The discovery of the vinca alkaloids—chemotherapeutic agents against cancer

1990 ◽  
Vol 68 (12) ◽  
pp. 1344-1351 ◽  
Author(s):  
Robert L. Noble
Keyword(s):  
Catharanthus Roseus ◽  
Indole Alkaloids ◽  
Chemotherapeutic Agents ◽  
Madagascar Periwinkle ◽  
Cancer Treatments ◽  
Highly Sensitive ◽  
Treatment Of Diabetes ◽  
The Subject

In folklore medicine, extracts of the leaves of the subtropical plant Catharanthus roseus (L.) G. Don (sometimes known as Madagascar periwinkle) were reputed to be useful in the treatment of diabetes. This review describes how attempts to verify the antidiabetic properties of the extracts led instead to the discovery and isolation of two complex indole alkaloids, vinblastine and vincristine, which are used in the clinical treatment of a variety of cancers. The two alkaloids, although structurally almost identical, nevertheless differ markedly in the type of tumors that they affect and in their toxic properties. These and related alkaloids have been the subject of many pharmacological and biochemical investigations both in vivo and in vitro in the search for improved cancer treatments. A model system used in these studies, a transplantable lymphoma in Noble strain rats designated Nb2 node, has serendipitously led to the development of a highly sensitive and specific bioassay for lactogenic hormones.Key words: Catharanthus roseus, vinblastine, vincristine, cancer chemotherapy, Nb rat lymphoma, lactogen bioassay.

5-Methyltryptophan Resistant Cells of Catharanthus roseus

1979 ◽  
Vol 34 (7-8) ◽  
pp. 541-545 ◽  
Author(s):  
Jürgen Schallenberg ◽  
Jochen Berlin
Keyword(s):  
Catharanthus Roseus ◽  
Indole Alkaloids ◽  
Indole Alkaloid ◽  
Synthetase Activity ◽  
Wild Type ◽  
Free Tryptophan ◽  
Alkaloid Synthesis ◽  
Resistant Cells

Several cell lines resistant to 5-methyltryptophan were selected from wild type cells of different Catharanthus roseus suspension cultures. The resistant cells had up to 30 times tne normal levels of free tryptophan. Despite the increased pool size of tryptophan anthranilate synthetase activity of resistant cells was as sensitive to inhibition by ʟ-tryptophan as wild type cells. The overproduction of tryptophan did not lead to intensified accumulation of tryptamine nor of indole alkaloids. This was supported by a low conversion of tryptophan to tryptamine in vivo and in vitro. The overpro­duction of one of the primary precursors was evidently not sufficient to stimulate the rate of indole alkaloid synthesis in Catharanthus cells.

scholarly journals ImprovingIn VivoEfficacy of Bioactive Molecules: An Overview of Potentially Antitumor Phytochemicals and Currently Available Lipid-Based Delivery Systems

2017 ◽  
Vol 2017 ◽  
pp. 1-34 ◽  
Author(s):  
Lamia Mouhid ◽  
Marta Corzo-Martínez ◽  
Carlos Torres ◽  
Luis Vázquez ◽  
Guillermo Reglero ◽  
...  
Keyword(s):  
Cancer Treatment ◽  
Delivery Systems ◽  
Chemotherapeutic Agents ◽  
Bioactive Molecules ◽  
Antitumoral Activity ◽  
Cancer Treatments ◽  
Bioactive Ingredients ◽  
New Formulation

Cancer is among the leading causes of morbidity and mortality worldwide. Many of the chemotherapeutic agents used in cancer treatment exhibit cell toxicity and display teratogenic effect on nontumor cells. Therefore, the search for alternative compounds which are effective against tumor cells but reduce toxicity against nontumor ones is of great importance in the progress or development of cancer treatments. In this sense, scientific knowledge about relevant aspects of nutrition intimately involved in the development and progression of cancer progresses rapidly. Phytochemicals, considered as bioactive ingredients present in plant products, have shown promising effects as potential therapeutic/preventive agents on cancer in severalin vitroandin vivoassays. However, despite their bioactive properties, phytochemicals are still not commonly used in clinical practice due to several reasons, mainly attributed to their poor bioavailability. In this sense, new formulation strategies are proposed as carriers to improve their bioefficacy, highlighting the use of lipid-based delivery systems. Here, we review the potential antitumoral activity of the bioactive compounds derived from plants and the current studies carried out in animal and human models. Furthermore, their association with lipids as a formulation strategy to enhance their efficacyin vivois also reported. The development of high effective bioactive supplements for cancer treatment based on the improvement of their bioavailability goes through this association.

scholarly journals Antioxidant Properties of Ergosterol and Its Role in Yeast Resistance to Oxidation

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1024
Author(s):  
Sebastien Dupont ◽  
Paul Fleurat-Lessard ◽  
Richtier Gonçalves Cruz ◽  
Céline Lafarge ◽  
Cédric Grangeteau ◽  
...  
Keyword(s):  
Computational Study ◽  
Antioxidant Properties ◽  
Beneficial Effects ◽  
Tert Butyl Hydroperoxide ◽  
Resistance To Oxidation ◽  
Specific Accumulation ◽  
The Subject

Although the functions and structural roles of sterols have been the subject of numerous studies, the reasons for the diversity of sterols in the different eukaryotic kingdoms remain unclear. It is thought that the specificity of sterols is linked to unidentified supplementary functions that could enable organisms to be better adapted to their environment. Ergosterol is accumulated by late branching fungi that encounter oxidative perturbations in their interfacial habitats. Here, we investigated the antioxidant properties of ergosterol using in vivo, in vitro, and in silico approaches. The results showed that ergosterol is involved in yeast resistance to tert-butyl hydroperoxide and protects lipids against oxidation in liposomes. A computational study based on quantum chemistry revealed that this protection could be related to its antioxidant properties operating through an electron transfer followed by a proton transfer mechanism. This study demonstrates the antioxidant role of ergosterol and proposes knowledge elements to explain the specific accumulation of this sterol in late branching fungi. Ergosterol, as a natural antioxidant molecule, could also play a role in the incompletely understood beneficial effects of some mushrooms on health.

scholarly journals Therapeutic Application of Brain-Specific Angiogenesis Inhibitor 1 for Cancer Therapy

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3562
Author(s):  
Mitra Nair ◽  
Chelsea Bolyard ◽  
Tae Jin Lee ◽  
Balveen Kaur ◽  
Ji Young Yoo
Keyword(s):  
Angiogenesis Inhibitor ◽  
Suppressor Gene ◽  
Chemotherapeutic Agents ◽  
Tumor Models ◽  
In Vivo Models ◽  
Herpes Simplex Viruses ◽  
Multiple Tumor ◽  
And Function

Brain-specific angiogenesis inhibitor 1 (BAI1/ADGRB1) is an adhesion G protein-coupled receptor that has been found to play key roles in phagocytosis, inflammation, synaptogenesis, the inhibition of angiogenesis, and myoblast fusion. As the name suggests, it is primarily expressed in the brain, with a high expression in the normal adult and developing brain. Additionally, its expression is reduced in brain cancers, such as glioblastoma (GBM) and peripheral cancers, suggesting that BAI1 is a tumor suppressor gene. Several investigators have demonstrated that the restoration of BAI1 expression in cancer cells results in reduced tumor growth and angiogenesis. Its expression has also been shown to be inversely correlated with tumor progression, neovascularization, and peri-tumoral brain edema. One method of restoring BAI1 expression is by using oncolytic virus (OV) therapy, a strategy which has been tested in various tumor models. Oncolytic herpes simplex viruses engineered to express the secreted fragment of BAI1, called Vasculostatin (Vstat120), have shown potent anti-tumor and anti-angiogenic effects in multiple tumor models. Combining Vstat120-expressing oHSVs with other chemotherapeutic agents has also shown to increase the overall anti-tumor efficacy in both in vitro and in vivo models. In the current review, we describe the structure and function of BAI1 and summarize its application in the context of cancer treatment.

scholarly journals Histone methyltransferase WHSC1 inhibits colorectal cancer cell apoptosis via targeting anti-apoptotic BCL2

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yu Wang ◽  
Liming Zhu ◽  
Mei Guo ◽  
Gang Sun ◽  
Kun Zhou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cell ◽  
Cell Apoptosis ◽  
B Cell Lymphoma ◽  
Histone Methyltransferase ◽  
Chemotherapeutic Agents ◽  
Cancer Cell Apoptosis ◽  
Active Transcription

AbstractWHSC1 is a histone methyltransferase that facilitates histone H3 lysine 36 dimethylation (H3K36me2), which is a permissive mark associated with active transcription. In this study, we revealed how WHSC1 regulates tumorigenesis and chemosensitivity of colorectal cancer (CRC). Our data showed that WHSC1 as well as H3K36me2 were highly expressed in clinical CRC samples, and high WHSC1 expression is associated with poorer prognosis in CRC patients. WHSC1 reduction promoted colon cancer cell apoptosis both in vivo and in vitro. We found that B cell lymphoma-2 (BCL2) expression, an anti-apoptotic protein, is markedly decreased in after WHSC1 depletion. Mechanistic characterization indicated that WHSC1 directly binds to the promoter region of BCL2 gene and regulate its H3K36 dimethylation level. What’s more, our study indicated that WHSC1 depletion promotes chemosensitivity in CRC cells. Together, our results suggested that WHSC1 and H3K36me2 modification might be optimal therapeutic targets to disrupt CRC progression and WHSC1-targeted therapy might potentially overcome the resistance of chemotherapeutic agents.

scholarly journals Reduced High-Dose Radiation-Induced Residual Genotoxic Damage by Induction of Radioadaptive Response and Prophylactic Mild Dietary Restriction in Mice

Dose-Response ◽  
2021 ◽  
Vol 19 (1) ◽  
pp. 155932582098216
Author(s):  
Bing Wang ◽  
Kaoru Tanaka ◽  
Takanori Katsube ◽  
Kouichi Maruyama ◽  
Yasuharu Ninomiya ◽  
...  
Keyword(s):  
Dietary Restriction ◽  
High Dose ◽  
Cancer Treatments ◽  
Hematopoietic Stem ◽  
Beneficial Effects ◽  
Radiation Induced ◽  
Potential Strategy ◽  
Higher Doses

Radioadaptive response (RAR) describes a phenomenon in a variety of in vitro and in vivo systems that a low-dose of priming ionizing radiation (IR) reduces detrimental effects of a subsequent challenge IR at higher doses. Among in vivo investigations, studies using the mouse RAR model (Yonezawa Effect) showed that RAR could significantly extenuate high-dose IR-induced detrimental effects such as decrease of hematopoietic stem cells and progenitor cells, acute radiation hematopoietic syndrome, genotoxicity and genomic instability. Meanwhile, it has been demonstrated that diet intervention has a great impact on health, and dietary restriction shows beneficial effects on numerous diseases in animal models. In this work, by using the mouse RAR model and mild dietary restriction (MDR), we confirmed that combination of RAR and MDR could more efficiently reduce radiogenotoxic damage without significant change of the RAR phenotype. These findings suggested that MDR may share some common pathways with RAR to activate mechanisms consequently resulting in suppression of genotoxicity. As MDR could also increase resistance to chemotherapy and radiotherapy in normal cells, we propose that combination of MDR, RAR, and other cancer treatments (i.e., chemotherapy and radiotherapy) represent a potential strategy to increase the treatment efficacy and prevent IR risk in humans.

scholarly journals Characterization and selective inhibition of myristoyl-CoA:protein N-myristoyltransferase from Trypanosoma brucei and Leishmania major

2006 ◽  
Vol 396 (2) ◽  
pp. 277-285 ◽  
Author(s):  
Chrysoula Panethymitaki ◽  
Paul W. Bowyer ◽  
Helen P. Price ◽  
Robin J. Leatherbarrow ◽  
Katherine A. Brown ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Leishmania Major ◽  
Homo Sapiens ◽  
Selective Inhibition ◽  
Fungal Species ◽  
Chemotherapeutic Agents ◽  
Human Pathogens ◽  
Ic50 Values

The eukaryotic enzyme NMT (myristoyl-CoA:protein N-myristoyltransferase) has been characterized in a range of species from Saccharomyces cerevisiae to Homo sapiens. NMT is essential for viability in a number of human pathogens, including the fungi Candida albicans and Cryptococcus neoformans, and the parasitic protozoa Leishmania major and Trypanosoma brucei. We have purified the Leishmania and T. brucei NMTs as active recombinant proteins and carried out kinetic analyses with their essential fatty acid donor, myristoyl-CoA and specific peptide substrates. A number of inhibitory compounds that target NMT in fungal species have been tested against the parasite enzymes in vitro and against live parasites in vivo. Two of these compounds inhibit TbNMT with IC50 values of <1 μM and are also active against mammalian parasite stages, with ED50 (the effective dose that allows 50% cell growth) values of 16–66 μM and low toxicity to murine macrophages. These results suggest that targeting NMT could be a valid approach for the development of chemotherapeutic agents against infectious diseases including African sleeping sickness and Nagana.

scholarly journals DNAJB6b is Downregulated in Synucleinopathies

2021 ◽  
pp. 1-13
Author(s):  
Jonas Folke ◽  
Sertan Arkan ◽  
Isak Martinsson ◽  
Susana Aznar ◽  
Gunnar Gouras ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Substantia Nigra Pars Compacta ◽  
Endogenous Protein ◽  
Highly Sensitive ◽  
Brain Material ◽  
Health And Disease ◽  
Isoform B

Background: α-synuclein (α-syn) aggregation contributes to the progression of multiple neurodegenerative diseases. We recently found that the isoform b of the co-chaperone DNAJB6 is a strong suppressor of a-syn aggregation in vivo and in vitro. However, nothing is known about the role of the endogenous isoform b of DNAJB6 (DNAJB6b) in health and disease, due to lack of specific antibodies. Objective: Here we generated a novel anti-DNAJB6b antibody to analyze the localization and expression this isoform in cells, in tissue and in clinical material. Methods: To address this we used immunocytochemistry, immunohistochemistry, as well as a novel quantitative DNAJB6 specific ELISA method. Results: The endogenous protein is mainly expressed in the cytoplasm and in neurites in vitro, where it is found more in dendrites than in axons. We further verified in vivo that DNAJB6b is expressed in the dopaminergic neurons of the substantia nigra pars compacta (SNpc), which is a neuronal subpopulation highly sensitive to α-syn aggregation, that degenerate to a large extend in patients with Parkinson’s disease (PD) and multiple system atrophy (MSA). When we analyzed the expression levels of DNAJB6b in brain material from PD and MSA patients, we found a downregulation of DNAJB6b by use of ELISA based quantification. Interestingly, this was also true when analyzing tissue from patients with progressive supranuclear palsy, a taupathic atypical parkinsonian disorder. However, the total level of DNAJB6 was upregulated in these three diseases, which may indicate an upregulation of the other major isoform of DNAJB6, DNAJB6a. Conclusion: This study shows that DNAJB6b is downregulated in several different neurodegenerative diseases, which makes it an interesting target to further investigate in relation to amyloid protein aggregation and disease progression.

scholarly journals Characterization of Iron Core–Gold Shell Nanoparticles for Anti-Cancer Treatments: Chemical and Structural Transformations During Storage and Use

Materials ◽  
2018 ◽  
Vol 11 (12) ◽  
pp. 2572 ◽  
Author(s):  
Ya-Na Wu ◽  
Dar-Bin Shieh ◽  
Li-Xing Yang ◽  
Hwo-Shuenn Sheu ◽  
Rongkun Thordarson ◽  
...  
Keyword(s):  
Au Nanoparticles ◽  
Iron Core ◽  
Cancer Treatments ◽  
Shell Nanoparticles ◽  
X Ray ◽  
Anti Cancer ◽  
One Year ◽  
Means Of Transmission

Finding a cancer-selective drug that avoids damaging healthy cells and organs is a holy grail in medical research. In our previous studies, gold-coated iron (Fe@Au) nanoparticles showed cancer selective anti-cancer properties in vitro and in vivo but were found to gradually lose that activity with storage or "ageing.” To determine the reasons for this diminished anti-cancer activity, we examined Fe@Au nanoparticles at different preparation and storage stages by means of transmission electron microscopy combined with and energy-dispersive X-ray spectroscopy, along with X-ray diffraction analysis and cell viability tests. We found that dried and reconstituted Fe@Au nanoparticles, or Fe@Au nanoparticles within cells, decompose into irregular fragments of γ-F2O3 and agglomerated gold clumps. These changes cause the loss of the particles’ anti-cancer effects. However, we identified that the anti-cancer properties of Fe@Au nanoparticles can be well preserved under argon or, better still, liquid nitrogen storage for six months and at least one year, respectively.

scholarly journals Nuclear factor-kB in thyroid carcinogenesis and progression: a novel therapeutic target for advanced thyroid cancer

2007 ◽  
Vol 51 (5) ◽  
pp. 843-851 ◽  
Author(s):  
Hiroyuki Namba ◽  
Vladimir Saenko ◽  
Shunichi Yamashita
Keyword(s):  
Thyroid Cancer ◽  
Transcriptional Activation ◽  
Chemotherapeutic Agents ◽  
Important Change ◽  
Jnk Pathway ◽  
In Vivo Experiments ◽  
Advanced Thyroid Cancer ◽  
Nf Kappab

Apoptosis is an essential physiological process of elimination of destined cells during the development and differentiation or after damage from external stresses such as ionizing radiation or chemotherapeutic agents. Disruption of apoptosis is proved to cause various diseases including cancer. Among numerous molecules involved in diverse anti- or pro-apoptotic signaling pathways, NF-kappaB is one of the key factors controlling anti-apoptotic responses. Its anti-apoptotic effect is thought to be mediated through not only transcriptional activation of dependent genes but also by crosstalking with the JNK pathway. Oncogenic proteins such as Ret/PTC, Ras and BRAF can induce NF-kappaB activation making it an important change in thyroid cancer. A number of specific or non-specific NF-kappaB inhibitors have been tried to take over the cascade in in vitro and in vivo experiments. These agents can induce massive apoptosis especially in combination with radio- or chemotherapy. Current results suggest that the inhibition of the NF-kappaB may be a promising strategy for advanced thyroid cancer treatment but further investigations are warranted to develop specific and clinically effective NF-kappaB inhibitors in future.

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