International Journal of Molecular Sciences

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29 pages, 5501 KiB

Open AccessArticle

Anticancer Activities of Thymus vulgaris L. in Experimental Breast Carcinoma In Vivo and In Vitro

by Peter Kubatka, Sona Uramova, Martin Kello, Karol Kajo, Marek Samec, Karin Jasek, Desanka Vybohova, Alena Liskova, Jan Mojzis, Marian Adamkov, Pavol Zubor, Karel Smejkal, Emil Svajdlenka, Peter Solar, Samson Mathews Samuel, Anthony Zulli, Monika Kassayova, Zora Lasabova, Taeg Kyu Kwon, Martin Pec, Jan Danko and Dietrich Büsselberg Show full author list Hide full author list

Int. J. Mol. Sci. 2019, 20(7), 1749; https://doi.org/10.3390/ijms20071749 - 9 Apr 2019

Cited by 83 | Viewed by 10081

Abstract

Naturally-occurring mixtures of phytochemicals present in plant foods are proposed to possess tumor-suppressive activities. In this work, we aimed to evaluate the antitumor effects of Thymus vulgaris L. in in vivo and in vitro mammary carcinoma models. Dried T. vulgaris (as haulm) was [...] Read more.

Naturally-occurring mixtures of phytochemicals present in plant foods are proposed to possess tumor-suppressive activities. In this work, we aimed to evaluate the antitumor effects of Thymus vulgaris L. in in vivo and in vitro mammary carcinoma models. Dried T. vulgaris (as haulm) was continuously administered at two concentrations of 0.1% and 1% in the diet in a chemically-induced rat mammary carcinomas model and a syngeneic 4T1 mouse model. After autopsy, histopathological and molecular analyses of rodent mammary carcinomas were performed. In addition, in vitro evaluations using MCF-7 and MDA-MB-231 cells were carried out. In mice, T. vulgaris at both doses reduced the volume of 4T1 tumors by 85% (0.1%) and 84% (1%) compared to the control, respectively. Moreover, treated tumors showed a substantial decrease in necrosis/tumor area ratio and mitotic activity index. In the rat model, T. vulgaris (1%) decreased the tumor frequency by 53% compared to the control. Analysis of the mechanisms of anticancer action included well-described and validated diagnostic and prognostic markers that are used in both clinical approach and preclinical research. In this regard, the analyses of treated rat carcinoma cells showed a CD44 and ALDH1A1 expression decrease and Bax expression increase. Malondialdehyde (MDA) levels and VEGFR-2 expression were decreased in rat carcinomas in both the T. vulgaris treated groups. Regarding the evaluations of epigenetic changes in rat tumors, we found a decrease in the lysine methylation status of H3K4me3 in both treated groups (H3K9m3, H4K20m3, and H4K16ac were not changed); up-regulations of miR22, miR34a, and miR210 expressions (only at higher doses); and significant reductions in the methylation status of four gene promoters—ATM serin/threonine kinase, also known as the NPAT gene (ATM); Ras-association domain family 1, isoform A (RASSF1); phosphatase and tensin homolog (PTEN); and tissue inhibitor of metalloproteinase-3 (TIMP3) (the paired-like homeodomain transcription factor (PITX2) promoter was not changed). In vitro study revealed the antiproliferative and proapoptotic effects of essential oils of T. vulgaris in MCF-7 and MDA-MB-231 cells (analyses of 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS); 5-bromo-20-deoxyuridine (BrdU); cell cycle; annexin V/PI; caspase-3/7; Bcl-2; PARP; and mitochondrial membrane potential). T. vulgaris L. demonstrated significant chemopreventive and therapeutic activities against experimental breast carcinoma. Full article

(This article belongs to the Special Issue The Effect of Dietary Factors on Cancer)

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17 pages, 2157 KiB

Open AccessArticle

Extracellular Spermine Activates DNA Methyltransferase 3A and 3B

by Taro Fukui, Kuniyasu Soda, Koichi Takao and Toshiki Rikiyama

Int. J. Mol. Sci. 2019, 20(5), 1254; https://doi.org/10.3390/ijms20051254 - 12 Mar 2019

Cited by 15 | Viewed by 5817

Abstract

We first demonstrated that long-term increased polyamine (spermine, spermidine, putrescine) intake elevated blood spermine levels in mice and humans, and lifelong consumption of polyamine-rich chow inhibited aging-associated increase in aberrant DNA methylation, inhibited aging-associated pathological changes, and extend lifespan of mouse. Because gene [...] Read more.

We first demonstrated that long-term increased polyamine (spermine, spermidine, putrescine) intake elevated blood spermine levels in mice and humans, and lifelong consumption of polyamine-rich chow inhibited aging-associated increase in aberrant DNA methylation, inhibited aging-associated pathological changes, and extend lifespan of mouse. Because gene methylation status is closely associated with aging-associated conditions and polyamine metabolism is closely associated with regulation of gene methylation, we investigated the effects of extracellular spermine supplementation on substrate concentrations and enzyme activities involved in gene methylation. Jurkat cells and human mammary epithelial cells were cultured with spermine and/or D,L-alpha-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase. Spermine supplementation inhibited enzymatic activities of adenosylmethionine decarboxylase in both cells. The ratio of decarboxylated S-adenosylmethionine to S-adenosyl-L-methionine increased by DFMO and decreased by spermine. In Jurkat cells cultured with DFMO, the protein levels of DNA methyltransferases (DNMTs) 1, 3A and 3B were not changed, however the activity of the three enzymes markedly decreased. The protein levels of these enzymes were not changed by addition of spermine, DNMT 3A and especially 3B were activated. We show that changes in polyamine metabolism dramatically affect substrate concentrations and activities of enzymes involved in gene methylation. Full article

(This article belongs to the Special Issue The Effect of Dietary Factors on Cancer)

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14 pages, 2186 KiB

Open AccessArticle

Phenethyl Isothiocyanate Exposure Promotes Oxidative Stress and Suppresses Sp1 Transcription Factor in Cancer Stem Cells

by Bijaya Upadhyaya, Yi Liu and Moul Dey

Int. J. Mol. Sci. 2019, 20(5), 1027; https://doi.org/10.3390/ijms20051027 - 27 Feb 2019

Cited by 19 | Viewed by 4517

Abstract

Aldehyde dehydrogenase 1 (ALDH1) is a cytosolic marker of cancer stem cells (CSCs), which are a sub-population within heterogeneous tumor cells. CSCs associate with therapy-resistance, self-renewal, malignancy, tumor-relapse, and reduced patient-survival window. ALDH1-mediated aldehyde scavenging helps CSCs to survive a higher level of [...] Read more.

Aldehyde dehydrogenase 1 (ALDH1) is a cytosolic marker of cancer stem cells (CSCs), which are a sub-population within heterogeneous tumor cells. CSCs associate with therapy-resistance, self-renewal, malignancy, tumor-relapse, and reduced patient-survival window. ALDH1-mediated aldehyde scavenging helps CSCs to survive a higher level of oxidative stress than regular cancer cells. Cruciferous vegetable-derived phenethyl isothiocyanate (PEITC) selectively induces reactive oxygen species (ROS), leading to apoptosis of cancer cells, but not healthy cells. However, this pro-oxidant role of PEITC in CSCs is poorly understood and is investigated here. In a HeLa CSCs model (hCSCs), the sphere-culture and tumorsphere assay showed significantly enriched ALDH^hi CSCs from HeLa parental cells (p < 0.05). Aldefluor assay and cell proliferation assay revealed that PEITC treatments resulted in a reduced number of ALDH^hi hCSCs in a concentration-dependent manner (p < 0.05). In the ROS assay, PEITC promoted oxidative stress in hCSCs (p ≤ 0.001). Using immunoblotting and flow cytometry techniques, we reported that PEITC suppressed the cancer-associated transcription factor (Sp1) and a downstream multidrug resistance protein (P-glycoprotein) (both, p < 0.05). Furthermore, PEITC-treatment of hCSCs, prior to xenotransplantation in mice, lowered the in vivo tumor-initiating potential of hCSCs. In summary, PEITC treatment suppressed the proliferation of ALDH1 expressing cancer stem cells as well as key factors that are involved with drug-resistance, while promoting oxidative stress and apoptosis in hCSCs. Full article

(This article belongs to the Special Issue The Effect of Dietary Factors on Cancer)

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11 pages, 1262 KiB

Open AccessArticle

Garcinol Sensitizes NSCLC Cells to Standard Therapies by Regulating EMT-Modulating miRNAs

by Mohd Farhan, Arshi Malik, Mohammad Fahad Ullah, Sarah Afaq, Mohd Faisal, Ammad Ahmad Farooqi, Bernhard Biersack, Rainer Schobert and Aamir Ahmad

Int. J. Mol. Sci. 2019, 20(4), 800; https://doi.org/10.3390/ijms20040800 - 13 Feb 2019

Cited by 46 | Viewed by 4423

Abstract

Garcinol, a dietary factor obtained from Garcinia indica, modulates several key cellular signaling pathways as well as the expression of miRNAs. Acquired resistance to standard therapies, such as erlotinib and cisplatin, is a hallmark of non-small cell lung cancer (NSCLC) cells that [...] Read more.

Garcinol, a dietary factor obtained from Garcinia indica, modulates several key cellular signaling pathways as well as the expression of miRNAs. Acquired resistance to standard therapies, such as erlotinib and cisplatin, is a hallmark of non-small cell lung cancer (NSCLC) cells that often involves miRNA-regulated epithelial-to-mesenchymal transition (EMT). We used A549 cells that were exposed to transforming growth factor beta 1 (TGF-β1), resulting in A549M cells with mesenchymal and drug resistant phenotype, and report that garcinol sensitized resistant cells with mesenchymal phenotype to erlotinib as well as cisplatin with significant decrease in their IC₅₀ values. It also potentiated the apoptosis-inducing activity of erlotinib in A549M and the endogenously mesenchymal H1299 NSCLC cells. Further, garcinol significantly upregulated several key EMT-regulating miRNAs, such as miR-200b, miR-205, miR-218, and let-7c. Antagonizing miRNAs, through anti-miRNA transfections, attenuated the EMT-modulating activity of garcinol, as determined by mRNA expression of EMT markers, E-cadherin, vimentin, and Zinc Finger E-Box Binding Homeobox 1 (ZEB1). This further led to repression of erlotinib as well as cisplatin sensitization, thus establishing the mechanistic role of miRNAs, particularly miR-200c and let-7c, in garcinol-mediated reversal of EMT and the resulting sensitization of NSCLC cells to standard therapies. Full article

(This article belongs to the Special Issue The Effect of Dietary Factors on Cancer)

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21 pages, 2412 KiB

Open AccessArticle

Potent Anti-Cancer Properties of Phthalimide-Based Curcumin Derivatives on Prostate Tumor Cells

by Silvia Belluti, Giulia Orteca, Valentina Semeghini, Giovanna Rigillo, Francesca Parenti, Erika Ferrari and Carol Imbriano

Int. J. Mol. Sci. 2019, 20(1), 28; https://doi.org/10.3390/ijms20010028 - 21 Dec 2018

Cited by 28 | Viewed by 5446

Abstract

Metastatic castration-resistant prostate cancer is commonly treated with chemotherapy, whose effect is less than satisfactory. This raised the need for novel agents for the treatment of prostate cancer. In the present study, five phthalimide-based curcumin derivatives were synthesized and completely characterized to assess [...] Read more.

Metastatic castration-resistant prostate cancer is commonly treated with chemotherapy, whose effect is less than satisfactory. This raised the need for novel agents for the treatment of prostate cancer. In the present study, five phthalimide-based curcumin derivatives were synthesized and completely characterized to assess improved stability, pharmacodynamics, and radical scavenging ability. To investigate the potential application in anti-cancer therapy, the anti-proliferative activity of the synthesized molecules was determined on aggressive prostate tumor cells. We demonstrated that the K3F21 derivative has increased potency compared to curcumin, in terms of GI50, anti-proliferative and anti-migrating activities. K3F21 inhibits anchorage-dependent and -independent growth of prostate cancer cells by altering the expression of key genes controlling cell proliferation, such as Cylins D1, B1 and B2, and apoptosis, among which Puma, Noxa, and Bcl-2 family members. Finally, the anti-cancer activity of K3F21 was demonstrated by the analysis of cancer-associated PI3K/AKT, ERK, and p38 signaling pathways. Full article

(This article belongs to the Special Issue The Effect of Dietary Factors on Cancer)

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13 pages, 2260 KiB

Open AccessArticle

Zinc Inhibits Expression of Androgen Receptor to Suppress Growth of Prostate Cancer Cells

by Phuong Kim To, Manh-Hung Do, Young-Suk Cho, Se-Young Kwon, Min Soo Kim and Chaeyong Jung

Int. J. Mol. Sci. 2018, 19(10), 3062; https://doi.org/10.3390/ijms19103062 - 8 Oct 2018

Cited by 14 | Viewed by 5223

Abstract

The prostate gland contains a high level of intracellular zinc, which is dramatically diminished during prostate cancer (PCa) development. Owing to the unclear role of zinc in this process, therapeutic applications using zinc are limited. This study aimed to clarify the role of [...] Read more.

The prostate gland contains a high level of intracellular zinc, which is dramatically diminished during prostate cancer (PCa) development. Owing to the unclear role of zinc in this process, therapeutic applications using zinc are limited. This study aimed to clarify the role of zinc and its underlying mechanism in the growth of PCa. ZnCl₂ suppressed the proliferation of androgen receptor (AR)-retaining PCa cells, whereas it did not affect AR-deficient PCa cells. In LNCaP and TRAMP-C2 cells, zinc downregulated the expression of AR in a dose- and time-dependent fashion. Zinc-mediated AR suppression accordingly inhibited the androgen-mediated transactivation and expression of the androgen target, prostate specific antigen (PSA). This phenomenon resulted from facilitated protein degradation, not transcriptional control. In studies using mice bearing TRAMP-C2 subcutaneous tumors, the intraperitoneal injection of zinc significantly reduced tumor size. Analyses of both xenograft tumors and normal prostates showed reduced expression of AR and increased cell death. Considering the significant loss of intracellular zinc and the dominant growth-modulating role of AR during PCa development, loss of zinc may be a critical step in the transformation of normal cells to cancer cells. This study provides the underlying mechanism by which zinc functions as a PCa suppressor, and forms the foundation for developing zinc-mediated therapeutics for PCa. Full article

(This article belongs to the Special Issue The Effect of Dietary Factors on Cancer)

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18 pages, 5451 KiB

Open AccessArticle

Combinational Proanthocyanidins and Resveratrol Synergistically Inhibit Human Breast Cancer Cells and Impact Epigenetic–Mediating Machinery

by Yifeng Gao and Trygve O. Tollefsbol

Int. J. Mol. Sci. 2018, 19(8), 2204; https://doi.org/10.3390/ijms19082204 - 27 Jul 2018

Cited by 66 | Viewed by 7599

Abstract

Breast cancer is the second most common cancer and the second leading cause of death from cancer among women in the United States (US). Cancer prevention and therapy through the use of phytochemicals that have epigenetic properties has gained considerable interest during the [...] Read more.

Breast cancer is the second most common cancer and the second leading cause of death from cancer among women in the United States (US). Cancer prevention and therapy through the use of phytochemicals that have epigenetic properties has gained considerable interest during the past few decades. Such dietary components include, but are not limited to, grape seed proanthocyanidins (GSPs) and resveratrol (Res), both of which are present in red wine. In this study, we report for the first time the synergistic effects of GSPs and Res on inhibiting MDA-MB-231 and MCF-7 human breast cancer cells. Our results of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays and clonogenic assays indicate that treatments with the combinations of GSPs and Res synergistically decreased cell viability and posttreatment cell proliferation in both cell lines. Additional analyses show that treatments with GSPs and Res in combination synergistically induced apoptosis in MDA-MB-231 cells by upregulating Bax expression and down-regulating Bcl-2 expression. DNA methyltransferase (DNMT) activity and histone deacetylase (HDAC) activity were greatly reduced in MDA-MB-231 and MCF-7 cells after treatments with GSPs and Res in combination. Collectively, our findings suggest that GSPs and Res synergistically inhibit human breast cancer cells through inducing apoptosis, as well as modulating DNA methylation and histone modifications. Full article

(This article belongs to the Special Issue The Effect of Dietary Factors on Cancer)

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12 pages, 3075 KiB

Open AccessArticle

Pterostilbene Suppresses Ovarian Cancer Growth via Induction of Apoptosis and Blockade of Cell Cycle Progression Involving Inhibition of the STAT3 Pathway

by Wei Wen, Gina Lowe, Cai M. Roberts, James Finlay, Ernest S. Han, Carlotta A. Glackin and Thanh Hue Dellinger

Int. J. Mol. Sci. 2018, 19(7), 1983; https://doi.org/10.3390/ijms19071983 - 7 Jul 2018

Cited by 50 | Viewed by 5296

Abstract

A growing body of evidence has demonstrated the promising anti-tumor effects of resveratrol in ovarian cancer cells, including its inhibitory effects on STAT3 activation. Nonetheless, the low bioavailability of resveratrol has reduced its attractiveness as a potential anti-cancer treatment. In contrast, pterostilbene, a [...] Read more.

A growing body of evidence has demonstrated the promising anti-tumor effects of resveratrol in ovarian cancer cells, including its inhibitory effects on STAT3 activation. Nonetheless, the low bioavailability of resveratrol has reduced its attractiveness as a potential anti-cancer treatment. In contrast, pterostilbene, a stilbenoid and resveratrol analog, has demonstrated superior bioavailability, while possessing significant antitumor activity in multiple solid tumors. In this study, the therapeutic potential of pterostilbene was evaluated in ovarian cancer cells. Pterostilbene reduces cell viability in several different ovarian cancer cell lines by suppressing cell cycle progression and inducing apoptosis. Further molecular study has shown that pterostilbene effectively suppressed phosphorylation of STAT3, as well as STAT3 downstream genes that regulate cell cycle and apoptosis, indicating that inhibition of STAT3 pathway may be involved in its anti-tumor activity. The addition of pterostilbene to the commonly used chemotherapy cisplatin demonstrated synergistic antiproliferative activity in several ovarian cancer cell lines. Pterostilbene additionally inhibited cell migration in multiple ovarian cancer cell lines. The above results suggest that pterostilbene facilitates significant anti-tumor activity in ovarian cancer via anti-proliferative and pro-apoptotic mechanisms, possibly via downregulation of JAK/STAT3 pathway. Pterostilbene thus presents as an attractive non-toxic alternative for potential adjuvant or maintenance chemotherapy in ovarian cancer. Full article

(This article belongs to the Special Issue The Effect of Dietary Factors on Cancer)

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Review

Jump to: Research

35 pages, 1811 KiB

Open AccessReview

Polyphenols as Immunomodulatory Compounds in the Tumor Microenvironment: Friends or Foes?

by Chiara Focaccetti, Valerio Izzi, Monica Benvenuto, Sara Fazi, Sara Ciuffa, Maria Gabriella Giganti, Vito Potenza, Vittorio Manzari, Andrea Modesti and Roberto Bei

Int. J. Mol. Sci. 2019, 20(7), 1714; https://doi.org/10.3390/ijms20071714 - 6 Apr 2019

Cited by 62 | Viewed by 6790

Abstract

Polyphenols are natural antioxidant compounds ubiquitously found in plants and, thus, ever present in human nutrition (tea, wine, chocolate, fruits and vegetables are typical examples of polyphenol-rich foods). Widespread evidence indicate that polyphenols exert strong antioxidant, anti-inflammatory, anti-microbial and anti-cancer activities, and thus, [...] Read more.

Polyphenols are natural antioxidant compounds ubiquitously found in plants and, thus, ever present in human nutrition (tea, wine, chocolate, fruits and vegetables are typical examples of polyphenol-rich foods). Widespread evidence indicate that polyphenols exert strong antioxidant, anti-inflammatory, anti-microbial and anti-cancer activities, and thus, they are generally regarded to as all-purpose beneficial nutraceuticals or supplements whose use can only have a positive influence on the body. A closer look to the large body of results of years of investigations, however, present a more complex scenario where polyphenols exert different and, sometimes, paradoxical effects depending on dose, target system and cell type and the biological status of the target cell. Particularly, the immunomodulatory potential of polyphenols presents two opposite faces to researchers trying to evaluate their usability in future cancer therapies: on one hand, these compounds could be beneficial suppressors of peri-tumoral inflammation that fuels cancer growth. On the other hand, they might suppress immunotherapeutic approaches and give rise to immunosuppressive cell clones that, in turn, would aid tumor growth and dissemination. In this review, we summarize knowledge of the immunomodulatory effects of polyphenols with a particular focus on cancer microenvironment and immunotherapy, highlighting conceptual pitfalls and delicate cell-specific effects in order to aid the design of future therapies involving polyphenols as chemoadjuvants. Full article

(This article belongs to the Special Issue The Effect of Dietary Factors on Cancer)

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19 pages, 669 KiB

Open AccessReview

Secondary Bile Acids and Short Chain Fatty Acids in the Colon: A Focus on Colonic Microbiome, Cell Proliferation, Inflammation, and Cancer

by Huawei Zeng, Shahid Umar, Bret Rust, Darina Lazarova and Michael Bordonaro

Int. J. Mol. Sci. 2019, 20(5), 1214; https://doi.org/10.3390/ijms20051214 - 11 Mar 2019

Cited by 330 | Viewed by 19829

Abstract

Secondary bile acids (BAs) and short chain fatty acids (SCFAs), two major types of bacterial metabolites in the colon, cause opposing effects on colonic inflammation at chronically high physiological levels. Primary BAs play critical roles in cholesterol metabolism, lipid digestion, and host–microbe interaction. [...] Read more.

Secondary bile acids (BAs) and short chain fatty acids (SCFAs), two major types of bacterial metabolites in the colon, cause opposing effects on colonic inflammation at chronically high physiological levels. Primary BAs play critical roles in cholesterol metabolism, lipid digestion, and host–microbe interaction. Although BAs are reabsorbed via enterohepatic circulation, primary BAs serve as substrates for bacterial biotransformation to secondary BAs in the colon. High-fat diets increase secondary BAs, such as deoxycholic acid (DCA) and lithocholic acid (LCA), which are risk factors for colonic inflammation and cancer. In contrast, increased dietary fiber intake is associated with anti-inflammatory and anticancer effects. These effects may be due to the increased production of the SCFAs acetate, propionate, and butyrate during dietary fiber fermentation in the colon. Elucidation of the molecular events by which secondary BAs and SCFAs regulate colonic cell proliferation and inflammation will lead to a better understanding of the anticancer potential of dietary fiber in the context of high-fat diet-related colon cancer. This article reviews the current knowledge concerning the effects of secondary BAs and SCFAs on the proliferation of colon epithelial cells, inflammation, cancer, and the associated microbiome. Full article

(This article belongs to the Special Issue The Effect of Dietary Factors on Cancer)

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34 pages, 805 KiB

Open AccessReview

Melatonin May Increase Anticancer Potential of Pleiotropic Drugs

by Bianka Bojková, Peter Kubatka, Tawar Qaradakhi, Anthony Zulli and Karol Kajo

Int. J. Mol. Sci. 2018, 19(12), 3910; https://doi.org/10.3390/ijms19123910 - 6 Dec 2018

Cited by 13 | Viewed by 6474

Abstract

Melatonin (N-acetyl-5-methoxytryptamine) is not only a pineal hormone, but also an ubiquitary molecule present in plants and part of our diet. Numerous preclinical and some clinical reports pointed to its multiple beneficial effects including oncostatic properties, and as such, it has become one [...] Read more.

Melatonin (N-acetyl-5-methoxytryptamine) is not only a pineal hormone, but also an ubiquitary molecule present in plants and part of our diet. Numerous preclinical and some clinical reports pointed to its multiple beneficial effects including oncostatic properties, and as such, it has become one of the most aspiring goals in cancer prevention/therapy. A link between cancer and inflammation and/or metabolic disorders has been well established and the therapy of these conditions with so-called pleiotropic drugs, which include non-steroidal anti-inflammatory drugs, statins and peroral antidiabetics, modulates a cancer risk too. Adjuvant therapy with melatonin may improve the oncostatic potential of these drugs. Results from preclinical studies are limited though support this hypothesis, which, however, remains to be verified by further research. Full article

(This article belongs to the Special Issue The Effect of Dietary Factors on Cancer)

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54 pages, 7812 KiB

Open AccessReview

Chemoprevention of Colorectal Cancer by Dietary Compounds

by Teodora Costea, Ariana Hudiță, Oana-Alina Ciolac, Bianca Gălățeanu, Octav Ginghină, Marieta Costache, Constanța Ganea and Maria-Magdalena Mocanu

Int. J. Mol. Sci. 2018, 19(12), 3787; https://doi.org/10.3390/ijms19123787 - 28 Nov 2018

Cited by 73 | Viewed by 12286

Abstract

Colorectal cancer is one of the leading causes of death, and the third most diagnosed type of cancer, worldwide. It is most common amongst men and women over 50 years old. Risk factors include smoking, alcohol, diet, physical inactivity, genetics, alterations in gut [...] Read more.

Colorectal cancer is one of the leading causes of death, and the third most diagnosed type of cancer, worldwide. It is most common amongst men and women over 50 years old. Risk factors include smoking, alcohol, diet, physical inactivity, genetics, alterations in gut microbiota, and associated pathologies (diabetes, obesity, chronic inflammatory bowel diseases). This review will discuss, in detail, the chemopreventive properties of some dietary compounds (phenolic compounds, carotenoids, iridoids, nitrogen compounds, organosulfur compounds, phytosterols, essential oil compounds, polyunsaturated fatty acids and dietary fiber) against colorectal cancer. We present recent data, focusing on in vitro, laboratory animals and clinical trials with the previously mentioned compounds. The chemopreventive properties of the dietary compounds involve multiple molecular and biochemical mechanisms of action, such as inhibition of cell growth, inhibition of tumor initiation, inhibition of adhesion, migration and angiogenesis, apoptosis, interaction with gut microbiota, regulation of cellular signal transduction pathways and xenobiotic metabolizing enzymes, etc. Moreover, this review will also focus on the natural dietary compounds’ bioavailability, their synergistic protective effect, as well as the association with conventional therapy. Dietary natural compounds play a major role in colorectal chemoprevention and continuous research in this field is needed. Full article

(This article belongs to the Special Issue The Effect of Dietary Factors on Cancer)

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24 pages, 2052 KiB

Open AccessReview

Targeting Cancer with Phytochemicals via Their Fine Tuning of the Cell Survival Signaling Pathways

by Salvatore Chirumbolo, Geir Bjørklund, Roman Lysiuk, Antonio Vella, Larysa Lenchyk and Taras Upyr

Int. J. Mol. Sci. 2018, 19(11), 3568; https://doi.org/10.3390/ijms19113568 - 12 Nov 2018

Cited by 87 | Viewed by 7970

Abstract

The role of phytochemicals as potential prodrugs or therapeutic substances against tumors has come in the spotlight in the very recent years, thanks to the huge mass of encouraging and promising results of the in vitro activity of many phenolic compounds from plant [...] Read more.

The role of phytochemicals as potential prodrugs or therapeutic substances against tumors has come in the spotlight in the very recent years, thanks to the huge mass of encouraging and promising results of the in vitro activity of many phenolic compounds from plant raw extracts against many cancer cell lines. Little but important evidence can be retrieved from the clinical and nutritional scientific literature, where flavonoids are investigated as major pro-apoptotic and anti-metastatic compounds. However, the actual role of these compounds in cancer is still far to be fully elucidated. Many of these phytochemicals act in a pleiotropic and poorly specific manner, but, more importantly, they are able to tune the reactive oxygen species (ROS) signaling to activate a survival or a pro-autophagic and pro-apoptosis mechanism, depending on the oxidative stress-responsive endowment of the targeted cell. This review will try to focus on this issue. Full article

(This article belongs to the Special Issue The Effect of Dietary Factors on Cancer)

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16 pages, 659 KiB

Open AccessReview

Anti-Cancer and Protective Effects of Royal Jelly for Therapy-Induced Toxicities in Malignancies

by Yasuyoshi Miyata and Hideki Sakai

Int. J. Mol. Sci. 2018, 19(10), 3270; https://doi.org/10.3390/ijms19103270 - 21 Oct 2018

Cited by 65 | Viewed by 7879

Abstract

Royal jelly (RJ) is a glandular secretion produced by worker honeybees and is a special food for the queen honeybee. It results in a significant prolongation of the lifespan of the queen honeybee compared with the worker honeybees through anti-inflammatory, anti-oxidant and anti-microbial [...] Read more.

Royal jelly (RJ) is a glandular secretion produced by worker honeybees and is a special food for the queen honeybee. It results in a significant prolongation of the lifespan of the queen honeybee compared with the worker honeybees through anti-inflammatory, anti-oxidant and anti-microbial activities. Consequently, RJ is used as cosmetic and dietary supplement throughout the world. In addition, in vitro studies and animal experiments have demonstrated that RJ inhibits cell proliferation and stimulates apoptosis in various types of malignant cells and affects the production of various chemokines, anti-oxidants and growth factors and the expression of cancer-related molecules in patients with malignancies, especially in patients treated with anti-cancer agents. Therefore, RJ is thought to exert anti-cancer effects on tumor growth and exhibit protective functions against drug-induced toxicities. RJ has also been demonstrated to be useful for suppression of adverse events, the maintenance of the quality of life during treatment and the improvement of prognosis in animal models and patients with malignancies. To understand the mechanisms of the beneficial effects of RJ, knowledge of the changes induced at the molecular level by RJ with respect to cell survival, inflammation, oxidative stress and other cancer-related factors is essential. In addition, the effects of combination therapies of RJ and other anti-cancer agents or natural compounds are important to determine the future direction of RJ-based treatment strategies. Therefore, in this review, we have covered the following five issues: (1) the anti-cancer effects of RJ and its main component, 10-hydroxy-2-decenoic acid; (2) the protective effects of RJ against anti-cancer agent-induced toxicities; (3) the molecular mechanisms of such beneficial effects of RJ; (4) the safety and toxicity of RJ; and (5) the future directions of RJ-based treatment strategies, with a discussion on the limitations of the study of the biological activities of RJ. Full article

(This article belongs to the Special Issue The Effect of Dietary Factors on Cancer)

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17 pages, 3986 KiB

Open AccessReview

The Cancer Prevention, Anti-Inflammatory and Anti-Oxidation of Bioactive Phytochemicals Targeting the TLR4 Signaling Pathway

by Chung-Yi Chen, Chiu-Li Kao and Chi-Ming Liu

Int. J. Mol. Sci. 2018, 19(9), 2729; https://doi.org/10.3390/ijms19092729 - 12 Sep 2018

Cited by 265 | Viewed by 15450

Abstract

Toll-like receptors (TLRs) are a well-known family of pattern recognition receptors that play an important role in a host immune system. TLR triggering leads to the induction of pro-inflammatory cytokines and chemokines, driving the activation of both innate and adaptive immunity. Recently, an [...] Read more.

Toll-like receptors (TLRs) are a well-known family of pattern recognition receptors that play an important role in a host immune system. TLR triggering leads to the induction of pro-inflammatory cytokines and chemokines, driving the activation of both innate and adaptive immunity. Recently, an increasing number studies have shown the link between TLRs and cancer. Among them, the toll-like receptor 4 (TLR4) signaling pathway is associated with inflammatory response and cancer progression. Dietary phytochemicals are potential modulators of immunological status with various pharmacological properties including anti-cancer, anti-oxidant and anti-inflammatory. Curcumin, 6-gingerol, 6-shogaol, 1-dehydro-10-gingerdione, epigallocatechin gallate (EGCG), luteolin, quercetin, resveratrol, caffeic acid phenethyl ester, xanthohumol, genistein, berberine, and sulforaphane can inhibit TLR4 activation. The aim of the present review is to describe the role of the TLR4 signaling pathway between inflammatory response and cancer progression. We further introduce bioactive phytochemicals with potential anti-inflammation and chemoprevention by inhibiting TLR activation. Full article

(This article belongs to the Special Issue The Effect of Dietary Factors on Cancer)

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23 pages, 4350 KiB

Open AccessReview

Beyond the Antioxidant Activity of Dietary Polyphenols in Cancer: the Modulation of Estrogen Receptors (ERs) Signaling

by Manuela Cipolletti, Virginia Solar Fernandez, Emiliano Montalesi, Maria Marino and Marco Fiocchetti

Int. J. Mol. Sci. 2018, 19(9), 2624; https://doi.org/10.3390/ijms19092624 - 5 Sep 2018

Cited by 75 | Viewed by 9374

Abstract

The potential “health benefits” of dietary polyphenols have been ascribed to their direct antioxidant activity and their impact on the regulation of cell and tissue redox balance. However, because of the relative poor bioavailability of many of these compounds, their effects could not [...] Read more.

The potential “health benefits” of dietary polyphenols have been ascribed to their direct antioxidant activity and their impact on the regulation of cell and tissue redox balance. However, because of the relative poor bioavailability of many of these compounds, their effects could not be easily explained by the antioxidant action, which may occur only at high circulating and tissue concentrations. Therefore, many efforts have been put forward to clarify the molecular mechanisms underlining the biological effect of polyphenols in physiological and pathological conditions. Polyphenols’ bioavailability, metabolism, and their effects on enzyme, membrane, and/or nuclear receptors and intracellular transduction mechanisms may define the overall impact of these compounds on cancer risk and progression, which is still debated and not yet clarified. Polyphenols are able to bind to estrogen receptor α (ERα) and β (ERβ), and therefore induce biological effects in human cells through mimicking or inhibiting the action of endogenous estrogens, even at low concentrations. In this work, the role and effects of food-contained polyphenols in hormone-related cancers will be reviewed, mainly focusing on the different polyphenols’ mechanisms of action with particular attention on their estrogen receptor-based effects, and on the consequences of such processes on tumor progression and development. Full article

(This article belongs to the Special Issue The Effect of Dietary Factors on Cancer)

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18 pages, 17608 KiB

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The Role of Curcumin in Prevention and Management of Metastatic Disease

by Beatrice E. Bachmeier, Peter H. Killian and Dieter Melchart

Int. J. Mol. Sci. 2018, 19(6), 1716; https://doi.org/10.3390/ijms19061716 - 9 Jun 2018

Cited by 66 | Viewed by 7561

Abstract

In the last two decades, targeted therapies have enhanced tumor patient care and treatment success, however, metastatic growth still cannot be stopped efficiently and, therefore, mortality rates remain high. Prevention strategies against formation of metastases are the most promising approach we have, however, [...] Read more.

In the last two decades, targeted therapies have enhanced tumor patient care and treatment success, however, metastatic growth still cannot be stopped efficiently and, therefore, mortality rates remain high. Prevention strategies against formation of metastases are the most promising approach we have, however, due to lack of clinical validation studies, they have not yet entered routine clinical care. In order to smooth the way for efficient prevention, further preclinical and large clinical studies are required. In this context, the underlying molecular mechanisms and factors that lead to metastatic growth have to be explored, and potential preventive agents have to be tested. Thereby, special attention has to be paid to natural bioactive compounds which do not exert major adverse effects, like the plant-derived polyphenol Curcumin, which is known to be a powerful antitumor agent. So far, most of the preclinical studies with Curcumin have focused on its effect on inhibiting tumor cell proliferation and invasion, although, it is known that it also inhibits metastatic spread in vivo. This review discusses the preventive potential of this natural compound not only against tumor onset, but also against formation of metastases. Full article

(This article belongs to the Special Issue The Effect of Dietary Factors on Cancer)

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