serrated lesions (SSL) in the large intestine and confers increased colorectal cancer (CRC) risk. However, the etiology of SPS is not known. SSL-derived organoids have not been previously studied but may help provide insights into SPS pathogenesis and identify novel biomarkers and chemopreventive strategies. This study examined effects of EGFR and COX pathway inhibition in organoid cultures derived from uninvolved colon and polyps of SPS patients. We also compared with organoids representing the hereditary gastrointestinal syndromes, Familial Adenomatous Polyposis (FAP) and Lynch syndrome (LS). Eighteen total organoid colon cultures were generated from uninvolved colon and polyps in SPS, FAP, LS, and non-syndromic screening colonoscopy patients. BRAF and KRAS mutation status was determined for each culture. Erlotinib (EGFR inhibitor) and sulindac (COX inhibitor) were applied individually and in combination. A 44-target gene custom mRNA panel (including WNT and COX pathway genes) and a 798-gene microRNA gene panel were used to quantitate organoid RNA expression by NanoString analysis. Erlotinib treatment significantly decreased levels of mRNAs associated with WNT and MAPK kinase signaling in organoids from uninvolved colon from all four patient categories and from all SSL and adenomatous polyps. Sulindac did not change the mRNA profile in any culture. Our findings suggest that EGFR inhibitors may contribute to the chemopreventive treatment of SSLs. These findings may also facilitate clinical trial design using these agents in SPS patients. Differentially expressed genes identified in our study (MYC, FOSL1, EGR1, IL33, LGR5 and FOXQ1) may be used to identify other new molecular targets for chemoprevention of SSLs.

Avocado-derived extracellular vesicles loaded with ginkgetin and berberine prevent inflammation and macrophage foam cell formation.

Atherosclerosis, a chronic inflammatory disease of aorta, remains the major cause of morbidity and mortality among cardiovascular disease patients. Macrophage foam cell formation and inflammation are critically involved in early stages of atherosclerosis, hence chemopreventive targeting of foam cell formation by nutraceuticals may be a promising approach to curbing the progression of atherosclerosis. However, many nutraceuticals including berberine and ginkgetin have low stability, tissue/cell penetration and bioavailability resulting in inadequate chemotherapeutic effects of these nutraceuticals. We have used avocado-derived extracellular vesicles (EV) isolated from avocado (EVAvo ) as a novel carrier of nutraceuticals, in a strategy to alleviate the build-up of macrophage foam cells and expression of inflammatory genes. Our key findings are: (i) Avocado is a natural source of plant-derived EVs as shown by the results from transmission electron microscopy, dynamic light scattering and NanoBrook Omni analysis and atomic force microscopy; (ii) EVAvo are taken up by macrophages, a critical cell type in atherosclerosis; (iii) EVAvo can be loaded with high amounts of ginkgetin and berberine; (iv) ginkgetin plus berberine-loaded EVAvo (EVAvo(B+G) ) suppress activation of NFκB and NLRP3, and inhibit expression of pro-inflammatory and atherogenic genes, specifically Cd36, Tnfα, Il1β and Il6; (v) EVAvo(B+G) attenuate oxidized low-density lipoprotein (oxLDL)-induced macrophage foam cell formation and (vi) EVAvo(B+G) inhibit oxLDL uptake but not its cell surface binding during foam cell formation. Overall, our results suggest that using EVAvo as a natural carrier of nutraceuticals may improve strategies to curb the progression of atherosclerosis by limiting inflammation and pro-atherogenic responses.

Novel sulindac derivatives for colorectal cancer chemoprevention that target cGMP phosphodiesterases to suppress Wnt/β-catenin transcriptional activity

<p class="MsoNormal" style="margin-top: 6pt; line-height: 13pt; text-align: justify;"><span lang="EN-US" style="font-size: 10pt; font-family: arial, helvetica, sans-serif;">Approximately 28 million individuals in the United States face the risk of developing precancerous colonic adenomas (polyps) and potentially progressing to colorectal cancer (CRC). While a promising strategy for CRC prevention involves pharmacological intervention, such as cancer chemoprevention or interception, currently, there are no FDA-approved drugs capable of preventing the formation or progression of adenomas to adenocarcinoma. Numerous clinical, epidemiological, and preclinical studies have offered compelling evidence supporting the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) in CRC chemoprevention. However, the prolonged use of NSAIDs is not FDA-approved due to potential life-threatening toxicities resulting from cyclooxygenase (COX) inhibition and the depletion of physiological prostaglandins. Despite indications that the COX inhibitory activity of NSAIDs may not be essential for their antineoplastic effects, the absence of a well-defined target impeded the development of derivatives that do not inhibit COX. Earlier research suggests that the inhibition of cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) may be responsible, at least in part, for the antineoplastic activity of the NSAID sulindac. This could potentially offer a novel target for CRC chemoprevention. To identify the cGMP PDE isozyme(s) contributing to the antineoplastic activity of sulindac, we synthesized a chemically diverse library of over 1500 compounds, all sharing the indene scaffold of sulindac. Subsequently, we screened these compounds for their impact on cancer cell growth and PDE inhibitory activity. From this screening, a series of lead compounds emerged. These compounds lacked COX-1 and COX-2 inhibitory activity, surpassing sulindac in potency to inhibit CRC cell growth. Importantly, they demonstrated greater selectivity by not affecting normal cell growth. Through chemical optimization, we identified several development candidates that selectively inhibit PDE5 and/or PDE10. These compounds activate cGMP/PKG signaling, suppressing Wnt/β-catenin transcription. This action counters the growth advantages resulting from APC or CTNNB1 mutations, which are responsible for most human CRCs. This review delves into the scientific literature supporting PDE5 and/or PDE10 as potential targets for CRC chemoprevention or interception. Our findings suggest a promising avenue for developing drugs that may effectively intervene in the progression of colorectal cancer, offering hope for improved preventive strategies in the future.</span></p>

Novel sulindac derivatives for colorectal cancer chemoprevention that target cGMP phosphodiesterases to suppress Wnt/β-catenin transcriptional activity

<p class="MsoNormal" style="margin-top: 6pt; line-height: 13pt; text-align: justify;"><span lang="EN-US" style="font-size: 10pt; font-family: arial, helvetica, sans-serif;">Approximately 28 million individuals in the United States face the risk of developing precancerous colonic adenomas (polyps) and potentially progressing to colorectal cancer (CRC). While a promising strategy for CRC prevention involves pharmacological intervention, such as cancer chemoprevention or interception, currently, there are no FDA-approved drugs capable of preventing the formation or progression of adenomas to adenocarcinoma. Numerous clinical, epidemiological, and preclinical studies have offered compelling evidence supporting the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) in CRC chemoprevention. However, the prolonged use of NSAIDs is not FDA-approved due to potential life-threatening toxicities resulting from cyclooxygenase (COX) inhibition and the depletion of physiological prostaglandins. Despite indications that the COX inhibitory activity of NSAIDs may not be essential for their antineoplastic effects, the absence of a well-defined target impeded the development of derivatives that do not inhibit COX. Earlier research suggests that the inhibition of cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) may be responsible, at least in part, for the antineoplastic activity of the NSAID sulindac. This could potentially offer a novel target for CRC chemoprevention. To identify the cGMP PDE isozyme(s) contributing to the antineoplastic activity of sulindac, we synthesized a chemically diverse library of over 1500 compounds, all sharing the indene scaffold of sulindac. Subsequently, we screened these compounds for their impact on cancer cell growth and PDE inhibitory activity. From this screening, a series of lead compounds emerged. These compounds lacked COX-1 and COX-2 inhibitory activity, surpassing sulindac in potency to inhibit CRC cell growth. Importantly, they demonstrated greater selectivity by not affecting normal cell growth. Through chemical optimization, we identified several development candidates that selectively inhibit PDE5 and/or PDE10. These compounds activate cGMP/PKG signaling, suppressing Wnt/β-catenin transcription. This action counters the growth advantages resulting from APC or CTNNB1 mutations, which are responsible for most human CRCs. This review delves into the scientific literature supporting PDE5 and/or PDE10 as potential targets for CRC chemoprevention or interception. Our findings suggest a promising avenue for developing drugs that may effectively intervene in the progression of colorectal cancer, offering hope for improved preventive strategies in the future.</span></p>

Development of a MEK inhibitor, NFX-179, as a chemoprevention agent for squamous cell carcinoma.

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer. Although cSCC contributes to substantial morbidity and mortality in high-risk individuals, deployment of otherwise effective chemoprevention of cSCC is limited by toxicities. Our systematic computational drug repurposing screen predicted that selumetinib, a MAPK (mitogen-activated protein kinase) kinase inhibitor (MEKi), would reverse transcriptional signatures associated with cSCC development, consistent with our genomic analysis implicating MEK as a chemoprevention target. Although systemic MEKi suppresses the formation of cSCC in mice, systemic MEKi can cause severe adverse effects. Here, we report the development of a metabolically labile MEKi, NFX-179, designed to potently and selectively suppress the MAPK pathway in the skin before rapid metabolism in the systemic circulation. NFX-179 was identified on the basis of its biochemical and cellular potency, selectivity, and rapid metabolism upon systemic absorption. In our ultraviolet-induced cSCC mouse model, topical application of NFX-179 gel reduced the formation of new cSCCs by an average of 60% at doses of 0.1% and greater at 28 days. We further confirmed the localized nature of these effects in an additional split-mouse randomized controlled study where suppression of cSCC was observed only in drug-treated areas. No toxicities were observed. NFX-179 inhibits the growth of human SCC cell lines in a dose-dependent manner, and topical NFX-179 application penetrates human skin and inhibits MAPK signaling in human cSCC explants. Together, our data provide a compelling rationale for using topical MEK inhibition through the application of NFX-179 gel as an effective strategy for cSCC chemoprevention.

A Review on some dietary phytochemicals as potential cancer chemoprevention and chemotherapeutic agents

Cancer is a disease with multiple etiologies and has gained the interest of researchers in search for its prevention and therapeutic targets. Mammalian cells are constantly exposed to electrophilic/oxidative stresses that are considered to be part of the most essential and pervasive causes of cancer. The Nuclear factor erythroid 2-related factor 2 (Nrf2) is crucial in either inducing or suppressing angiogenesis. As a result, it has been implicated in numerous stages of carcinogenesis through association with several signaling pathways and molecules. This transcription factor may be regarded as key target for chemoprevention of cancer. As a transcription factor, Nrf2 exert a great function in ARE-driven genes expression. More so, it plays an important role in the up-regulation of these genes towards oxidative challenges. Numerous phytochemicals especially in fruits as well as edible vegetables have shown to activate Nrf2 and elicit antioxidant response. Inducing the synthesis of antioxidant/phase II detoxifying enzymes (UDP-glucuronyltransferase, Heme oxygenase-1, NAD(P)H: quinone oxidoreductase and Glutathione-s-transferase) by natural compounds present in diet is among the most efficient approaches for cancer prevention in human. This review discusses Keap1-Nrf2-ARE pathway as a prime target for cancer chemoprevention, its underlying mechanisms and modulation by dietary phytochemicals as well as effects of combination of phytochemicals.

Dietary phytochemicals targeting Nf-<i>K</i>B signalling pathways: Potential cancer chemoprevention strategy

Chemoprevention is an approach involving the use of natural or synthetic substances to prevent the risk of development many diseases including cancer. Nuclear factor–kappa B (NF-kB) signaling pathways is crucial in either inducing processes of inflammation and apoptosis. As a result, it is implicated in numerous stages of carcinogenesis through collaboration with several signaling pathways and molecules. This transcription factor may be regarded as key target for cancer chemoprevention. Phytochemicals available in food as well as green plants have been demonstrated to have cancer protection activities by modulating important cellular signaling pathways including NF-kB pathway. Numerous phytochemicals, primarily components of edible vegetables and plants, have been reported in the literature to modulate NF-kB. Suppressing NF-kB may provide protection to the normal cells against development and spread of cancer. Majority of phytochemicals use various mechanisms to inhibit NF-kB. Different phytochemicals combinations present in a natural food may enhance their modulating potential on NF-kB and consequently elicit cancer prevention. This article reviews the current understanding of the potential effect of some phytochemicals and their combinations on NF-kB activities.

AKR1B1 inhibition using NARI-29-an Epalrestat analogue-alleviates Doxorubicin-induced cardiotoxicity via modulating Calcium/CaMKII/MuRF-1 axis

The clinical use of doxorubicin (Dox) is narrowed due to its carbonyl reduction to doxorubicinol (Doxol) implicating resistance and cardiotoxicity. Hence, in the present study we have evaluated the cardioprotective effect of AKR1B1 (or aldose reductase, AR) inhibitor NARI-29 (epalrestat (EPS) analogue) and its effect in the Dox-modulated calcium/CaMKII/MuRF1 axis. Initially, the breast cancer patient survival associated with AKR1B1 expression was calculated using Kaplan Meier-plotter (KM-plotter). Further, breast cancer, cardiomyoblast (H9c2), and macrophage (RAW 264.7) cell lines were used to establish the in vitro combination effect of NARI-29 and Dox. To develop the cardiotoxicity model, mice were given Dox 2.5 mg/kg (i.p.), biweekly. The effect of AKR1B1 inhibition using NARI-29 on molecular and cardiac functional changes was measured using echocardiography, fluorescence-imaging, ELISA, immunoblotting, flowcytometry, High-Performance Liquid Chromatography with Fluorescence Detection (HPLC-FD) and cytokine-bead array methods. The bioinformatics data suggested that a high expression of AKR1B1 is associated with significantly low survival of breast cancer patients undergoing chemotherapy; hence, it could be a target for chemo-sensitization and chemo-prevention. Further, in vitro studies showed that AKR1B1 inhibition with NARI-29 has increased the accumulation and sensitized Dox to breast cancer cell lines. However, treatment with NARI-29 has alleviated the Dox-induced toxicity to cardiomyocytes and decreased the secretion of inflammatory cytokines from RAW 264.7 cells. In vivo studies revealed that the NARI-29 (25 and 50 mg/kg) has prevented the functional, histological, biochemical, and molecular alterations induced by Dox treatment. Moreover, we have shown that NARI-29 has prevented the carbonyl reduction of Dox to Doxol in the mouse heart, which reduced the calcium overload, prevented phosphorylation of CaMKII, and reduced the expression of MuRF1 to protect from cardiac injury and apoptosis. Hence in conclusion, AKR1B1 inhibitor NARI-29 could be used as an adjuvant therapeutic agent with Dox to prevent cardiotoxicity and synergize anti-breast cancer activity.

Cyclooxygenase and Lipoxygenase Gene Expression in the Inflammogenesis of Colorectal Cancer: Correlated Expression of EGFR, JAK STAT and Src Genes, and a Natural Antisense Transcript, RP11-C67.2.2

We examined the expression of major inflammatory genes, cyclooxygenase-1, 2 (COX1, COX2), arachidonate-5-lipoxygenase (ALOX5), and arachidonate-5-lipoxygenase activating protein (ALOX5AP) among 469 tumor specimens of colorectal cancer in The Cancer Genome Atlas (TCGA). Among 411 specimens without mutations in mismatch repair (MMR) genes, the mean expression of each of the inflammatory genes ranked above the 80th percentile, and the overall mean cyclooxygenase expression (COX1+COX2) ranked in the upper 99th percentile of all genes. Similar levels were observed for 58 cases with MMR mutations. Pearson correlation coefficients exceeding r = 0.70 were observed between COX and LOX mRNA levels with genes of major cell-signaling pathways involved in tumorigenesis (Src, JAK STAT, MAPK, PI3K). We observed a novel association (r = 0.78) between ALOX5 expression and a natural antisense transcript (NAT), RP11-67C2.2, a long non-coding mRNA gene, 462 base pairs in length that is located within the terminal intron of the ALOX5 gene on chromosome 10q11.21. Tumor-promoting genes highly correlated with the expression of COX1, COX2, ALOX5 and ALOX5AP are known to increase mitogenesis, mutagenesis, angiogenesis, cell survival, immunosuppression and metastasis in the inflammogenesis of colorectal cancer. These genes and the novel NAT, RP1167C2.2 are potential molecular targets for chemoprevention and therapy of colorectal cancer.

Comprehensive DNA Methylation Analysis Indicates That Pancreatic Intraepithelial Neoplasia Lesions Are Acinar-Derived and Epigenetically Primed for Carcinogenesis.

Analysis of DNA methylation landscapes provides insights into the cell-of-origin of PanIN lesions, clarifies the role of PanIN lesions as metaplastic precursors to human PDAC, and suggests potential targets for chemoprevention.

Molecular Pathways of Carcinogenesis in Familial Adenomatous Polyposis.

Familial adenomatous polyposis (FAP) is a genetic syndrome characterized by the presence of multiple polyps in the gastrointestinal tract and a wide range of systemic extra-intestinal manifestations. Patients affected will inevitably undergo abdominal surgery due to the malignant transformation of one or more adenomas. The pathogenesis of the disease is based on a loss of function mutation in adenomatous polyposis coli (APC), a tumor-suppressor gene, inherited following a Mendelian pattern. This gene is a key component of multiple cell functions that cooperate for homeostasis; when mutated, it contributes to the progression of colorectal adenoma into cancer. Recent studies have demonstrated that several additional mechanisms may influence this process, such as alterations in gut microbiota composition and mucosal barrier immunity, interaction with the immune microenvironment and inflammation, the hormone estrogen, and other signaling pathways. These factors represent promising targets of future therapies and chemoprevention, aiming to alter the progressive nature of the disease and improve the quality of life of families affected. Therefore, we performed a narrative review about the current knowledge of the aforementioned pathways involved in colorectal cancer pathogenesis in FAP, exploring the genetic and environmental factors that may contribute to the development of CRC in FAP.

LTA4H extensively associates with mRNAs and lncRNAs indicative of its novel regulatory targets.

The RNA-binding metabolic enzyme LTA4H is a novel target for cancer chemoprevention and chemotherapy. Recent research shows that the increased expression of LTA4H in laryngeal squamous cell carcinoma (LSCC) promotes tumor proliferation, migration, and metastasis. However, its mechanism remains unclear. To investigate the potential role of LTA4H in LSCC, we employed the improved RNA immunoprecipitation and sequencing (iRIP-Seq) experiment to get the expression profile of LTA4H binding RNA in HeLa model cells, a cancer model cell that is frequently used in molecular mechanism research. We found that LTA4H extensively binds with mRNAs/pre-mRNAs and lncRNAs. In the LTA4H binding peak, the frequency of the AAGG motif reported to interact with TRA2β4 was high in both replicates. More notably, LTA4H-binding genes were significantly enriched in the mitotic cell cycle, DNA repair, RNA splicing-related pathways, and RNA metabolism pathways, which means that LTA4H has tumor-related alternative splicing regulatory functions. QRT-PCR validation confirmed that LTA4H specifically binds to mRNAs of carcinogenesis-associated genes, including LTBP3, ROR2, EGFR, HSP90B1, and lncRNAs represented by NEAT1. These results suggest that LTA4H may combine with genes associated with LSCC as an RNA-binding protein to perform a cancer regulatory function. Our study further sheds light on the molecular mechanism of LTA4H as a clinical therapy target for LSCC.

Epigallocatechin Gallate (EGCG), an Active Phenolic Compound of Green Tea, Inhibits Tumor Growth of Head and Neck Cancer Cells by Targeting DNA Hypermethylation

Head and neck cancers are among the deadliest cancers, ranked sixth globally in rates of high mortality and poor patient prognoses. The prevalence of head and neck squamous cell carcinoma (HNSCC) is associated with smoking and excessive alcohol consumption. Despite several advances in diagnostic and interventional methods, the morbidity of subjects with HNSCC has remained unchanged over the last 30 years. Epigenetic alterations, such as DNA hypermethylation, are commonly associated with several cancers, including HNSCC. Thus, epigenetic changes are considered promising therapeutic targets for chemoprevention. Here, we investigated the effect of EGCG on DNA hypermethylation and the growth of HNSCC. First, we assessed the expression levels of global DNA methylation in HNSCC cells (FaDu and SCC-1) and observed enhanced methylation levels compared with normal human bronchial epithelial cells (NHBE). Treatment of EGCG to HNSCC cells significantly inhibited global DNA hypermethylation by up to 70-80% after 6 days. Inhibition of DNA hypermethylation in HNSCC cells was confirmed by the conversion of 5-methylcytosine (5-mc) into 5-hydroxy methylcytosine (5hmC). DNA methyltransferases regulate DNA methylation. Next, we checked the effect of EGCG on the expression levels of DNA methyltransferases (DNMTs) and DNMT activity. Treatment of EGCG to HNSCC cells significantly reduced DNMT activity to 60% in SCC-1 and 80% in FaDu cells. The protein levels of DNMT3a and DNMT3b were downregulated in both cell lines after EGCG treatment. EGCG treatment to HNSCC cells reactivated tumor suppressors and caused decreased cell proliferation. Our in vivo study demonstrated that administration of EGCG (0.5%, w/w) as a supplement within an AIN76A diet resulted in inhibition of tumor growth in FaDu xenografts in nude mice (80%; p < 0.01) compared with non-EGCG-treated controls. The growth inhibitory effect of dietary EGCG on the HNSCC xenograft tumors was associated with the inhibition of DNMTs and reactivation of silenced tumor suppressors. Together, our study provides evidence that EGCG acts as a DNA demethylating agent and can reactivate epigenetically silenced tumor suppressors to inhibit the growth of HNSCC cells.

Identification of gene profiles related to the development of oral cancer using a deep learning technique

BackgroundOral cancer (OC) is a debilitating disease that can affect the quality of life of these patients adversely. Oral premalignant lesion patients have a high risk of developing OC. Therefore, identifying robust survival subgroups among them may significantly improve patient therapy and care. This study aimed to identify prognostic biomarkers that predict the time-to-development of OC and survival stratification for patients using state-of-the-art machine learning and deep learning.MethodsGene expression profiles (29,096 probes) related to 86 patients from the GSE26549 dataset from the GEO repository were used. An autoencoder deep learning neural network model was used to extract features. We also used a univariate Cox regression model to select significant features obtained from the deep learning method (P < 0.05). High-risk and low-risk groups were then identified using a hierarchical clustering technique based on 100 encoded features (the number of units of the encoding layer, i.e., bottleneck of the network) from autoencoder and selected by Cox proportional hazards model and a supervised random forest (RF) classifier was used to identify gene profiles related to subtypes of OC from the original 29,096 probes.ResultsAmong 100 encoded features extracted by autoencoder, seventy features were significantly related to time-to-OC-development, based on the univariate Cox model, which was used as the inputs for the clustering of patients. Two survival risk groups were identified (P value of log-rank test = 0.003) and were used as the labels for supervised classification. The overall accuracy of the RF classifier was 0.916 over the test set, yielded 21 top genes (FUT8-DDR2-ATM-CD247-ETS1-ZEB2-COL5A2-GMAP7-CDH1-COL11A2-COL3A1-AHR-COL2A1-CHORDC1-PTP4A3-COL1A2-CCR2-PDGFRB-COL1A1-FERMT2-PIK3CB) associated with time to developing OC, selected among the original 29,096 probes.ConclusionsUsing deep learning, our study identified prominent transcriptional biomarkers in determining high-risk patients for developing oral cancer, which may be prognostic as significant targets for OC therapy. The identified genes may serve as potential targets for oral cancer chemoprevention. Additional validation of these biomarkers in experimental prospective and retrospective studies will launch them in OC clinics.

Broccoli sprouts delay prostate cancer formation and decrease prostate cancer severity with a concurrent decrease in HDAC3 protein expression in TRAMP mice

Background: Cruciferous vegetables have been associated with the chemoprevention of cancer. Epigenetic regulators have been identified as important targets for prostate cancer chemoprevention. Treatment of human prostate cancer cells with sulforaphane (SFN), a chemical from broccoli and broccoli sprouts, inhibits epigenetic regulators such as histone deacetylase (HDAC) enzymes, but it is not known whether consumption of a diet high in broccoli sprouts impacts epigenetic mechanisms in an in vivo model of prostate cancer. Objective: In the transgenic adenocarcinoma of the mouse prostate (TRAMP) model, we tested the hypothesis that a broccoli sprout diet suppresses prostate cancer, inhibits HDAC expression, alters histone modifications, and changes the expression of genes regulated by HDACs. Methods: TRAMP mice were fed a 15% broccoli sprout, or control AIN93G diet; tissue samples were collected at 12 and 28 weeks of age. Results: Mice fed broccoli sprouts had detectable levels of SFN metabolites in liver, kidney, colon, and prostate tissues. Broccoli sprouts reduced prostate cancer incidence, and progression to invasive cancer by 11- and 2.4-fold at 12 and 28 weeks of age, respectively. There was a significant decline in HDAC3 protein expression in the epithelial cells of prostate ventral and anterior lobes at 12 weeks. Broccoli sprout consumption also decreased histone H3 lysine 9 tri-methylation in the ventral lobe (12 week), and decreased histone H3 lysine 18 acetylation in all prostate lobes (28 weeks). A decline in p16 mRNA levels, a gene regulated by HDAC3, was associated with broccoli sprouts consumption, but no significant changes were noted at the protein level. Conclusions: Broccoli sprout intake caused a decline in prostate cancer occurrence and HDAC3 protein expression in the prostate, extending prior work that implicated loss of HDAC3/corepressor interactions as a key preventive mechanism by SFN in vivo.

The Myths and Realities of Prostate Cancer Chemoprevention – A Journey Through Scientific Evidences

The goals of primary chemoprevention of any disease include decreasing the incidence of disease, reducing treatment-related adverse events, cutting down the cost of treatment and bringing down the mortality due to the disease. Increased prevalence of prostate cancer and identification of large numbers of newly detected disease due to the availability of better screening measures, long latency of the disease and peculiar molecular basis of pathogenesis make prostate cancer an attractive target of chemoprevention. This article reviews the experimental and epidemiological data available from 1998 to 2023 on the effectiveness, safety and toxicity of various nutritional and other agents proposed to be used for prostate cancer chemoprevention either to reduce the incidence of this cancer and/or slow down the disease progression. No single agent has been categorically proved to be the best for chemoprevention of prostate cancer as of now. Although majority of studies do not propose adopting chemoprevention in the entire elderly men population, it may be ideal that the men at higher risk of contracting prostate cancer like those having positive family history would be the best choice for implementing chemoprevention.

Metabolic reprograming of cancer as a therapeutic target

Our understanding of metabolic reprogramming in cancer has tremendously improved along with the technical progression of metabolomic analysis. Metabolic changes in cancer cells proved much more complicated than the classical Warburg effect. Previous studies have approached metabolic changes as therapeutic and/or chemopreventive targets. Recently, several clinical trials have reported anti-cancer agents associated with metabolism. However, whether cancer cells are dependent on metabolic reprogramming or favor suitable conditions remains nebulous. Both scenarios are possibly intertwined. Identification of downstream molecules and the understanding of mechanisms underlying reprogrammed metabolism can improve the effectiveness of cancer therapy. Here, we review several examples of the metabolic reprogramming of cancer cells and the therapies targeting the metabolism-related molecules as well as discuss practical approaches to improve the next generation of cancer therapies focused on the metabolic reprogramming of cancer.

Transethosomal Gel for the Topical Delivery of Celecoxib: Formulation and Estimation of Skin Cancer Progression.

The topical delivery of therapeutics is a promising strategy for managing skin conditions. Cyclooxygenase-2 (COX-2) inhibitors showed a possible target for chemoprevention and cancer management. Celecoxib (CXB) is a selective COX-2 inhibitor that impedes cell growth and generates apoptosis in different cell tumors. Herein, an investigation proceeded to explore the usefulness of nano lipid vesicles (transethosomes) (TES) of CXB to permit penetration of considerable quantities of the drug for curing skin cancer. The prepared nanovesicles were distinguished for drug encapsulation efficiency, vesicle size, PDI, surface charge, and morphology. In addition, FT-IR and DSC analyses were also conducted to examine the influence of vesicle components. The optimized formulation was dispersed in various hydrogel bases. Furthermore, in vitro CXB release and ex vivo permeability studies were evaluated. A cytotoxicity study proceeded using A431 and BJ1 cell lines. The expression alteration of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene and DNA damage and fragmentation using qRT-PCR and comet assays were also investigated. Optimized CXB-TES formulation was spherically shaped and displayed a vesicle size of 75.9 ± 11.4 nm, a surface charge of -44.7 ± 1.52 mV, and an entrapment efficiency of 88.8 ± 7.2%. The formulated TES-based hydrogel displayed a sustained in vitro CXB release pattern for 24 h with an enhanced flux and permeation across rat skin compared with the control (free drug-loaded hydrogel). Interestingly, CXB-TES hydrogel has a lower cytotoxic effect on normal skin cells compared with TES suspension and CXB powder. Moreover, the level of expression of the CDKN2A gene was significantly (p ≤ 0.01, ANOVA/Tukey) decreased in skin tumor cell lines compared with normal skin cell lines, indicating that TES are the suitable carrier for topical delivery of CXB to the cancer cells suppressing their progression. In addition, apoptosis demonstrated by comet and DNA fragmentation assays was evident in skin cancer cells exposed to CXB-loaded TES hydrogel formulation. In conclusion, our results illustrate that CXB-TES-loaded hydrogel could be considered a promising carrier and effective chemotherapeutic agent for the management of skin carcinoma.

Abstract IA006: Reverse-engineering discovery of targets, involved cell types, and compounds for liver cancer chemoprevention

Abstract Hepatocellular carcinoma (HCC) is a cancer type with clinically unequivocal and well-defined predisposing conditions, namely chronic fibrotic liver diseases caused by viral hepatitis and metabolic disorders. By following up the at-risk patient cohort, natural history of HCC development can be captured over the timeframe of one to two decades. Archived biospecimens are often available from the time of initial liver disease diagnosis, and unbiased molecular profiling of the specimens provides unique opportunities to interrogate molecular dysregulations confidently correlated with the real long-term clinical outcome, i.e., HCC development from early-stage liver diseases. This “reverse-engineering” strategy helps increase the likelihood of identifying clinically relevant therapeutic targets without solely relying on data from experimental preclinical models. This is particularly useful in cancer chemoprevention target discovery given the the requirement of overwhelmingly lengthy and costly clinical validation of experimentally derived candidate targets, which is often practically infeasible. Utilizing this strategy, we could successfully identify HCC chemoprevention targets (e.g., cellular signaling such as EGFR pathway, circulating bioactive lipids), involved cell types (e.g., hepatic myofibroblasts, conventional dendritic cells), and compounds (e.g., small molecular signaling pathway inhibitors, generic agents), streamline the process of their clinical validation, and facilitate translation of promising chemoprevention agents to the care of liver disease patients. Citation Format: Yujin Hoshida. Reverse-engineering discovery of targets, involved cell types, and compounds for liver cancer chemoprevention [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr IA006.