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Article ; Online: Efficacy of a Covalent Microtubule Stabilizer in Taxane-Resistant Ovarian Cancer Models.

Yee, Samantha S / Risinger, April L

2021 Volume 26, Issue 13

Abstract: Ovarian cancer often has a poor clinical prognosis because of late detection, frequently after metastatic progression, as well as acquired resistance to taxane-based therapy. Herein, we evaluate a novel class of covalent microtubule stabilizers, the C-22, ...

Abstract	Ovarian cancer often has a poor clinical prognosis because of late detection, frequently after metastatic progression, as well as acquired resistance to taxane-based therapy. Herein, we evaluate a novel class of covalent microtubule stabilizers, the C-22,23-epoxytaccalonolides, for their efficacy against taxane-resistant ovarian cancer models in vitro and in vivo. Taccalonolide AF, which covalently binds β-tubulin through its C-22,23-epoxide moiety, demonstrates efficacy against taxane-resistant models and shows superior persistence in clonogenic assays after drug washout due to irreversible target engagement. In vivo, intraperitoneal administration of taccalonolide AF demonstrated efficacy against the taxane-resistant NCI/ADR-RES ovarian cancer model both as a flank xenograft, as well as in a disseminated orthotopic disease model representing localized metastasis. Taccalonolide-treated animals had a significant decrease in micrometastasis of NCI/ADR-RES cells to the spleen, as detected by quantitative RT-PCR, without any evidence of systemic toxicity. Together, these findings demonstrate that taccalonolide AF retains efficacy in taxane-resistant ovarian cancer models in vitro and in vivo and that its irreversible mechanism of microtubule stabilization has the unique potential for intraperitoneal treatment of locally disseminated taxane-resistant disease, which represents a significant unmet clinical need in the treatment of ovarian cancer patients.
MeSH term(s)	Animals ; Apoptosis ; Bridged-Ring Compounds/pharmacology ; Cell Proliferation ; Drug Resistance, Neoplasm/drug effects ; Female ; Humans ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Microtubules/drug effects ; Neoplasm Micrometastasis ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/metabolism ; Ovarian Neoplasms/pathology ; Steroids/pharmacology ; Taxoids/pharmacology ; Tubulin Modulators/pharmacology ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays
Chemical Substances	Bridged-Ring Compounds ; Steroids ; Taxoids ; Tubulin Modulators ; taccalonolide AF ; taxane (1605-68-1)
Language	English
Publishing date	2021-07-03
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules26134077
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Article: Targeting and extending the eukaryotic druggable genome with natural products: cytoskeletal targets of natural products

Risinger, April L. / Du, Lin

Natural product reports. 2020 May 27, v. 37, no. 5

2020

Abstract: We review recent progress on natural products that target cytoskeletal components, including microtubules, actin, intermediate filaments, and septins and highlight their demonstrated and potential utility in the treatment of human disease. The anticancer ...

Abstract	We review recent progress on natural products that target cytoskeletal components, including microtubules, actin, intermediate filaments, and septins and highlight their demonstrated and potential utility in the treatment of human disease. The anticancer efficacy of microtubule targeted agents identified from plants, microbes, and marine organisms is well documented. We highlight new microtubule targeted agents currently in clinical evaluations for the treatment of drug resistant cancers and the accumulating evidence that the anticancer efficacy of these agents is not solely due to their antimitotic effects. Indeed, the effects of microtubule targeted agents on interphase microtubules are leading to their potential for more mechanistically guided use in cancers as well as neurological disease. The discussion of these agents as more targeted drugs also prompts a reevaluation of our thinking about natural products that target other components of the cytoskeleton. For instance, actin active natural products are largely considered chemical probes and non-selective toxins. However, studies utilizing these probes have uncovered aspects of actin biology that can be more specifically targeted to potentially treat cancer, neurological disorders, and infectious disease. Compounds that target intermediate filaments and septins are understudied, but their continued discovery and mechanistic evaluations have implications for numerous therapeutic indications.
Keywords	actin ; antimitotic agents ; drug resistance ; genome ; human diseases ; infectious diseases ; interphase ; microtubules ; nervous system diseases ; therapeutics
Language	English
Dates of publication	2020-0527
Size	p. 634-652.
Publishing place	The Royal Society of Chemistry
Document type	Article
ZDB-ID	2002546-4
ISSN	1460-4752 ; 0265-0568
ISSN (online)	1460-4752
ISSN	0265-0568
DOI	10.1039/c9np00053d
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Taccalonolide C-6 Analogues, Including Paclitaxel Hybrids, Demonstrate Improved Microtubule Polymerizing Activities.

Risinger, April L / Hastings, Shayne D / Du, Lin

Journal of natural products

2021 Volume 84, Issue 6, Page(s) 1799–1805

Abstract: The C-22,23-epoxy taccalonolides are microtubule stabilizers that bind covalently to β-tubulin with a high degree of specificity. We semisynthesized and performed biochemical and cellular evaluations on 20 taccalonolide analogues designed to improve ... ...

Abstract	The C-22,23-epoxy taccalonolides are microtubule stabilizers that bind covalently to β-tubulin with a high degree of specificity. We semisynthesized and performed biochemical and cellular evaluations on 20 taccalonolide analogues designed to improve target engagement. Most notably, modification of C-6 on the taccalonolide backbone with the C-13
MeSH term(s)	HeLa Cells ; Humans ; Molecular Docking Simulation ; Molecular Structure ; Paclitaxel/analogs & derivatives ; Steroids/pharmacology ; Structure-Activity Relationship ; Tubulin ; Tubulin Modulators/pharmacology
Chemical Substances	Steroids ; Tubulin ; Tubulin Modulators ; Paclitaxel (P88XT4IS4D)
Language	English
Publishing date	2021-06-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	304325-3
ISSN	1520-6025 ; 0163-3864
ISSN (online)	1520-6025
ISSN	0163-3864
DOI	10.1021/acs.jnatprod.1c00211
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Article ; Online: Targeting and extending the eukaryotic druggable genome with natural products: cytoskeletal targets of natural products.

Risinger, April L / Du, Lin

Natural product reports

2019 Volume 37, Issue 5, Page(s) 634–652

Abstract: Covering: 2014-2019We review recent progress on natural products that target cytoskeletal components, including microtubules, actin, intermediate filaments, and septins and highlight their demonstrated and potential utility in the treatment of human ... ...

Abstract	Covering: 2014-2019We review recent progress on natural products that target cytoskeletal components, including microtubules, actin, intermediate filaments, and septins and highlight their demonstrated and potential utility in the treatment of human disease. The anticancer efficacy of microtubule targeted agents identified from plants, microbes, and marine organisms is well documented. We highlight new microtubule targeted agents currently in clinical evaluations for the treatment of drug resistant cancers and the accumulating evidence that the anticancer efficacy of these agents is not solely due to their antimitotic effects. Indeed, the effects of microtubule targeted agents on interphase microtubules are leading to their potential for more mechanistically guided use in cancers as well as neurological disease. The discussion of these agents as more targeted drugs also prompts a reevaluation of our thinking about natural products that target other components of the cytoskeleton. For instance, actin active natural products are largely considered chemical probes and non-selective toxins. However, studies utilizing these probes have uncovered aspects of actin biology that can be more specifically targeted to potentially treat cancer, neurological disorders, and infectious disease. Compounds that target intermediate filaments and septins are understudied, but their continued discovery and mechanistic evaluations have implications for numerous therapeutic indications.
MeSH term(s)	Actins/metabolism ; Animals ; Biological Products/chemistry ; Biological Products/pharmacology ; Colchicine/chemistry ; Colchicine/metabolism ; Colchicine/pharmacology ; Cytoskeleton/drug effects ; Cytoskeleton/metabolism ; Drug Resistance, Neoplasm/drug effects ; Eukaryotic Cells/cytology ; Eukaryotic Cells/drug effects ; Genome ; Humans ; Maytansine/chemistry ; Maytansine/metabolism ; Maytansine/pharmacology ; Microtubules/drug effects ; Microtubules/metabolism ; Neoplasms/drug therapy ; Neoplasms/genetics ; Nervous System Diseases/drug therapy ; Nervous System Diseases/pathology ; Taxoids/chemistry ; Taxoids/pharmacology
Chemical Substances	Actins ; Biological Products ; Taxoids ; Maytansine (14083FR882) ; Colchicine (SML2Y3J35T)
Language	English
Publishing date	2019-11-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2002546-4
ISSN	1460-4752 ; 0265-0568
ISSN (online)	1460-4752
ISSN	0265-0568
DOI	10.1039/c9np00053d
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Taccalonolide C-6 Analogues, Including Paclitaxel Hybrids, Demonstrate Improved Microtubule Polymerizing Activities

Risinger, April L. / Hastings, Shayne D. / Du, Lin

Journal of natural products. 2021 June 10, v. 84, no. 6

2021

Abstract	The C-22,23-epoxy taccalonolides are microtubule stabilizers that bind covalently to β-tubulin with a high degree of specificity. We semisynthesized and performed biochemical and cellular evaluations on 20 taccalonolide analogues designed to improve target engagement. Most notably, modification of C-6 on the taccalonolide backbone with the C-13 N-acyl-β-phenylisoserine side chain of paclitaxel provided compounds with 10-fold improved potency for biochemical tubulin polymerization as compared to that of the unmodified epoxy taccalonolide AJ. Covalent docking demonstrated that the C-13 paclitaxel side chain occupied a binding pocket adjacent to the core taccalonolide pocket near the M-loop of β-tubulin. Although paclitaxel-taccalonolide hybrids demonstrated improved in vitro biochemical potency, they retained features of the taccalonolide chemotype, including a lag in tubulin polymerization and high degree of cellular persistence after drug washout associated with covalent binding. Together, these data demonstrate that C-6 modifications can improve the target engagement of this covalent class of microtubule drugs without substantively changing their mechanism of action.
Keywords	chemical bonding ; chemotypes ; drugs ; epoxides ; mechanism of action ; microtubules ; paclitaxel ; polymerization ; tubulin
Language	English
Dates of publication	2021-0610
Size	p. 1799-1805.
Publishing place	American Chemical Society and American Society of Pharmacognosy
Document type	Article
ZDB-ID	304325-3
ISSN	1520-6025 ; 0163-3864
ISSN (online)	1520-6025
ISSN	0163-3864
DOI	10.1021/acs.jnatprod.1c00211
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Correction: Eribulin rapidly inhibits TGF-β-induced Snail expression and can induce Slug expression in a Smad4-dependent manner.

Kaul, Roma / Risinger, April L / Mooberry, Susan L

British journal of cancer

2020 Volume 124, Issue 4, Page(s) 855

Language	English
Publishing date	2020-10-15
Publishing country	England
Document type	Published Erratum
ZDB-ID	80075-2
ISSN	1532-1827 ; 0007-0920
ISSN (online)	1532-1827
ISSN	0007-0920
DOI	10.1038/s41416-020-01115-w
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Article ; Online: Efficacy of a Covalent Microtubule Stabilizer in Taxane-Resistant Ovarian Cancer Models

Samantha S. Yee / April L. Risinger

Molecules, Vol 26, Iss 4077, p

2021 Volume 4077

Abstract	Ovarian cancer often has a poor clinical prognosis because of late detection, frequently after metastatic progression, as well as acquired resistance to taxane-based therapy. Herein, we evaluate a novel class of covalent microtubule stabilizers, the C-22,23-epoxytaccalonolides, for their efficacy against taxane-resistant ovarian cancer models in vitro and in vivo. Taccalonolide AF, which covalently binds β-tubulin through its C-22,23-epoxide moiety, demonstrates efficacy against taxane-resistant models and shows superior persistence in clonogenic assays after drug washout due to irreversible target engagement. In vivo, intraperitoneal administration of taccalonolide AF demonstrated efficacy against the taxane-resistant NCI/ADR-RES ovarian cancer model both as a flank xenograft, as well as in a disseminated orthotopic disease model representing localized metastasis. Taccalonolide-treated animals had a significant decrease in micrometastasis of NCI/ADR-RES cells to the spleen, as detected by quantitative RT-PCR, without any evidence of systemic toxicity. Together, these findings demonstrate that taccalonolide AF retains efficacy in taxane-resistant ovarian cancer models in vitro and in vivo and that its irreversible mechanism of microtubule stabilization has the unique potential for intraperitoneal treatment of locally disseminated taxane-resistant disease, which represents a significant unmet clinical need in the treatment of ovarian cancer patients.
Keywords	microtubule stabilizers ; taxanes ; drug resistance ; natural products ; ovarian cancer ; metastasis ; Organic chemistry ; QD241-441
Subject code	616 ; 610
Language	English
Publishing date	2021-07-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Taccalonolide Microtubule Stabilizers.

Yee, Samantha S / Du, Lin / Risinger, April L

Progress in the chemistry of organic natural products

2020 Volume 112, Page(s) 183–206

Abstract: Microtubule stabilizers are a mainstay in the treatment of many solid cancers and continue to find utility in combination therapy with molecularly targeted anticancer agents and immunotherapeutics. However, innate and acquired resistance to microtubule ... ...

Abstract	Microtubule stabilizers are a mainstay in the treatment of many solid cancers and continue to find utility in combination therapy with molecularly targeted anticancer agents and immunotherapeutics. However, innate and acquired resistance to microtubule stabilizers can limit their clinical efficacy. The taccalonolides are a unique class of microtubule stabilizers isolated from plants of Tacca that circumvent clinically relevant mechanisms of drug resistance. Although initial reports suggested that the microtubule-stabilizing activity of the taccalonolides was independent of direct tubulin binding, additional studies have identified that potent C-22, C-23 epoxidized taccalonolides covalently bind the Aspartate 226 residue of β-tubulin and that this interaction is critical for their microtubule-stabilizing activity. The taccalonolides have distinct properties as compared to other microtubule stabilizers with regard to their biochemical effects on tubulin structure and dynamics that promote distinct cellular phenotypes. Some taccalonolides have demonstrated in vivo antitumor efficacy in drug-resistant tumor models with exquisite potency and long-lasting antitumor efficacy as a result of their irreversible target engagement. The recent identification of a site on the taccalonolide scaffold that is amenable to modification has provided evidence of the specificity of the taccalonolide-tubulin interaction. This also affords an opportunity to further optimize the targeted delivery of the taccalonolides to further improve their anticancer efficacy and potential for clinical development.
MeSH term(s)	Dioscoreaceae/chemistry ; Dioscoreaceae/metabolism ; Microtubules/drug effects ; Steroids/chemistry ; Steroids/pharmacology ; Structure-Activity Relationship ; Tubulin/metabolism
Chemical Substances	Steroids ; Tubulin
Language	English
Publishing date	2020-12-11
Publishing country	Austria
Document type	Journal Article ; Review
ISSN	2191-7043
ISSN	2191-7043
DOI	10.1007/978-3-030-52966-6_3
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Article ; Online: In Vivo Evaluation of (-)-Zampanolide Demonstrates Potent and Persistent Antitumor Efficacy When Targeted to the Tumor Site.

Takahashi-Ruiz, Leila / Morris, Joseph D / Crews, Phillip / Johnson, Tyler A / Risinger, April L

Molecules (Basel, Switzerland)

2022 Volume 27, Issue 13

Abstract: Microtubule-stabilizing agents (MSAs) are a class of compounds used in the treatment of triple-negative breast cancer (TNBC), a subtype of breast cancer where chemotherapy remains the standard-of-care for patients. Taxanes like paclitaxel and docetaxel ... ...

Abstract	Microtubule-stabilizing agents (MSAs) are a class of compounds used in the treatment of triple-negative breast cancer (TNBC), a subtype of breast cancer where chemotherapy remains the standard-of-care for patients. Taxanes like paclitaxel and docetaxel have demonstrated efficacy against TNBC in the clinic, however new classes of MSAs need to be identified due to the rise of taxane resistance in patients. (-)-Zampanolide is a covalent microtubule stabilizer that can circumvent taxane resistance in vitro but has not been evaluated for in vivo antitumor efficacy. Here, we determine that (-)-zampanolide has similar potency and efficacy to paclitaxel in TNBC cell lines, but is significantly more persistent due to its covalent binding. We also provide the first reported in vivo antitumor evaluation of (-)-zampanolide where we determine that it has potent and persistent antitumor efficacy when delivered intratumorally. Future work on zampanolide to further evaluate its pharmacophore and determine ways to improve its systemic therapeutic window would make this compound a potential candidate for clinical development through its ability to circumvent taxane-resistance mechanisms.
MeSH term(s)	Antineoplastic Agents/chemistry ; Cell Line, Tumor ; Humans ; Macrolides/chemistry ; Microtubules/metabolism ; Paclitaxel/chemistry ; Triple Negative Breast Neoplasms/drug therapy ; Triple Negative Breast Neoplasms/metabolism
Chemical Substances	Antineoplastic Agents ; Macrolides ; zampanolide ; Paclitaxel (P88XT4IS4D)
Language	English
Publishing date	2022-07-01
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules27134244
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Article ; Online: Microtubule-Targeting Drugs: More than Antimitotics.

Kaul, Roma / Risinger, April L / Mooberry, Susan L

Journal of natural products

2019 Volume 82, Issue 3, Page(s) 680–685

Abstract: Nature has yielded numerous compounds that bind to tubulin/microtubules and disrupt microtubule function. Even with the advent of targeted therapies for cancer, natural products and their derivatives that target microtubules are some of the most ... ...

Abstract	Nature has yielded numerous compounds that bind to tubulin/microtubules and disrupt microtubule function. Even with the advent of targeted therapies for cancer, natural products and their derivatives that target microtubules are some of the most effective drugs used in the treatment of solid tumors and hematological malignancies. For decades, these drugs were thought to work solely through their ability to inhibit mitosis. Accumulating evidence demonstrates that their actions are much more complex, in that they also have significant effects on microtubules in nondividing cells that inhibit a diverse range of signaling events important for carcinogenesis. The abilities of these drugs to inhibit oncogenic signaling likely underlies their efficacy, especially in solid tumors. In this review, we describe the role of microtubules in cells, the proliferation paradox of cells in culture as compared to cancers in patients, and evidence that microtubule-targeting drugs inhibit cellular signaling pathways important for tumorigenesis. The potential mechanisms behind differences in the clinical indications and efficacy of these natural-product-derived drugs are also discussed. Microtubules are an important target for structurally diverse natural products, and a fuller understanding of the mechanisms of action of these drugs will promote their optimal use.
MeSH term(s)	Antimitotic Agents/pharmacology ; Antineoplastic Agents/pharmacology ; Biological Products/pharmacology ; Humans ; Microtubules/drug effects ; Mitosis/drug effects ; Molecular Structure
Chemical Substances	Antimitotic Agents ; Antineoplastic Agents ; Biological Products
Language	English
Publishing date	2019-03-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	304325-3
ISSN	1520-6025 ; 0163-3864
ISSN (online)	1520-6025
ISSN	0163-3864
DOI	10.1021/acs.jnatprod.9b00105
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