Nanoformulation of a Novel Pyrano[2,3-c] Pyrazole Heterocyclic Compound AMDPC Exhibits Anti-Cancer Activity via Blocking the Cell Cycle through a P53-Independent Pathway

Pyrano[2,3-c]pyrazole derivatives have been reported as exerting various biological activities. One compound with potential anti-tumor activity was screened out by MTT assay from series of dihydropyrazopyrazole derivatives we had synthesized before using a one-pot, four-component reaction, and was named as 6-amino-4-(2-hydroxyphenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (hereinafter abbreviated as AMDPC). The IC50 of AMDPC against Bcap-37 breast cancer cells was 46.52 μg/mL. Then the hydrophobic AMDPC was encapsulated in PEG-PLGA block copolymers, and then self-assembled as polymeric micelle (mPEG-PLGA/AMDPC) to improve both physiochemical and release profiles. The effect of mPEG-PLGA/AMDPC on BCAP-37 cancer cells showed similar anti-tumor effects as AMDPC. Furthermore, the anti-tumor mechanism of mPEG-PLGA/AMDPC was investigated, which can probably be attributed to stimulating the expression of P21 gene and therefore protein production on BCAP-37 cells, and then blocked the cell cycle through the P53-independent pathway both in S phase and G2 phase. Thus, mPEG-PLGA/AMDPC is a promising therapeutic agent for cancer treatment, and further in vivo studies will be developed.

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Low-Molecular-Weight Fucoidan as Complementary Therapy of Fluoropyrimidine-Based Chemotherapy in Colorectal Cancer

10.20944/preprints202106.0492.v1 ◽

2021 ◽

Author(s):

Ching-Wen Huang ◽

Yen-Cheng Chen ◽

Tzu-Chieh Yin ◽

Po-Jung Chen ◽

Tsung-Kun Chang ◽

...

Keyword(s):

Cell Cycle ◽

Molecular Weight ◽

Cell Viability ◽

Signaling Pathway ◽

Complementary Therapy ◽

In Vivo Studies ◽

Low Molecular Weight ◽

Tumor Cell Migration ◽

Anti Cancer

This study investigated the roles of low-molecular-weight fucoidan (LMWF) in enhancing the anti-cancer effects of fluoropyrimidine-based chemotherapy. HCT116 and Caco-2 cells were treated with LMWF and 5-FU. Cell viability, cell cycle, apoptosis, and migration were analyzed in both cell types. Potential mechanisms underlying how LMWF enhances the anti-cancer effects of fluoropyrimidine-based chemotherapy were also explored. The cell viability of HCT116 and Caco-2 cells was significantly reduced after treatment with a LMWF-5-FU combination. In HCT116 cells, LMWF enhanced the suppressive effects of 5-FU on cell viability through the 1) induction of cell cycle arrest in the S phase and 2) late apoptosis mediated by the Jun-N-terminal kinase (JNK) signaling pathway. In Caco-2 cells, LMWF enhanced the suppressive effects of 5-FU on cell viability through both c-mesenchymal–epithelial transition (MET)/ Kirsten Rat Sarcoma virus (KRAS)/ extracellular signal-regulated kinase (ERK) and c-MET/ phosphatidyl-inositol 3-kinases (PI3K)/ protein kinase B (AKT) signaling pathways. Moreover, LMWF enhanced the suppressive effects of 5-FU on tumor cell migration through the c-MET/ matrix metalloproteinase (MMP)-2 signaling pathway in both HCT116 and Caco-2 cells. Our results demonstrated that LMWF is a potential complementary therapy for enhancing the efficacies of fluoropyrimidine-based chemotherapy in colorectal cancers (CRCs) with the wild-type or mutated KRAS gene through different mechanisms. However, in vivo studies and in clinical trials are required to validate the results of the present study.

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10-4-4, A Cardiac Glycoside Block Growth in Cancer Cells via Nuclear Receptor Nur77 Mediated Na+/K+- ATPase Endocytosis

10.21203/rs.3.rs-942023/v1 ◽

2021 ◽

Author(s):

Mengjie Hu ◽

Yang Xu ◽

Yuzhou Bao ◽

Jinshan Tang ◽

Mingyu Li ◽

...

Keyword(s):

Cell Cycle ◽

Liver Cancer ◽

Cancer Cells ◽

Nuclear Receptor ◽

Cardiac Glycoside ◽

Nuclear Export ◽

M Cell ◽

Cycle Arrest ◽

Anti Cancer

Abstract Background Cancer is second only to heart disease as a cause of death. Develop new and more effective treatment strategies for cancer remain a major challenge for human medicine today. Nur77, an orphan member for the nuclear receptor superfamily, inhibits growth in cancer cells by translocation to cytoplasmic. Small molecules that trigger Nur77 nuclear export may be an ideal anti-cancer candidate. Methods Cell proliferation was evaluated by 3-(4, 5-dimethylthiazol-2-y1)-2, 5-diphenyl tetrazolium bromide (MTT) assay. The protein expression level were detected by western blot analysis. Immunostaining and cell fractionation assays were used to assess subcelluar localization of Nur77. Cell apoptosis, cell cycle and calcium were detected by flow cytometry. Zebrafish liver cancer models were used to determine anti-cancer effect of 10-4-4 in vivo. Results In this study, we exhibit 10-4-4 a cardiac glycoside, extracted from Antiaris toxicaria lesch, has sensitivity to cancer cells. 10-4-4 induces apoptosis and G2/M cell cycle arrest in HepG2 cells. Consistently, 10-4-4 augments Nur77 expression and cytoplasmic localization, its restraint of cancer cells growth is Nur77 dependent. Meanwhile, as a cardiac glycoside, 10-4-4 inhibits Na+/K+- ATPase (NaK) activation. To further confirm the molecular mechanism of 10-4-4, we found the association between Nur77 and NaK. The suppression of NaK by 10-4-4 increases the level of intracellular Ca2+. Ca2+, as a second messenger, specific activates protein kinase C (PKC). PKC has been reported on the influence of Nur77 nuclear export. Identical conclusions are obtained in this studies that 10-4-4 induces PKC activation play an important role in Nur77 nuclear export. Notably, the cytoplasmic Nur77 induced by 10-4-4 interaction with NaK to induce NaK endocytosis, and then trigger G2/M cell cycle arrest and apoptosis. Studies in Zebrafish shows that 10-4-4 potently inhibits the growth of liver cancer cells in vivo. Conclusions Our results exhibit that 10-4-4 possesses an anti-cancer activity in vitro and in vivo via NaK-Nur77 signaling pathway and maybe offers a novel strategy in development of chemotherapeutic anti-cancer drug.

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Potent anti-cancer activity of Alnus nitida against lung cancer cells; in vitro and in vivo studies

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2018.11.138 ◽

2019 ◽

Vol 110 ◽

pp. 254-264 ◽

Cited By ~ 1

Author(s):

Moniba Sajid ◽

Chao Yan ◽

Dawei Li ◽

Siva Bharath Merugu ◽

Hema Negi ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Cells ◽

Lung Cancer Cells ◽

In Vivo Studies ◽

Anti Cancer ◽

Cancer Activity

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Promising Anticancer Activities of Alismatis rhizome and Its Triterpenes via p38 and PI3K/Akt/mTOR Signaling Pathways

Nutrients ◽

10.3390/nu13072455 ◽

2021 ◽

Vol 13 (7) ◽

pp. 2455

Author(s):

Eungyeong Jang ◽

Jang-Hoon Lee

Keyword(s):

Cancer Cells ◽

Signaling Pathways ◽

Biological Activities ◽

Experimental Models ◽

Mtor Signaling ◽

Flowering Plant ◽

In Vivo Studies ◽

Anticancer Activities

The flowering plant genus Alisma, which belongs to the family Alismataceae, comprises 11 species, including Alisma orientale, Alisma canaliculatum, and Alisma plantago-aquatica. Alismatis rhizome (Ze xie in Chinese, Takusha in Japanese, and Taeksa in Korean, AR), the tubers of medicinal plants from Alisma species, have long been used to treat inflammatory diseases, hyperlipidemia, diabetes, bacterial infection, edema, oliguria, diarrhea, and dizziness. Recent evidence has demonstrated that its extract showed pharmacological activities to effectively reverse cancer-related molecular targets. In particular, triterpenes naturally isolated from AR have been found to exhibit antitumor activity. This study aimed to describe the biological activities and plausible signaling cascades of AR and its main compounds in experimental models representing cancer-related physiology and pathology. Available in vitro and in vivo studies revealed that AR extract possesses anticancer activity against various cancer cells, and the efficacy might be attributed to the cytotoxic and antimetastatic effects of its alisol compounds, such as alisol A, alisol B, and alisol B 23-acetate. Several beneficial functions of triterpenoids found in AR might be due to p38 activation and inhibition of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathways. Moreover, AR and its triterpenes inhibit the proliferation of cancer cells that are resistant to chemotherapy. Thus, AR and its triterpenes may play potential roles in tumor attack, as well as a therapeutic remedy alone and in combination with other chemotherapeutic drugs.

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Genus Ophiorrhiza: A Review of Its Distribution, Traditional Uses, Phytochemistry, Biological Activities and Propagation

Molecules ◽

10.3390/molecules25112611 ◽

2020 ◽

Vol 25 (11) ◽

pp. 2611 ◽

Cited By ~ 1

Author(s):

Muhammad Taher ◽

Siti Syazwani Shaari ◽

Deny Susanti ◽

Dayar Arbain ◽

Zainul Amiruddin Zakaria

Keyword(s):

Biological Activities ◽

Wide Distribution ◽

In Vivo Studies ◽

Active Compounds ◽

Phytochemical Content ◽

Traditional Uses ◽

Anti Cancer ◽

Anticancer Compound

Almost 50 species of Ophiorrhiza plants were reviewed in this work and the main objective is to critically analyse their distribution, phytochemical content, biological activity, and propagation. Moreover, the information would be useful in promoting the relevant uses of the plant, especially in the medicinal fields based on in vitro and in vivo studies. To this end, scientific sources, including theses, PubMed, Google Scholar, International Islamic University Malaysia IIUM EBSCO, PubChem, and Elsevier, were accessed for publications regarding the Ophiorrhiza genus in this review. Scientific literature regarding the Ophiorrhiza plants revealed their wide distribution across Asia and the neighbouring countries, whereby they were utilised as traditional medicine to treat various diseases. In particular, various active compounds, such as alkaloids, flavonoids, and terpenoids, were reported in the plant. Furthermore, the Ophiorrhiza species showed highly diverse biological activities, such as anti-cancer, antiviral, antimicrobial, and more. The genus propagation reported could produce a high quality and quantity of potent anticancer compound, namely camptothecin (CPT). Hence, it is believed that the relevant uses of natural compounds present in the plants can replace the existing crop of synthetic anticancer drugs associated with a multitude of unbearable side effects. Additionally, more future studies on the Ophiorrhiza species should be undertaken to establish the links between its traditional uses, active compounds, and pharmacological activities reported.

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Amygdalin from Apricot Kernels Induces Apoptosis and Causes Cell Cycle Arrest in Cancer Cells: An Updated Review

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520618666180105161136 ◽

2019 ◽

Vol 18 (12) ◽

pp. 1650-1655 ◽

Cited By ~ 13

Author(s):

Mohammad Saleem ◽

Jawaria Asif ◽

Muhammad Asif ◽

Uzma Saleem

Keyword(s):

Cell Cycle ◽

Cancer Cells ◽

Time Frame ◽

Central Process ◽

Naturally Occurring ◽

Current Review ◽

Anti Cancer ◽

Apoptotic Proteins ◽

Cancer Agent

Background: Amygdalin is a cyanogenic glycoside which is described as a naturally occurring anticancer agent. Current review highlights apoptosis-inducing attributes of amygdalin towards different cancers and its potential application as an anti-cancer agent in cancer therapy. Method: Data about amygdalin was retrieved from all major scientific databases i.e., PubMed, ScienceDirect, Google Scholar, Scopus and Medline by using combination of keywords like amygdalin, apoptosis, laetrile, vitamin B- 17, pro-apoptotic proteins, anti-apoptotic proteins, hydrogen cyanide, mechanism of action of amygdalin and amygdalin therapy on humans. However, no specific time frame was followed for collection of data. Results: Data collected from already published articles revealed that apoptosis is a central process activated by amygdalin in cancer cells. It is suggested to stimulate apoptotic process by upregulating expression of Bax (proapoptotic protein) and caspase-3 and downregulating expression of Bcl-2 (anti-apoptotic protein). It also promotes arrest of cell cycle in G0/G1 phase and decrease number of cells entering S and G2/M phases. Thus, it is proposed to enhance deceleration of cell cycle by blocking cell proliferation and growth. Conclusion: The current review epitomizes published information and provides complete interpretations about all known anti-cancer mechanisms of amygdalin, possible role of naturally occurring amygdalin in fight against cancer and mistaken belief about cyanide toxicity causing potential of amygdalin. However, well-planned clinical trials are still needed to be conducted to prove effectiveness of this substance in vivo and to get approval for human use.

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Low-Molecular-Weight Fucoidan as Complementary Therapy of Fluoropyrimidine-Based Chemotherapy in Colorectal Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22158041 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8041

Author(s):

Ching-Wen Huang ◽

Yen-Cheng Chen ◽

Tzu-Chieh Yin ◽

Po-Jung Chen ◽

Tsung-Kun Chang ◽

...

Keyword(s):

Cell Cycle ◽

Molecular Weight ◽

Cell Viability ◽

Signaling Pathway ◽

Complementary Therapy ◽

In Vivo Studies ◽

Low Molecular Weight ◽

Tumor Cell Migration ◽

Anti Cancer

This study investigated the roles of low-molecular-weight fucoidan (LMWF) in enhancing the anti-cancer effects of fluoropyrimidine-based chemotherapy. HCT116 and Caco-2 cells were treated with LMWF and 5-FU. Cell viability, cell cycle, apoptosis, and migration were analyzed in both cell types. Potential mechanisms underlying how LMWF enhances the anti-cancer effects of fluoropyrimidine-based chemotherapy were also explored. The cell viability of HCT116 and Caco-2 cells was significantly reduced after treatment with a LMWF-–5FU combination. In HCT116 cells, LMWF enhanced the suppressive effects of 5-FU on cell viability through the 1) induction of cell cycle arrest in the S phase and 2) late apoptosis mediated by the Jun-N-terminal kinase (JNK) signaling pathway. In Caco-2 cells, LMWF enhanced the suppressive effects of 5-FU on cell viability through both the c-mesenchymal–epithelial transition (MET)/Kirsten rat sarcoma virus (KRAS)/extracellular signal-regulated kinase (ERK) and the c-MET/phosphatidyl-inositol 3-kinases (PI3K)/protein kinase B (AKT) signaling pathways. Moreover, LMWF enhanced the suppressive effects of 5-FU on tumor cell migration through the c-MET/matrix metalloproteinase (MMP)-2 signaling pathway in both HCT116 and Caco-2 cells. Our results demonstrated that LMWF is a potential complementary therapy for enhancing the efficacies of fluoropyrimidine-based chemotherapy in colorectal cancers (CRCs) with the wild-type or mutated KRAS gene through different mechanisms. However, in vivo studies and in clinical trials are required in order to validate the results of the present study.

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Eupatilin Inhibits the Proliferation and Migration of Prostate Cancer Cells through Modulation of PTEN and NF-κB Signaling

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520620666200811113549 ◽

2020 ◽

Vol 20 ◽

Author(s):

Riza Serttas ◽

Cagla Koroglu ◽

Suat Erdogan

Keyword(s):

Prostate Cancer ◽

Cell Cycle ◽

Cancer Cells ◽

Therapeutic Potential ◽

In Vivo Studies ◽

Migration And Invasion ◽

Prostate Cancer Cells ◽

And Migration ◽

Proliferation And Migration

Background: Despite advances in treatment of prostate cancer, side effects and the risks of developing drug resistance require new therapeutic agents. Eupatilin is a secondary metabolite of Artemisia asiatica and has shown potential anti-tumor activity in some cancers, but its potential in prostate cancer treatment has not yet been evaluated. Objective: The aim of the study was to investigate the effectiveness of eupatilin on prostate cancer cell proliferation and migration. Methods: Human prostate cancer PC3 and LNCaP cells were exposed to eupatilin and its efficacy on cell survival was determined by MTT test. Apoptosis and cell cycle phases were evaluated by image-based cytometer. Cell migration and invasion was evaluated by wound healing and matrigel migration assays; the expression of mRNA and protein were assessed by RT-qPCR and Western blot,respectively. Results: Eupatilin time- and dose-dependently reduced the viability of prostate cancer cells. Exposure of PC3 cells to 12.5 µM - 50 µM eupatilin resulted in apoptosis by upregulating the expression of caspase 3, Bax and cytochrome c. Annexin V assessment also confirmed that eupatilin causes apoptosis. The treatment significantly upregulated mRNA expression of p53, p21, and p27, causing cell cycle arrest in the G1 phase. Administration of eupatilin inhibited migration and invasion of the cells by down-regulating the expression of Twist, Slug and MMP-2, -7. In addition, the agent increased protein expression of tumor suppressor PTEN, while transcription factor NF-κB expression was reduced. Conclusion: Eupatilin strongly prevents proliferation of prostate cancer cells, and suppresses migration and invasion. Because of its therapeutic potential, the clinical use of eupatilin in prostate cancer should also be supported by in vivo studies.

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Metabolomics of Healthy Berry Fruits

Current Medicinal Chemistry ◽

10.2174/0929867323666161206100006 ◽

2019 ◽

Vol 25 (37) ◽

pp. 4888-4902 ◽

Cited By ~ 3

Author(s):

Gilda D'Urso ◽

Sonia Piacente ◽

Cosimo Pizza ◽

Paola Montoro

Keyword(s):

Biological Activities ◽

Biologically Active ◽

In Vivo Studies ◽

Bioactive Metabolites ◽

Active Metabolites ◽

Positive Effects ◽

Cell Functions ◽

Berry Fruits

The consumption of berry-type fruits has become very popular in recent years because of their positive effects on human health. Berries are in fact widely known for their health-promoting benefits, including prevention of chronic disease, cardiovascular disease and cancer. Berries are a rich source of bioactive metabolites, such as vitamins, minerals, and phenolic compounds, mainly anthocyanins. Numerous in vitro and in vivo studies recognized the health effects of berries and their function as bioactive modulators of various cell functions associated with oxidative stress. Plants have one of the largest metabolome databases, with over 1200 papers on plant metabolomics published only in the last decade. Mass spectrometry (MS) and NMR (Nuclear Magnetic Resonance) are the most important analytical technologies on which the emerging ''omics'' approaches are based. They may provide detection and quantization of thousands of biologically active metabolites from a tissue, working in a ''global'' or ''targeted'' manner, down to ultra-trace levels. In the present review, we highlighted the use of MS and NMR-based strategies and Multivariate Data Analysis for the valorization of berries known for their biological activities, important as food and often used in the preparation of nutraceutical formulations.

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Cancer Treatment with Liposomes Based Drugs and Genes Co-delivery Systems

Current Medicinal Chemistry ◽

10.2174/0929867325666180111093937 ◽

2018 ◽

Vol 25 (28) ◽

pp. 3319-3332 ◽

Cited By ~ 8

Author(s):

Chuanmin Zhang ◽

Shubiao Zhang ◽

Defu Zhi ◽

Jingnan Cui

Keyword(s):

Cell Cycle ◽

Cancer Cells ◽

Synergistic Effects ◽

Resistance Mechanisms ◽

Delivery Systems ◽

Cell Cycle Checkpoints ◽

Drug Efflux ◽

Cancer Resistance ◽

Cancer Models ◽

Anti Cancer

There are several mechanisms by which cancer cells develop resistance to treatments, including increasing anti-apoptosis, increasing drug efflux, inducing angiogenesis, enhancing DNA repair and altering cell cycle checkpoints. The drugs are hard to reach curative effects due to these resistance mechanisms. It has been suggested that liposomes based co-delivery systems, which can deliver drugs and genes to the same tumor cells and exhibit synergistic anti-cancer effects, could be used to overcome the resistance of cancer cells. As the co-delivery systems could simultaneously block two or more pathways, this might promote the death of cancer cells by sensitizing cells to death stimuli. This article provides a brief review on the liposomes based co-delivery systems to overcome cancer resistance by the synergistic effects of drugs and genes. Particularly, the synergistic effects of combinatorial anticancer drugs and genes in various cancer models employing multifunctional liposomes based co-delivery systems have been discussed. This review also gives new insights into the challenges of liposomes based co-delivery systems in the field of cancer therapy, by which we hope to provide some suggestions on the development of liposomes based co-delivery systems.

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