Cancer Chemopreventive Activity Research Articles

Morusin-Cu(II)-indocyanine green nanoassembly ignites mitochondrial dysfunction for chemo-photothermal tumor therapy

Nanoscale drug delivery systems derived from natural bioactive materials accelerate the innovation and evolution of cancer treatment modalities. Morusin (Mor) is a prenylated flavonoid compound with high cancer chemoprevention activity, however, the poor water solubility, low active pharmaceutical ingredient (API) loading content, and instability compromise its bioavailability and therapeutic effectiveness. Herein, a full-API carrier-free nanoparticle is developed based on the self-assembly of indocyanine green (ICG), copper ions (Cu2+) and Mor, termed as IMCNs, via coordination-driven and π-π stacking for synergistic tumor therapy. The IMCNs exhibits a desirable loading content of Mor (58.7 %) and pH/glutathione (GSH)-responsive motif. Moreover, the photothermal stability and photo-heat conversion efficiency (42.8 %) of IMCNs are improved after coordination with Cu2+ and help to achieve photothermal therapy. Afterward, the released Cu2+ depletes intracellular overexpressed GSH and mediates Fenton-like reactions, and further synergizes with ICG at high temperatures to expand oxidative damage. Furthermore, the released Mor elicits cytoplasmic vacuolation, expedites mitochondrial dysfunction, and exerts chemo-photothermal therapy after being combined with ICG to suppress the migration of residual live tumor cells. In vivo experiments demonstrate that IMCNs under laser irradiation could excellently inhibit tumor growth (89.6 %) through the multi-modal therapeutic performance of self-enhanced chemotherapy/coordinated-drugs/ photothermal therapy (PTT), presenting a great potential for cancer therapy.

Antiproliferative, apoptosis-inducing, and GSTP1 demethylation activities of Ellagitannins isolated from Cornus alba L.

This study aimed to prove the prostate cancer chemopreventive activity of compounds isolated from CA. We evaluated these compounds using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and evaluated their NF-κB inhibitory activity and apoptosis-inducing activity using western blot analysis and flow cytometry, respectively. Their DNA methylation activity was also evaluated via a methylation-specific polymerase chain reaction in androgen-dependent (LNCaP) and androgen-independent (PC-3) prostate cancer cell lines. Camptothin B (1), cornusiin B (2), and cornusiin A (3), which were isolated in our previous work, relatively reduced the protein expression levels in PCa cells. Among them, cornusiin B (2) exhibited excellent NF-κB inhibitory activity. Also, concentration-dependently increased the unmethylated DNA content and decreased the methylated DNA content in both PC-3 and LNCaP cells. Therefore, cornusiin B (2), which was isolated from CA, has the potential to act as a chemopreventive agent for prostate cancer.

Synthesis, structural elucidation, physico-chemical quantum properties and in silico interaction analysis of 2-methyl-3-((4-nitrobenzyl)oxy)quinoxaline

MNBQ has been synthesized and its crystal structure was solved by direct method and refined by full matrix least squares procedure. The crystal structure is stabilized with elaborate network of intermolecular CH…O hydrogen bonds and van der-Waal's forces to form supramolecular structures. 3D Hirshfeld surfaces and allied 2D fingerprint plots were analysed for non-covalent interactions. The Hirshfeld surface analysis of the crystal structure indicates that the most important contributions for the crystal packing are from H···H (37.5 %) and O···H/H···O (21.8 %) interactions. Theoretical (DFT) studies on the molecular structure, vibrational spectra, Mulliken charges, HOMO, LUMO, MESP surfaces have been performed at B3LYP /6-311++G (d,p) level of theory. The geometrical parameters of the optimized compound are in good agreement with the XRD experimental data. Molecular docking studies supported by in silico drug likeness screening suggested that MNBQ might possess potent cancer chemopreventive activity.

Beneficial Effects of Red Wine Polyphenols on Human Health: Comprehensive Review.

Polyphenols are secondary plant metabolites synthesized during the development of the grape berry as a response to stress conditions. They are important constituents in red wines that contribute to the sensory properties and antioxidant activity of wines. Due to the development of highly sophisticated analytical devices, it is now possible to characterize the structure of highly polymerized polyphenols and obtain a full polyphenol profile of red wines. Red wine polyphenols include the ones present in grapes as well as new polyphenol products formed during the winemaking process. Among them, the most important groups and their representatives are flavanols (catechin), stilbenes (trans-resveratrol), flavonols (quercetin) and hydroxybenzoic acids (gallic acid). It is known that polyphenols exhibit beneficial effects on human health, such as anti-inflammatory, anticarcinogenic and cardio-protective effects. Many studies have been conducted on the health effects of red wine polyphenols in cancer chemopreventive activities, neuroprotective effects and impact on cardiovascular diseases, gut microbiota in humans, etc. This review will provide major scientific findings on the impact of red wine polyphenols on human health as well as a review of polyphenols present in red wines and their main features.

Main Determinants Affecting the Antiproliferative Activity of Stilbenes and Their Gut Microbiota Metabolites in Colon Cancer Cells: A Structure–Activity Relationship Study

trans-Resveratrol can be catabolized by the gut microbiota to dihydroresveratrol, 3,4'-dihydroxy-trans-stilbene, lunularin, and 4-hydroxydibenzyl. These metabolites can reach relevant concentrations in the colon. However, not all individuals metabolize RSV equally, as it depends on their RSV gut microbiota metabotype (i.e., lunularin producers vs. non-producers). However, how this microbial metabolism affects the cancer chemopreventive activity of stilbenes and their microbial metabolites is poorly known. We investigated the structure-antiproliferative activity relationship of dietary stilbenes, their gut microbial metabolites, and various analogs in human cancer (Caco-2 and HT-29) and non-tumorigenic (CCD18-Co) colon cells. The antiproliferative IC50 values of pterostilbene, oxy-resveratrol, piceatannol, resveratrol, dihydroresveratrol, lunularin, 3,4'-dihydroxy-trans-stilbene, pinosylvin, dihydropinosylvin, 4-hydroxy-trans-stilbene, 4-hydroxydibenzyl, 3-hydroxydibenzyl, and 4-trans-stilbenemethanol were calculated. IC50 values were correlated with 34 molecular characteristics by bi- and multivariate analysis. Little or no activity on CCD18-Co was observed, while Caco-2 was more sensitive than HT-29, which was explained by their different capacities to metabolize the compounds. Caco-2 IC50 values ranged from 11.4 ± 10.1 μM (4-hydroxy-trans-stilbene) to 73.9 ± 13.8 μM (dihydropinosylvin). In HT-29, the values ranged from 24.4 ± 11.3 μM (4-hydroxy-trans-stilbene) to 96.7 ± 6.7 μM (4-hydroxydibenzyl). At their IC50, most compounds induced apoptosis and arrested the cell cycle at the S phase, pterostilbene at G2/M, while 4-hydroxy-trans-stilbene and 3,4'-dihydroxy-trans-stilbene arrested at both phases. Higher Connolly values (larger size) hindered the antiproliferative activity, while a lower pKa1 enhanced the activity in Caco-2, and higher LogP values (more hydrophobicity) increased the activity in HT-29. Reducing the styrene double bond in stilbenes was the most critical feature in decreasing the antiproliferative activity. These results (i) suggest that gut microbiota metabolism determines the antiproliferative effects of dietary stilbenes. Therefore, RSV consumption might exert different effects in individuals depending on their gut microbiota metabotypes associated with RSV metabolism, and (ii) could help design customized drugs with a stilbenoid and (or) dibenzyl core against colorectal cancer.

Promising Phyto-Antioxidant Methanolic Extract from Canarium Odontophyllum Miq. (Dabai) Leaves against UVB Induced B164A5 Melanoma Cells as a Potential Skin Chemoprevention Agent

The high incidence and mortality of skin cancer along with the development of chemotherapy resistance have urged researchers to look into alternative strategies to combat cancer. Chemoprevention is one of the well-researched strategies using natural products. Canarium odontophyllum Miq. (dabai) is a local seasonal fruit that is mainly found in Sarawak, Malaysia. The leaves of the fruit harbor many medicinal useful phytochemicals that provide a new insight for chemoprevention. The present research has been planned to study the chemopreventive activity of methanolic extract of C. odontophyllum Miq. leaves on UVB induced B164A5 melanoma cells through its antioxidant profiles. The extract displayed statistically significant (p<0.05) antioxidant activity by enhancing superoxide dismutase, SOD (1023.02 ± 106.74 U/mg protein) and catalase (0.12 ± 0.003 U/mg protein) activities compared to negative control. Low oxidative damage was also observed whereby the protein carbonyl and malondialdehyde levels were significantly reduced (p<0.05), 1.69 ± 0.296 nmol/mg protein and 1.181 ± 0.03 nmol/mg protein respectively. In conclusion, the extract exhibited a promising skin cancer chemoprevention activity through its significant antioxidant activities. These findings evidently pave the path for further investigations in chemoprevention strategy.

Sulfated Extract of Abelmoschus Esculentus: A Potential Cancer Chemo-preventive Agent.

Abelmoschus esculentus (AE) (okra), is an edible plant used in many food applications. This study explored whether sulfated AE (SAE) has promising cancer chemopreventive activities that may recommend it as a functional food supplement instead of (or in addition to) AE for the population at risk of cancer and in the health food industry. Cytochrome P450-1A (CYP1A) was estimated by fluorescence enzymatic reaction, using β-naphthoflavone-treated cells (CYP1A inducer). Peroxyl and hydroxyl radical scavenging was assayed by oxygen radical absorbance capacity assay. Flow cytometry was used to analyze apoptosis/necrosis in MCF-7 cells, cell cycle phases in MCF-7 cells, and macrophage binding to fluorescein isothiocyanate-lipopolysaccharide (FITC-LPS). Nitric oxide was determined by Griess assay in LPS-stimulated macrophages, and cytotoxicity was determined by MTT assay. Diethylnitrosamine (DEN) was used to induce hepatic tumor initiation in rats. Placental glutathione-S-transferase (GSTP; an initiation marker) was stained in a fluorescence immunohistochemical analysis of liver sections, and histopathological changes were examined. SAE exhibited strong antitumor initiation and antitumor promotion activities. It suppressed CYP1A, scavenged peroxyl and hydroxyl radicals, induced macrophage proliferation, suppressed macrophage binding to FITC-LPS, inhibited nitric oxide generation, showed specific cytotoxicity to human breast MCF-7 adenocarcinoma cells, and disturbed the cell cycle phases (S and G2/M phases) in association with an increased percentage of apoptotic/necrotic MCF-7 cells. Over a short time period, DEN stimulated liver cancer initiation, but SAE treatment reduced the DEN-induced histopathological alterations and inhibited CYP1A and GSTP. SAE extract has the potential for use as an alternative to AE in health foods to provide cancer chemoprevention in populations at risk for cancer.

Ent-abietane diterpenoid lactone glycosides and a phenolic glycoside from Phlogacanthus pulcherrimus T. Anderson with cytotoxic and cancer chemopreventive activities

Nine undescribed ent-abietane diterpenoid lactone glycosides, pulcherrimosides A–I, and a phenolic glycoside, phlogoside A, together with ten known compounds were isolated from the aerial parts of Phlogacanthus pulcherrimus T. Anderson. Their structures were established through spectral methods, especially 2D NMR and HRESIMS analyses, and by acid hydrolysis. The absolute configurations of pulcherrimosides A-I were determined through the interpretation of electronic circular dichroism (ECD) data. Some of the isolates were evaluated for their in vitro cytotoxic and cancer chemopreventive properties. Helioscopinolide A and 17-hydroxyhelioscopinolide A showed good cytotoxic activity against HeLa cells with IC50 values of 18.16 ± 0.58 and 16.60 ± 0.23 μM, respectively. Pulcherrimoside D inhibited superoxide anion radical formation in the xanthine/xanthine oxidase (XXO) assay with an IC50 value of 59.5 μM. Helioscopinolide A and pulcherrimoside D were strong aromatase inhibitors with IC50 values of 9.0 and 11.9 μM, respectively. Among the tested compounds, pulcherrimoside D was considered an interesting cancer chemopreventive agent for further study as it provided good activity in several in vitro cancer preventive assays and was not toxic to normal cells.

Michael acceptor-dependent pro-oxidative intervention against angiogenesis by [6]-dehydroshogaol, a pungent constituent of ginger

Accumulating evidence suggests that ginger and its pungent constituents harbor a wealth of biological activities including cancer chemopreventive activity. However, relatively few researches focus on [6]-dehydroshogaol (6-DHS) compared with other ginger pungent constituents such as [6]-shogaol (6S). In this work, we selected three ginger compounds, 6-DHS, 6S and [6]-paradol (6P) differentiated by the presence and number of the Michael acceptor units, to probe structural basis and mechanism of 6-DHS in inhibiting angiogenesis, a key step for tumor growth and metastasis. It was found that their antiangiogenic activity is significantly dependent on the presence and number of Michael acceptor units. Benefiting from its two Michael acceptor units, 6-DHS is the most potent inhibitor of thioredoxin reductase and depletor of glutathione, thereby being the most active generator of reactive oxygen species, which is responsible for its strongest ability to inhibit angiogenesis. This work highlights 6-DHS being a Michael acceptor-dependent pro-oxidative angiogenesis inhibitor.

Dietary Organosulfur-Containing Compounds and Their Health-Promotion Mechanisms.

Dietary organosulfur-containing compounds (DOSCs) in fruits, vegetables, and edible mushrooms may hold the key to the health-promotion benefits of these foods. Yet their action mechanisms are not clear, partially due to their high reactivity, which leads to the formation of complex compounds during postharvest processing. Among postharvest processing methods, thermal treatment is the most common way to process these edible plants rich in DOSCs, which undergo complex degradation pathways with the generation of numerous derivatives over a short time. At low temperatures, DOSCs are biotransformed slowly during fermentation to different metabolites (e.g., thiols, sulfides, peptides), whose distinctive biological activity remains largely unexplored. In this review, we discuss the bioavailability of DOSCs in human digestion before illustrating their potential mechanisms for health promotion related to cardiovascular health, cancer chemoprevention, and anti-inflammatory and antimicrobial activities. In particular, it is interesting that different DOSCs react with glutathione or cysteine, leading to the slow release of hydrogen sulfide (H2S), which has broad bioactivity in chronic disease prevention. In addition, DOSCs may interact with protein thiol groups of different protein targets of importance related to inflammation and phase II enzyme upregulation, among other action pathways critical for health promotion.

Cancer chemopreventive and antioxidant activities of seed, skin, and pulp of Maximo hybrid grapes (IAC 138-22) at five different ripening stages

ABSTRACT: This study evaluated the composition and the cancer chemopreventive and antioxidant activities of the seed, skin, and pulp of Maximo hybrid grapes (IAC 138-22) harvested at different ripening stages. The content of total phenolic compounds and tannins were determined by the Folin-Ciocaulteau method, and total anthocyanins were determined using the differential pH method. Different chemical methods assessed the antioxidant activity. Cell viability (macrophage and melanoma skin cancer) and cancer chemopreventive activity were tested in cell lines by quinone reductase induction assay, TNF-α-induced NF-κB inhibitory activity assay, and aromatase inhibitory activity assay. The hybrid grape had high phenolic contents in both seeds and skin, significantly reduced upon ripening. The results showed that fruit ripening significantly affected both the composition and the antioxidant and cancer chemopreventive activities. Except for the anthocyanin content, the most significant results were observed for green seeds, with the greenest stage showing the best results. The green seeds showed the highest antioxidant activity, even when compared to free resveratrol. In the assessment of cancer chemopreventive activity, the green seeds showed the ability to inhibit N-FκB and aromatase activity, important factors for the early stage of cancer development. Besides, no extracts showed cytotoxicity. Therefore, this grape’s green seeds showed strong antioxidant and cancer chemopreventive activities confirmed herein, suggesting beneficial health effects.

Cancer Chemopreventive Role of Dietary Terpenoids by Modulating Keap1-Nrf2-ARE Signaling System—A Comprehensive Update

ROS, RNS, and carcinogenic metabolites generate excessive oxidative stress, which changes the basal cellular status and leads to epigenetic modification, genomic instability, and initiation of cancer. Epigenetic modification may inhibit tumor-suppressor genes and activate oncogenes, enabling cells to have cancer promoting properties. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that in humans is encoded by the NFE2L2 gene, and is activated in response to cellular stress. It can regulate redox homoeostasis by expressing several cytoprotective enzymes, including NADPH quinine oxidoreductase, heme oxygenase-1, UDP-glucuronosyltransferase, glutathione peroxidase, glutathione-S-transferase, etc. There is accumulating evidence supporting the idea that dietary nutraceuticals derived from commonly used fruits, vegetables, and spices have the ability to produce cancer chemopreventive activity by inducing Nrf2-mediated detoxifying enzymes. In this review, we discuss the importance of these nutraceuticals in cancer chemoprevention and summarize the role of dietary terpenoids in this respect. This approach was taken to accumulate the mechanistic function of these terpenoids to develop a comprehensive understanding of their direct and indirect roles in modulating the Keap1-Nrf2-ARE signaling system.

Suppression of Colon Tumorigenesis in Mutant Apc Mice by a Novel PDE10 Inhibitor that Reduces Oncogenic β-Catenin.

Previous studies have reported that phosphodiesterase 10A (PDE10) is overexpressed in colon epithelium during early stages of colon tumorigenesis and essential for colon cancer cell growth. Here we describe a novel non-COX inhibitory derivative of the anti-inflammatory drug, sulindac, with selective PDE10 inhibitory activity, ADT 061. ADT 061 potently inhibited the growth of colon cancer cells expressing high levels of PDE10, but not normal colonocytes that do not express PDE10. The concentration range by which ADT 061 inhibited colon cancer cell growth was identical to concentrations that inhibit recombinant PDE10. ADT 061 inhibited PDE10 by a competitive mechanism and did not affect the activity of other PDE isozymes at concentrations that inhibit colon cancer cell growth. Treatment of colon cancer cells with ADT 061 activated cGMP/PKG signaling, induced phosphorylation of oncogenic β-catenin, inhibited Wnt-induced nuclear translocation of β-catenin, and suppressed TCF/LEF transcription at concentrations that inhibit cancer cell growth. Oral administration of ADT 061 resulted in high concentrations in the colon mucosa and significantly suppressed the formation of colon adenomas in the Apc+/min-FCCC mouse model of colorectal cancer without discernable toxicity. These results support the development of ADT 061 for the treatment or prevention of adenomas in individuals at risk of developing colorectal cancer. PREVENTION RELEVANCE: PDE10 is overexpressed in colon tumors whereby inhibition activates cGMP/PKG signaling and suppresses Wnt/β-catenin transcription to selectively induce apoptosis of colon cancer cells. ADT 061 is a novel PDE10 inhibitor that shows promising cancer chemopreventive activity and tolerance in a mouse model of colon cancer.

Improvement of Nutraceutical Value of Parsley Leaves (Petroselinum crispum) upon Field Applications of Beneficial Microorganisms

Parsley (Petroselinum crispum) is an important aromatic herb that has gained importance in food and cosmetic industry, and it is used as medicinal plant due to the presence of compounds with biological activity. Several studies have demonstrated antioxidant, antimicrobial or cancer chemopreventive activity of different parts of parsley plants. We showed that the nutritional value of parsley leaves can be improved by treatments with beneficial microorganisms on the field crop. Streptomyces fulvissimus strain AtB-42 and Trichoderma harzianum strain T22 were applied, as singly or in combination (microbial consortium), at transplanting and two weeks later. After harvesting, plants were subjected to metabolomic analysis by LC and GC-MS. Spectrometric analysis resulted in the identification of seven polar metabolites. Results showed a significant difference in relative abundance of these metabolites among treatments. The AtB-42 application, alone or in combination with T22, induced the accumulation of petroselinic acid, while T22, alone or in combination, induced the accumulation of xanthotoxol/bergaptol and its derivative xanthotoxin/bergapten. The microbial consortium increased the accumulation of capsanthone compared to single treatments. No statistically relevant differences were found for the volatile fraction. It can be concluded that S. fulvissimus and T. harzianum significantly induced metabolic profile change of parsley and the accumulation of metabolites with nutraceutical value.

Methylseleninic acid overcomes programmed death-ligand 1-mediated resistance of prostate cancer and lung cancer.

Programmed death-ligand 1 (PD-L1)-mediated resistance has become a great challenge for tumor treatment. Cisplatin increased tumor PD-L1 expression, promoted chemotherapy resistance. Interferon-γ (IFN-γ)-induced PD-L1 expression might facilitate immunotherapy resistance. Methylseleninic acid (MSeA), a selenium (Se) compound, offered superior cancer chemo-preventive activities and enhanced tumor sensitivity to diverse chemotherapeutic drugs. This study explored the effects of MSeA on the PD-L1-mediated resistance using both in vitro and in vivo models. Results showed that MSeA substantially attenuated cisplatin-induced PD-L1 expression via inhibiting protein kinase B phosphorylation, thereby potentiated cisplatin cytotoxicity in prostate and lung cancer cell models. In lung cancer xenograft model, MSeA significantly suppressed cisplatin-induced PD-L1 expression, consequently enhanced T-cell immunity, ultimately improved the therapeutic efficacy of cisplatin. Moreover, IFN-γ-induced tumor PD-L1 expression was remarkably reduced by MSeA, with correlated reductions in janus kinase 2 and signal transducer and activator of transcription 3 (STAT3) phosphorylation in prostate and lung cancer cell models. Our findings, for the first time, demonstrated that MSeA is a potential agent to overcome PD-L1-mediated chemotherapy and immunotherapy resistance. Such information might have potential clinical implications for prostate and lung cancer treatment.

The degradation kinetics and mechanism of moringin in aqueous solution and the cytotoxicity of degraded products

In this work, we investigated the degradation of moringin (4-[(α-l-rhamnosyloxy)benzyl]-isothiocyanate), a major bioactive isothiocyanate (ITC) found in moringa seeds (Moringa oleifera Lam), at various food processing conditions. Moringin degrades rapidly to several water-soluble products via a pseudo-first-order kinetics. By analyzing the reaction products, the degradation mechanism was found to be through hydrolyzing to (A) 1-O-(4-hydroxymethylphenyl) α-l-rhamnopyranoside (rhamnobenzyl alcohol RBA) or (B) rhamnobenzylamine. The formed amine further reacts with moringin to form N,N′-bis{4-[(α-l-rhamnosyloxy)benzyl]}thiourea (di-rhamnobenzyl thiourea, DRBTU). In addition, moringin isomerizes to 4-[(α-l-rhamnosyloxy)benzyl]thiocyanate (RBTC), which further reacts with moringin to form S,N-bis{4-[(α-l-rhamnosyloxy)benzyl]}-dithiocarbamate (DRBDTC). Furthermore, pH was found to have an effect on the degradation of moringin. RBA and RBTC were major degraded products in neutral and acidic conditions while thiourea (DRBTU) was in alkaline condition. Although moringin showed higher cytotoxicity to cancer cells, its degraded products showed very weak or no activities, suggesting that the isothiocyanate group of ITCs is essential for their cancer chemoprevention activities.

Selenium as a Bioactive Micronutrient in the Human Diet and Its Cancer Chemopreventive Activity.

This review answers the question of why selenium is such an important trace element in the human diet. Daily dietary intake of selenium and its content in various food products is discussed in this paper, as well as the effects of its deficiency and excess in the body. Moreover, the biological activity of selenium, which it performs mainly through selenoproteins, is discussed. These specific proteins are responsible for thyroid hormone management, fertility, the aging process, and immunity, but their key role is to maintain a redox balance in cells. Furthermore, taking into account world news and the current SARS-CoV-2 virus pandemic, the impact of selenium on the course of COVID-19 is also discussed. Another worldwide problem is the number of new cancer cases and cancer-related mortality. Thus, the last part of the article discusses the impact of selenium on cancer risk based on clinical trials (including NPC and SELECT), systematic reviews, and meta-analyses. Additionally, this review discusses the possible mechanisms of selenium action that prevent cancer development.

Protective Role of Vanillic Acid against Diethylnitrosamine- and 1,2-Dimethylhydrazine-Induced Hepatocarcinogenesis in Rats.

This study aimed to evaluate the cancer chemopreventive activity of vanillic acid (VA) in diethylnitrosamine- and 1,2-dimethylhydrazine-induced liver and colon carcinogenesis in rats. VA did not induce the formation of hepatic glutathione S-transferase placental form (GST-P) positive foci and colonic aberrant crypt foci, demonstrating no carcinogenic activity. VA (75 mg kg−1 body weight) could significantly reduce the number and areas of hepatic GST-P positive foci when administered before carcinogen injections, but no such effect was seen when it was administered after carcinogen injection. No protection was seen in the colon when VA was treated before or after carcinogen injection. Immunohistochemical studies demonstrated the decreased expression of proliferating cell nuclear antigen and the induction of apoptosis. Mechanistic studies showed that VA significantly induced the expression of GSTA-5 and Nrf-2 genes, which are associated with the detoxification system. Likewise, the antiproliferative effect was noticed by the reduction of Cyclin D1 expression. The apoptotic activity may be due to the upregulation of Caspase-3 and Bad levels and downregulation of the Bcl-2 level. These data suggest that VA exhibited significant protection against diethylnitrosamine- and 1,2-dimethylhydrazine-induced hepatocarcinogenesis, which might be related to the induction of the detoxifying enzyme, the reduction of proliferation and the induction of apoptosis.

Comparative metabolites profiling of Caryota mitis & Caryota urens via UPLC/MS and isolation of two novel in silico chemopreventive flavonoids.

Caryota mitis and Caryota urens (F. Arecaceae) are well reported in Ayurvedic medicine and involved in several edible food products. Herein, the first comparative profiling of their leaf and fruit metabolites of both species via HR-UPLC/PDA/ESI-MS and multivariate data analyses is presented. A total of 142 metabolites were detected with seven reported for the first time in F. Arecaceae and a novel O-caffeoylshikimic acid conjugate. Screening of plants' leaf crude extracts via in vitro DCPIP kinetic assay revealed the induction of phase II cytoprotective enzyme NQO1 by 4.5- to 5-fold versus control, suggestive of potential chemopreventive activity. Two novel sulfated flavonols that is quercetin-3-O-sulfate-4'-O-rhamnosyl (1→6)-β-d-glucoside (F1) and kaempferol-3-O-sulfate-4'-O-rhamnosyl(1→6)-β-d-glucoside (F3) in addition to another five known flavonoids were isolated from C. mitis ethanol extract and identified via MS and NMR spectroscopic techniques. Among isolated compounds, F1 and F3 exhibited the highest docking score as KEAP-1 inhibitors and Nrf2 activators posing them as potential chemopreventive drug leads. PRACTICAL APPLICATIONS: The study extends the usages of this edible less explored Caryota species to a potential cancer chemopreventive action. Guided by the extensive chemical information presented herein, additional uses could be suggested for these plants with 142 identified metabolites including androst-en-diol that has aphrodisiac and muscle building effects. The presented multivariate data analyses could aid phytochemists in plants classification and mapping (chemotaxonomy) since several metabolites are reported herein for the first time either in family or genus.

Diterpenoid anthraquinones as chemopreventive agents altered microRNA and transcriptome expressions in cancer cells

ObjectiveCryptotanshinone (CPT) and dihydrotanshinone (DHT) are diterpenoid anthraquinone compounds extracted from traditional Chinese herbal medicine (TCM). Recent studies have shown that CPT regulates the signal transduction pathways via microRNA (miRNA) alterations. However, few studies have investigated the role of DHT in miRNA alterations affecting cell-signaling pathways. This study aimed to investigate the miRNA alterations and post-transcriptional regulation activities of DHT in comparison to CPT. MethodsHepG2 and HT-29 cells were treated with DHT or CPT for 72 h. MiRNA, transcription factor encoding mRNA, and downstream gene expression were determined using real-time quantitative PCR. Protein expression was analyzed using western blotting. ResultsThe results revealed that CPT and DHT targeted cell proliferation and apoptosis signaling pathways via miR-15a-5p, miR-27a-5p, miR-100−5p, and miR-200a-5p alterations.In silico target predictions showed that downregulation of epidermal growth factor receptor (EGFR) mRNA expression by DHT might also suppress the expression of STAT family proteins and lead to anti-proliferation effects. We also found that, compared to CPT, DHT might possess higher potency in cell growth regulation via multi-miRNA and transcription factor alterations. ConclusionThis study revealed that CPT and DHT targeted cell proliferation and apoptosis signaling pathways via alterations in miRNAs and transcription factors. In addition, the findings of this study suggest that DHT is more potent than CPT in cancer chemopreventive activities. Therefore, DHT at a low dose is a TCM compound with less toxic side effects and may contribute to the development of natural medicine as a potential cancer chemopreventive agent.