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15 pages, 12148 KiB

Open AccessArticle

Resveratrol Analogs and Prodrugs Differently Affect the Survival of Breast Cancer Cells Impairing Estrogen/Estrogen Receptor α/Neuroglobin Pathway

by Emiliano Montalesi, Patrizio Cracco, Filippo Acconcia, Marco Fiocchetti, Giovanna Iucci, Chiara Battocchio, Elisabetta Orlandini, Lidia Ciccone, Susanna Nencetti, Maurizio Muzzi, Sandra Moreno, Iole Venditti and Maria Marino

Int. J. Mol. Sci. 2023, 24(3), 2148; https://doi.org/10.3390/ijms24032148 - 21 Jan 2023

Cited by 4 | Viewed by 1542

Abstract

Breast cancer is the first leading tumor in women in terms of incidence worldwide. Seventy percent of cases are estrogen receptor (ER) α-positive. In these malignancies, 17β-estradiol (E2) via ERα increases the levels of neuroglobin (NGB), a compensatory protein that protects cancer cells [...] Read more.

Breast cancer is the first leading tumor in women in terms of incidence worldwide. Seventy percent of cases are estrogen receptor (ER) α-positive. In these malignancies, 17β-estradiol (E2) via ERα increases the levels of neuroglobin (NGB), a compensatory protein that protects cancer cells from stress-induced apoptosis, including chemotherapeutic drug treatment. Our previous data indicate that resveratrol (RSV), a plant-derived polyphenol, prevents E2/ERα-induced NGB accumulation in this cellular context, making E2-dependent breast cancer cells more prone to apoptosis. Unfortunately, RSV is readily metabolized, thus preventing its effectiveness. Here, four different RSV analogs have been developed, and their effect on the ERα/NGB pathway has been compared with RSV conjugated with highly hydrophilic gold nanoparticles as prodrug to evaluate if RSV derivatives maintain the breast cancer cells’ susceptibility to the chemotherapeutic drug paclitaxel as the original compound. Results demonstrate that RSV conjugation with gold nanoparticles increases RSV efficacy, with respect to RSV analogues, reducing NGB levels and enhancing the pro-apoptotic action of paclitaxel, even preventing the anti-apoptotic action exerted by E2 treatment on these cells. Overall, RSV conjugation with gold nanoparticles makes this complex a promising agent for medical application in breast cancer treatment. Full article

(This article belongs to the Special Issue Natural Products and Phytochemicals in Preventing and Treating Cancers)

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13 pages, 2348 KiB

Open AccessArticle

Antitumor Effect of Korean Red Ginseng through Blockade of PD-1/PD-L1 Interaction in a Humanized PD-L1 Knock-In MC38 Cancer Mouse Model

by Eun-Ji Lee, Ju-Hye Yang, Hye Jin Yang, Chong-Kwan Cho, Jang-Gi Choi and Hwan-Suck Chung

Int. J. Mol. Sci. 2023, 24(3), 1894; https://doi.org/10.3390/ijms24031894 - 18 Jan 2023

Cited by 2 | Viewed by 1914

Abstract

Blocking immune checkpoints, programmed death-1 (PD-1) and its ligand PD-L1, has proven a promising anticancer strategy for enhancing cytotoxic T cell activity. Although we previously demonstrated that ginsenoside Rg3, Rh2, and compound K block the interaction of PD-1 and PD-L1, the antitumor effect [...] Read more.

Blocking immune checkpoints, programmed death-1 (PD-1) and its ligand PD-L1, has proven a promising anticancer strategy for enhancing cytotoxic T cell activity. Although we previously demonstrated that ginsenoside Rg3, Rh2, and compound K block the interaction of PD-1 and PD-L1, the antitumor effect through blockade of this interaction by Korean Red Ginseng alone is unknown. Therefore, we determined the effects of Korean Red Ginseng extract (RGE) on the PD-1/PD-L1 interaction and its antitumor effects using a humanized PD-1/PD-L1-expressing colorectal cancer (CRC) mouse model. RGE significantly blocked the interaction between human PD-1 and PD-L1 in a competitive ELISA. The CD8⁺ T cell-mediated tumor cell killing effect of RGE was evaluated using murine hPD-L1-expressing MC38 cells and tumor-infiltrating hPD-1-expressing CD8⁺ T cells isolated from hPD-L1 MC38 tumor-bearing hPD-1 mice. RGE also reduced the survival of hPD-L1 MC38 cells in a cell co-culture system using tumor-infiltrating CD8⁺ T cells as effector cells combined with hPD-L1 MC38 target cells. RGE or Keytruda (positive control) treatment markedly suppressed the growth of hPD-L1 MC38 allograft tumors, increased CD8⁺ T cell infiltration into tumors, and enhanced the production of Granzyme B. RGE exhibits anticancer effects through the PD-1/PD-L1 blockade, which warrants its further development as an immunotherapy. Full article

(This article belongs to the Special Issue Natural Products and Phytochemicals in Preventing and Treating Cancers)

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30 pages, 9042 KiB

Open AccessArticle

Enhanced Cytotoxic Activity of PEGylated Curcumin Derivatives: Synthesis, Structure–Activity Evaluation, and Biological Activity

by Dawid Lazewski, Malgorzata Kucinska, Edward Potapskiy, Joanna Kuzminska, Lukasz Popenda, Artur Tezyk, Tomasz Goslinski, Marcin Wierzchowski and Marek Murias

Int. J. Mol. Sci. 2023, 24(2), 1467; https://doi.org/10.3390/ijms24021467 - 11 Jan 2023

Cited by 3 | Viewed by 2322

Abstract

Curcumin has been modified in various ways to broaden its application in medicine and address its limitations. In this study, we present a series of curcumin-based derivatives obtained by replacing the hydroxy groups in the feruloyl moiety with polyethylene glycol (PEG) chains and [...] Read more.

Curcumin has been modified in various ways to broaden its application in medicine and address its limitations. In this study, we present a series of curcumin-based derivatives obtained by replacing the hydroxy groups in the feruloyl moiety with polyethylene glycol (PEG) chains and the addition of the BF₂ moiety to the carbonyl groups. Tested compounds were screened for their cytotoxic activity toward two bladder cancer cell lines, 5637 and SCaBER, and a noncancerous cell line derived from lung fibroblasts (MRC-5). Cell viability was analyzed under normoxic and hypoxic conditions (1% oxygen). Structure–activity relationships (SARs) are discussed, and curcumin derivatives equipped within feruloyl moieties with 3-methoxy and 4-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy} substituents (5) were selected for further analysis. Compound 5 did not affect the viability of MRC-5 cells and exerted a stronger cytotoxic effect under hypoxic conditions. However, the flow cytometry studies showed that PEGylation did not improve cellular uptake. Another observation was that the lack of serum proteins limits the intracellular uptake of curcumin derivative 5. The preliminary mechanism of action studies indicated that compound 5 under hypoxic conditions induced G2/M arrest in a dose-dependent manner and increased the expression of stress-related proteins such as p21/CIP1, phosphorylated HSP27, ADAMTS-1, and phosphorylated JNK. In summary, the results of the studies indicated that PEGylated curcumin is a more potent compound against bladder cancer cell lines than the parent compound, and derivative 5 is worthy of further investigation to clarify its mechanism of anticancer action under hypoxic conditions. Full article

(This article belongs to the Special Issue Natural Products and Phytochemicals in Preventing and Treating Cancers)

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20 pages, 4932 KiB

Open AccessArticle

Effects of Combined Pentadecanoic Acid and Tamoxifen Treatment on Tamoxifen Resistance in MCF−7/SC Breast Cancer Cells

by Ngoc Bao To, Vi Nguyen-Phuong Truong, Meran Keshawa Ediriweera and Somi Kim Cho

Int. J. Mol. Sci. 2022, 23(19), 11340; https://doi.org/10.3390/ijms231911340 - 26 Sep 2022

Cited by 8 | Viewed by 2494

Abstract

Estrogen receptors are indicators of breast cancer adaptability to endocrine therapies, such as tamoxifen. Deficiency or absence of estrogen receptor α (ER−α) in breast cancer cells results in reduced efficacy of endocrine therapy. Here, we investigated the effect of combined tamoxifen and pentadecanoic [...] Read more.

Estrogen receptors are indicators of breast cancer adaptability to endocrine therapies, such as tamoxifen. Deficiency or absence of estrogen receptor α (ER−α) in breast cancer cells results in reduced efficacy of endocrine therapy. Here, we investigated the effect of combined tamoxifen and pentadecanoic acid therapy on ER−α−under−expressing breast cancer cells. Drug resistance gene expression patterns were determined by RNA sequencing analysis and in vitro experiments. For the first time, we demonstrate that the combined treatment of pentadecanoic acid, an odd−chain fatty acid, and tamoxifen synergistically suppresses the growth of human breast carcinoma MCF−7 stem cells (MCF−7/SCs), which were found to be tamoxifen−resistant and showed reduced ER−α expression compared with the parental MCF−7 cells. In addition, the combined treatment synergistically induced apoptosis and accumulation of sub−G1 cells and suppressed epithelial−to−mesenchymal transition (EMT). Exposure to this combination induces re−expression of ER−α at the transcriptional and protein levels, along with suppression of critical survival signal pathways, such as ERK1/2, MAPK, EGFR, and mTOR. Collectively, decreased ER−α expression was restored by pentadecanoic acid treatment, resulting in reversal of tamoxifen resistance. Overall, pentadecanoic acid exhibits the potential to enhance the efficacy of endocrine therapy in the treatment of ER−α−under−expressing breast cancer cells. Full article

(This article belongs to the Special Issue Natural Products and Phytochemicals in Preventing and Treating Cancers)

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12 pages, 15623 KiB

Open AccessArticle

Endothelium-Dependent Induction of Vasculogenic Mimicry in Human Triple-Negative Breast Cancer Cells Is Inhibited by Calcitriol and Curcumin

by Gabriela Morales-Guadarrama, Edgar A. Méndez-Pérez, Janice García-Quiroz, Euclides Avila, Rocío García-Becerra, Alejandro Zentella-Dehesa, Fernando Larrea and Lorenza Díaz

Int. J. Mol. Sci. 2022, 23(14), 7659; https://doi.org/10.3390/ijms23147659 - 11 Jul 2022

Cited by 4 | Viewed by 2457

Abstract

In highly aggressive tumors, cancer cells may form channel-like structures through a process known as vasculogenic mimicry (VM). VM is generally associated with metastasis, mesenchymal phenotype, and treatment resistance. VM can be driven by antiangiogenic treatments and/or tumor microenvironment-derived factors, including those from [...] Read more.

In highly aggressive tumors, cancer cells may form channel-like structures through a process known as vasculogenic mimicry (VM). VM is generally associated with metastasis, mesenchymal phenotype, and treatment resistance. VM can be driven by antiangiogenic treatments and/or tumor microenvironment-derived factors, including those from the endothelium. Curcumin, a turmeric product, inhibits VM in some tumors, while calcitriol, the most active vitamin D metabolite, exerts potent antineoplastic effects. However, the effect of these natural products on VM in breast cancer remains unknown. Herein, we studied the effect of both compounds on triple-negative breast cancer (TNBC) VM-capacity in a co-culture model. The process of endothelial cell-induced VM in two human TNBC cell lines was robustly inhibited by calcitriol and partially by curcumin. Calcitriol promoted TNBC cells’ morphological change from spindle-like to cobblestone-shape, while curcumin diminished VM 3D-structure. Notably, the treatments dephosphorylated several active kinases, especially those involved in the PI3K/Akt pathway. In summary, calcitriol and curcumin disrupted endothelium-induced VM in TNBC cells partially by PI3K/Akt inactivation and mesenchymal phenotype inhibition. Our results support the possible use of these natural compounds as adjuvants for VM inactivation in patients with malignant tumors inherently capable of forming VM, or those with antiangiogenic therapy, warranting further in vivo studies. Full article

(This article belongs to the Special Issue Natural Products and Phytochemicals in Preventing and Treating Cancers)

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11 pages, 3233 KiB

Open AccessArticle

Suppression of the Proliferation of Huh7 Hepatoma Cells Involving the Downregulation of Mutant p53 Protein and Inactivation of the STAT 3 Pathway with Ailanthoidol

by Tsui-Hwa Tseng, Chau-Jong Wang, Yean-Jang Lee, Yi-Chia Shao, Chien-Heng Shen, Ko-Chao Lee, Shui-Yi Tung and Hsing-Chun Kuo

Int. J. Mol. Sci. 2022, 23(9), 5102; https://doi.org/10.3390/ijms23095102 - 4 May 2022

Cited by 6 | Viewed by 2273

Abstract

Ailanthoidol (ATD) has been isolated from the barks of Zanthoxylum ailanthoides and displays anti-inflammatory, antioxidant, antiadipogenic, and antitumor promotion activities. Recently, we found that ATD suppressed TGF-β1-induced migration and invasion of HepG2 cells. In this report, we found that ATD exhibited more potent [...] Read more.

Ailanthoidol (ATD) has been isolated from the barks of Zanthoxylum ailanthoides and displays anti-inflammatory, antioxidant, antiadipogenic, and antitumor promotion activities. Recently, we found that ATD suppressed TGF-β1-induced migration and invasion of HepG2 cells. In this report, we found that ATD exhibited more potent cytotoxicity in Huh7 hepatoma cells (mutant p53: Y220C) than in HepG2 cells (wild-type p53). A trypan blue dye exclusion assay and colony assay showed ATD inhibited the growth of Huh7 cells. ATD also induced G1 arrest and reduced the expression of cyclin D1 and CDK2. Flow cytometry analysis with Annexin-V/PI staining demonstrated that ATD induced significant apoptosis in Huh7 cells. Moreover, ATD increased the expression of cleaved PARP and Bax and decreased the expression of procaspase 3/8 and Bcl-xL/Bcl-2. In addition, ATD decreased the expression of mutant p53 protein (mutp53), which is associated with cell proliferation with the exploration of p53 siRNA transfection. Furthermore, ATD suppressed the phosphorylation of the signal transducer and activator of transcription 3 (STAT3) and the expression of mevalonate kinase (MVK). Consistent with ATD, the administration of S3I201 (STAT 3 inhibitor) reduced the expression of Bcl-2/Bcl-xL, cyclin D1, mutp53, and MVK. These results demonstrated ATD’s selectivity against mutp53 hepatoma cells involving the downregulation of mutp53 and inactivation of STAT3. Full article

(This article belongs to the Special Issue Natural Products and Phytochemicals in Preventing and Treating Cancers)

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Review

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12 pages, 841 KiB

Open AccessReview

Efficacy and Safety of Ginger on the Side Effects of Chemotherapy in Breast Cancer Patients: Systematic Review and Meta-Analysis

by Soo-Dam Kim, Eun-Bin Kwag, Ming-Xiao Yang and Hwa-Seung Yoo

Int. J. Mol. Sci. 2022, 23(19), 11267; https://doi.org/10.3390/ijms231911267 - 24 Sep 2022

Cited by 13 | Viewed by 5432

Abstract

Cancer is one of the leading causes of death in the world, with breast cancer being the most prevalent cancer. Chemotherapy-induced nausea and vomiting (CINV) is one of the most serious side effects of chemotherapy. Because the current CINV treatment option has several [...] Read more.

Cancer is one of the leading causes of death in the world, with breast cancer being the most prevalent cancer. Chemotherapy-induced nausea and vomiting (CINV) is one of the most serious side effects of chemotherapy. Because the current CINV treatment option has several flaws, alternative treatment options are required. Ginger has traditionally been used to treat nausea and vomiting, and it also has anticancer properties in breast cancer cells. Based on these findings, researchers investigated whether using ginger to treat CINV in breast cancer patients is both effective and safe. We searched PubMed, Embase, Cochrane Library, CNKI, and Wanfang from inception to June 2022. Outcomes included Rhodes Index Scores of Nausea, Vomiting, and Retching, severity and frequency of CINV. Five RCTs were included. We pooled all included data and performed subgroup analysis by types of CINV. Overall, authors found that ginger was associated with a reduction in CINV. Subgroup and sensitivity analysis revealed that managing severity of acute CINV in breast cancer patients with ginger was efficient. In terms of managing delayed CINV in breast cancer patients, ginger was also statistically significant. The authors concluded that ginger may be helpful in lowering both acute and delayed CINV in breast cancer patients. Since there were no serious side effects, ginger is thought to be safe. Full article

(This article belongs to the Special Issue Natural Products and Phytochemicals in Preventing and Treating Cancers)

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19 pages, 1252 KiB

Open AccessReview

Advances in Anti-Cancer Activities of Flavonoids in Scutellariae radix: Perspectives on Mechanism

by Yiqing Gu, Qi Zheng, Guifang Fan and Runping Liu

Int. J. Mol. Sci. 2022, 23(19), 11042; https://doi.org/10.3390/ijms231911042 - 20 Sep 2022

Cited by 11 | Viewed by 2625

Abstract

Despite encouraging progresses in the development of novel therapies, cancer remains the dominant cause of disease-related mortality and has become a leading economic and healthcare burden worldwide. Scutellariae radix (SR, Huangqin in Chinese) is a common herb used in traditional Chinese medicine, with [...] Read more.

Despite encouraging progresses in the development of novel therapies, cancer remains the dominant cause of disease-related mortality and has become a leading economic and healthcare burden worldwide. Scutellariae radix (SR, Huangqin in Chinese) is a common herb used in traditional Chinese medicine, with a long history in treating a series of symptoms resulting from cancer, like dysregulated immune response and metabolic abnormalities. As major bioactive ingredients extracted from SR, flavonoids, including baicalein, wogonin, along with their glycosides (baicalin and wogonoside), represent promising pharmacological and anti-tumor activities and deserve extensive research attention. Emerging evidence has made great strides in elucidating the multi-targeting therapeutic mechanisms and key signaling pathways underlying the efficacious potential of flavonoids derived from SR in the field of cancer treatment. In this current review, we aim to summarize the pharmacological actions of flavonoids against various cancers in vivo and in vitro. Moreover, we also make a brief summarization of the endeavor in developing a drug delivery system or structural modification to enhance the bioavailability and biological activities of flavonoid monomers. Taken together, flavonoid components in SR have great potential to be developed as adjuvant or even primary therapies for the clinical management of cancers and have a promising prospect. Full article

(This article belongs to the Special Issue Natural Products and Phytochemicals in Preventing and Treating Cancers)

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12 pages, 837 KiB

Open AccessReview

Experimental Evidence for the Anti-Metastatic Action of Ginsenoside Rg3: A Systematic Review

by Hyeon-Muk Oh, Chong-Kwan Cho and Chang-Gue Son

Int. J. Mol. Sci. 2022, 23(16), 9077; https://doi.org/10.3390/ijms23169077 - 13 Aug 2022

Cited by 6 | Viewed by 1892

Abstract

Cancer metastasis is the leading cause of death in cancer patients. Due to the limitations of conventional cancer treatment, such as chemotherapy, there is a need for novel therapeutics to prevent metastasis. Ginsenoside Rg3, a major active component of Panax ginseng C.A. Meyer, [...] Read more.

Cancer metastasis is the leading cause of death in cancer patients. Due to the limitations of conventional cancer treatment, such as chemotherapy, there is a need for novel therapeutics to prevent metastasis. Ginsenoside Rg3, a major active component of Panax ginseng C.A. Meyer, inhibits tumor growth and has the potential to prevent tumor metastasis. Herein, we systematically reviewed the anti-metastatic effects of Rg3 from experimental studies. We searched for articles in three research databases, MEDLINE (PubMed), EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) through March 2022. In total, 14 studies (eight animal and six in vitro) provide data on the anti-metastatic effects of Rg3 and the relevant mechanisms. The major anti-metastatic mechanisms of Rg3 involve cancer stemness, epithelial mesenchymal transition (EMT) behavior, and angiogenesis. Taken together, Rg3 would be one of the herbal resources in anti-metastatic drug developments through further well-designed investigations and clinical studies. Our review provides valuable reference data for Rg3-derived studies targeting tumor metastasis. Full article

(This article belongs to the Special Issue Natural Products and Phytochemicals in Preventing and Treating Cancers)

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30 pages, 1128 KiB

Open AccessReview

Application of Perinatal Derivatives on Oncological Preclinical Models: A Review of Animal Studies

by Ricardo Teixo, Ana Salomé Pires, Eurico Pereira, Beatriz Serambeque, Inês Alexandra Marques, Mafalda Laranjo, Slavko Mojsilović, Roberto Gramignoli, Peter Ponsaerts, Andreina Schoeberlein and Maria Filomena Botelho

Int. J. Mol. Sci. 2022, 23(15), 8570; https://doi.org/10.3390/ijms23158570 - 2 Aug 2022

Cited by 2 | Viewed by 2656

Abstract

The increasing cancer incidence has certified oncological management as one of the most critical challenges for the coming decades. New anticancer strategies are still needed, despite the significant advances brought to the forefront in the last decades. The most recent, promising therapeutic approaches [...] Read more.

The increasing cancer incidence has certified oncological management as one of the most critical challenges for the coming decades. New anticancer strategies are still needed, despite the significant advances brought to the forefront in the last decades. The most recent, promising therapeutic approaches have benefitted from the application of human perinatal derivatives (PnD), biological mediators with proven benefits in several fields beyond oncology. To elucidate preclinical results and clinic outcomes achieved in the oncological field, we present a narrative review of the studies resorting to animal models to assess specific outcomes of PnD products. Recent preclinical evidence points to promising anticancer effects offered by PnD mediators isolated from the placenta, amniotic membrane, amniotic fluid, and umbilical cord. Described effects include tumorigenesis prevention, uncontrolled growth or regrowth inhibition, tumor homing ability, and adequate cell-based delivery capacity. Furthermore, PnD treatments have been described as supportive of chemotherapy and radiological therapies, particularly when resistance has been reported. However, opposite effects of PnD products have also been observed, offering support and trophic effect to malignant cells. Such paradoxical and dichotomous roles need to be intensively investigated. Current hypotheses identify as explanatory some critical factors, such as the type of the PnD biological products used or the manufacturing procedure to prepare the tissue/cellular treatment, the experimental design (including human-relevant animal models), and intrinsic pathophysiological characteristics. The effective and safe translation of PnD treatments to clinical practice relies on the collaborative efforts of all researchers working with human-relevant oncological preclinical models. However, it requires proper guidelines and consensus compiled by experts and health workers who accurately describe the methodology of tissue collection, PnD isolation, manufacturing, preservation, and delivery to the final user. Full article

(This article belongs to the Special Issue Natural Products and Phytochemicals in Preventing and Treating Cancers)

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