Utilization of 6-(methylsulfinyl)hexyl isothiocyanate for sensitization of tumor cells to antitumor agents in combination therapies

Background: Triple Negative Breast Cancer (TNBC) represents the approximately 15% of breast cancers that lack expression of Estrogen (ER) and Progesterone Receptors (PR) and do not exhibit amplification of the human epidermal growth factor receptor 2 (HER2) gene, imposing difficulties to treatment. Interactions between tumor cells and their microenvironment facilitate tumor cell invasion in the surrounding tissues, intravasation through newly formed vessels, and dissemination to form metastasis. To treat metastasis from breast and many other cancer types, chemotherapy is one of the most extensively used methods. However, its efficacy and safety remain a primary concern, as well as its toxicity and other side effects. Thus, there is increasing interest in natural antitumor agents. In a previous work, we have demonstrated that [10]-gingerol is able to revert malignant phenotype in breast cancer cells in 3D culture and, moreover, to inhibit the dissemination of TNBC to multiple organs including lung, bone and brain, in spontaneous and experimental in vivo metastasis assays in mouse model. Objective: This work aims to investigate the in vitro effects of [10]-gingerol, using human MDA-MB-231TNBC cells, in comparison to non-tumor MCF-10A breast cells, in order to understand the antitumor and antimetastatic effects found in vivo and in a 3D environment. Methods: We investigated different steps of the metastatic process in vitro, such as cell migration, invasion, adhesion and MMP activity. In addition, we analyzed the anti-apoptotic and genotoxic effects of [10]-gingerol using PEAnnexin, DNA fragmentation, TUNEL and comet assays, respectively. Results: [10]-gingerol was able to inhibit cell adhesion, migration, invasion and to induce apoptosis more effectively in TNBC cells, when compared to non-tumor cells, demonstrating that these mechanisms can be involved in the antitumor and antimetastatic effects of [10]-gingerol, found both in 3D culture and in vivo. Conclusion: Taken together, results found here are complementary to previous studies of our group and others and demonstrate that additional mechanisms, besides apoptotic cell death, is used by [10]-gingerol to accomplish its antitumor and antimetastatic effects. Our results indicate a potential for this natural compound as an antitumor molecule or as an adjuvant for chemotherapeutics already used in the clinic.

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Modulation of Membrane Permeability, Cell Proliferation and Cytotoxicity of Antitumor Agents by External ATP in Mouse Tumor Cells

Japanese Journal of Cancer Research ◽

10.1111/j.1349-7006.1992.tb02361.x ◽

1992 ◽

Vol 83 (1) ◽

pp. 121-126 ◽

Cited By ~ 13

Author(s):

Tsutomu Mure ◽

Kaiso Sano ◽

Takayuki Kitagawa

Keyword(s):

Cell Proliferation ◽

Membrane Permeability ◽

Tumor Cells ◽

Antitumor Agents ◽

Mouse Tumor

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The Challenge of Culturing Human Colorectal Tumor Cells: Establishment of a Cell Culture Model by the Comparison of Different Methodological Approaches

Tumori Journal ◽

10.1177/030089160909500312 ◽

2009 ◽

Vol 95 (3) ◽

pp. 343-347 ◽

Cited By ~ 15

Author(s):

Alessandra Failli ◽

Rita Consolini ◽

Annalisa Legitimo ◽

Roberto Spisni ◽

Maura Castagna ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Culture ◽

Tumor Cells ◽

Antitumor Agents ◽

Methodological Approach ◽

Primary Cultures ◽

Isolated Cells ◽

Human Colon Cancer ◽

Viable Cells ◽

Methodological Approaches

Background Because colorectal cancer is a significant cause of morbidity and mortality in the Western population, knowledge of the molecular and biological alterations associated with its development is important. Since primary human colon cancer cultures from fresh tumor tissue are technically difficult to obtain, experiments in most laboratories are performed on colon epithelial cell lines, but these represent just one stage of tumor progression. Only primary cultures of neoplastic colonocytes may reflect the actual responsiveness of tumors at certain developmental stages to antitumor agents. Methods This paper analyzes several critical points concerning primary cultures, ranging from cell isolation to culture conditions, and compares different methodological approaches to isolate and cultivate a pure fraction of viable tumor cells. Samples of resected colorectal cancers were collected from 20 patients (stage T3 or T4). We compared in vitro several approaches of tissue disaggregation including mechanical disaggregation and enzymatic dissociation with trypsin or collagenase. Isolated cells were maintained in a short-term serum-free culture system. Evaluation of the purity and tumoral nature of isolated cells was performed by immunochemistry. Results We established the antibiotic concentration necessary during transport and washing of the specimens to prevent microbial overgrowth. We demonstrated that the number of viable cells was dependent on the dissociation method used. Mechanical disaggregation is not a valid dissociation method because of the high mortality of cells and might be used only in samples for molecular analysis. Comparison of the enzymatic digestion procedures showed that digestion with trypsin allowed the highest recovery of viable cells. Conclusion In this paper we analyzed several critical aspects of cell culture procedures and designed a methodological approach suitable for functional studies of colorectal cancer.

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Alvaxanthone, a Thymidylate Synthase Inhibitor with Nematocidal and Tumoricidal Activities

Molecules ◽

10.3390/molecules25122894 ◽

2020 ◽

Vol 25 (12) ◽

pp. 2894 ◽

Cited By ~ 1

Author(s):

Piotr Maj ◽

Mattia Mori ◽

Justyna Sobich ◽

Joanna Markowicz ◽

Łukasz Uram ◽

...

Keyword(s):

Tumor Cells ◽

Thymidylate Synthase ◽

Antitumor Agents ◽

3D Structure ◽

Three Dimensional ◽

Human Tumor ◽

Selective Toxicity ◽

C Elegans ◽

Synthase Inhibitor

With the aim to identify novel inhibitors of parasitic nematode thymidylate synthase (TS), we screened in silico an in-house library of natural compounds, taking advantage of a model of nematode TS three-dimensional (3D) structure and choosing candidate compounds potentially capable of enzyme binding/inhibition. Selected compounds were tested as (i) inhibitors of the reaction catalyzed by TSs of different species, (ii) agents toxic to a nematode parasite model (C. elegans grown in vitro), (iii) inhibitors of normal human cell growth, and (iv) antitumor agents affecting human tumor cells grown in vitro. The results pointed to alvaxanthone as a relatively strong TS inhibitor that causes C. elegans population growth reduction with nematocidal potency similar to the anthelmintic drug mebendazole. Alvaxanthone also demonstrated an antiproliferative effect in tumor cells, associated with a selective toxicity against mitochondria observed in cancer cells compared to normal cells.

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Drug responses are conserved across patient-derived xenograft models of melanoma leading to identification of novel drug combination therapies

British Journal of Cancer ◽

10.1038/s41416-019-0696-y ◽

2019 ◽

Vol 122 (5) ◽

pp. 648-657 ◽

Cited By ~ 1

Author(s):

Ryan J. Ice ◽

Michelle Chen ◽

Max Sidorov ◽

Tam Le Ho ◽

Rinette W. L. Woo ◽

...

Keyword(s):

Metastatic Melanoma ◽

Antitumor Agents ◽

Treatment Options ◽

Braf Inhibitor ◽

Drug Combinations ◽

Response To Therapy ◽

Combination Therapies ◽

Mek Inhibitors ◽

Patient Derived Xenograft ◽

Novel Drug

Abstract Background Patient-derived xenograft (PDX) mouse tumour models can predict response to therapy in patients. Predictions made from PDX cultures (PDXC) would allow for more rapid and comprehensive evaluation of potential treatment options for patients, including drug combinations. Methods We developed a PDX library of BRAF-mutant metastatic melanoma, and a high-throughput drug-screening (HTDS) platform utilising clinically relevant drug exposures. We then evaluated 34 antitumor agents across eight melanoma PDXCs, compared drug response to BRAF and MEK inhibitors alone or in combination with PDXC and the corresponding PDX, and investigated novel drug combinations targeting BRAF inhibitor-resistant melanoma. Results The concordance of cancer-driving mutations across patient, matched PDX and subsequent PDX generations increases as variant allele frequency (VAF) increases. There was a high correlation in the magnitude of response to BRAF and MEK inhibitors between PDXCs and corresponding PDXs. PDXCs and corresponding PDXs from metastatic melanoma patients that progressed on standard-of-care therapy demonstrated similar resistance patterns to BRAF and MEK inhibitor therapy. Importantly, HTDS identified novel drug combinations to target BRAF-resistant melanoma. Conclusions The biological consistency observed between PDXCs and PDXs suggests that PDXCs may allow for a rapid and comprehensive identification of treatments for aggressive cancers, including combination therapies.

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Redox-active ferrocene-modified pyrimidines and adenine as antitumor agents: structure, separation of enantiomers, and inhihibition of the DNA synthesis in tumor cells

Russian Chemical Bulletin ◽

10.1007/s11172-013-0298-4 ◽

2013 ◽

Vol 62 (9) ◽

pp. 2056-2064 ◽

Cited By ~ 18

Author(s):

L. V. Snegur ◽

S. I. Zykova ◽

A. A. Simenel ◽

Yu. S. Nekrasov ◽

Z. A. Starikova ◽

...

Keyword(s):

Dna Synthesis ◽

Tumor Cells ◽

Antitumor Agents ◽

Separation Of Enantiomers ◽

Redox Active

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Antiproliferative Activity of Neem Leaf Extracts Obtained by a Sequential Pressurized Liquid Extraction

Pharmaceuticals ◽

10.3390/ph11030076 ◽

2018 ◽

Vol 11 (3) ◽

pp. 76 ◽

Cited By ~ 3

Author(s):

Klebson Santos ◽

Andriele Barbosa ◽

Victor Freitas ◽

Ana Muniz ◽

Marcelo Mendonça ◽

...

Keyword(s):

Tumor Cells ◽

Antiproliferative Activity ◽

Antitumor Agents ◽

Fixed Bed ◽

Human Tumor ◽

Liquid Extraction ◽

Pressurized Liquid Extraction ◽

Ionization Mass ◽

Malignant Cells ◽

Neem Leaves

Azadirachta indica A. Juss (neem) extracts have been used in pharmaceutical applications as antitumor agents, due to their terpenes and phenolic compounds. To obtain extracts from neem leaves with potential antiproliferative effect, a sequential process of pressurized liquid extraction was carried out in a fixed bed extractor at 25 °C and 100 bar, using hexane (SH), ethyl acetate (SEA), and ethanol (SE) as solvents. Extractions using only ethanol (EE) was also conducted to compare the characteristics of the fractionated extracts. The results obtained by liquid chromatography-electrospray ionization mass spectrometry suggested a higher concentration of terpenes in the SEA extract in comparison to SH, SE, and EE extracts. Therefore, antiproliferative activity showed that SEA extracts were the most efficient inhibitor to human tumor cells MCF-7, NCI-H460, HeLa, and HepG2. Hepatocellular cells were more resistant to SH, SEA, SE, and EE compared to breast, lung, hepatocellular, and cervical malignant cells. Neem fractioned extracts obtained in the present study seem to be more selective for malignant cells compared to the non-tumor cells.

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Strengths and Challenges of Secretory Ribonucleases as AntiTumor Agents

Pharmaceutics ◽

10.3390/pharmaceutics13010082 ◽

2021 ◽

Vol 13 (1) ◽

pp. 82

Author(s):

Jessica Castro ◽

Marc Ribó ◽

Maria Vilanova ◽

Antoni Benito

Keyword(s):

Cancer Cells ◽

Tumor Cells ◽

Antitumor Agents ◽

Rna Degradation ◽

Molecular Profile ◽

Dna Targeting ◽

Ribonucleolytic Activity ◽

Downstream Effects ◽

Tumor Cell Heterogeneity ◽

Effective Drugs

Approaches to develop effective drugs to kill cancer cells are mainly focused either on the improvement of the currently used chemotherapeutics or on the development of targeted therapies aimed at the selective destruction of cancer cells by steering specific molecules and/or enhancing the immune response. The former strategy is limited by its genotoxicity and severe side effects, while the second one is not always effective due to tumor cell heterogeneity and variability of targets in cancer cells. Between these two strategies, several approaches target different types of RNA in tumor cells. RNA degradation alters gene expression at different levels inducing cell death. However, unlike DNA targeting, it is a pleotropic but a non-genotoxic process. Among the ways to destroy RNA, we find the use of ribonucleases with antitumor properties. In the last few years, there has been a significant progress in the understanding of the mechanism by which these enzymes kill cancer cells and in the development of more effective variants. All the approaches seek to maintain the requirements of the ribonucleases to be specifically cytotoxic for tumor cells. These requirements start with the competence of the enzymes to interact with the cell membrane, a process that is critical for their internalization and selectivity for tumor cells and continue with the downstream effects mainly relying on changes in the RNA molecular profile, which are not only due to the ribonucleolytic activity of these enzymes. Although the great improvements achieved in the antitumor activity by designing new ribonuclease variants, some drawbacks still need to be addressed. In the present review, we will focus on the known mechanisms used by ribonucleases to kill cancer cells and on recent strategies to solve the shortcomings that they show as antitumor agents, mainly their pharmacokinetics.

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