Microtubules: A dynamic target in cancer therapy

Pasquier, Eddy; Kavallaris, Maria

doi:10.1002/iub.25

Cited by 175 publications

(135 citation statements)

References 29 publications

Supporting

Mentioning

129

Contrasting

Unclassified

Order By: Relevance

“…[38][39][40][41][42][43][44] Microtubules are formed via a dynamic process of polymerization and depolymerization of Scheme 2. Synthesis of piperlongumine analogues 2-6.…”

Section: Tubulin Polymerization Assaymentioning

confidence: 99%

Synthetic Analogue of the Natural Product Piperlongumine as a Potent Inhibitor of Breast Cancer Cell Line Migration

Valli¹,

Altei²,

Santos³

et al. 2017

J. Braz. Chem. Soc.

View full text Add to dashboard Cite

Piperlongumine is a natural amide alkaloid isolated from several species of Piper and is described in the literature as selectively cytotoxic to several cancer cell lines. Inhibiting cell migration has gained considerable interest as an approach for discovering antimetastatic agents because this process is fundamental to metastasis. Piperlongumine, selected from cell-based assay screening of NuBBE Database, inhibited the migration of MDA-MB-231 breast cancer cells with an EC 50 of 3.0 ± 1.0 µM by the Boyden chamber assay. A series of five analogous compounds based on the structure of piperlongumine were designed, synthesized and evaluated in cell migration and cytotoxicity assays. The analogue designed by molecular simplification ((E)-N-acryloyl-3-(3,4,5-trimethoxyphenyl)acrylamide) was the most active of the series, with an EC 50 of 1.5 ± 1 µM. Additionally, this compound was selectively cytotoxic, with a selectivity index (SI) of 4.4. Keywords: piperlongumine, piplartine, piperamide, cytotoxicity, cell migration inhibition IntroductionMetastasis is the process by which undifferentiated cancer cells migrate to other parts of the body.1,2 Suppression of metastasis is an urgent need in cancer treatment, as most existing drugs only inhibit cell proliferation.3 Traditionally, chemotherapy is based on cytotoxic therapeutic agents that inhibit proliferation and cause cell death. However, the strategy of inhibiting cell migration has recently gained considerable interest. 4 Several compounds that inhibit the process of metastasis have been described to date. 5,6 Paclitaxel, which was originally discovered as an antimitotic agent that disrupts the cell cycle in cancer cells by stabilizing microtubules, exhibits marked and selective inhibition of tumor cell migration. 7As extensively reviewed elsewhere, biodiversity in nature has provided unique chemical scaffolds that have been used as templates for medicinal chemistry and drug discovery. [8][9][10][11][12][13] The availability of natural compound libraries is of significant importance for integrating natural products and medicinal chemistry, especially for the identification of new bioactive agents and the rational design of compounds in drug discovery.14 Within this context, we selected the natural product piperlongumine (1), also known as piplartine, from cell-based assay screening of NuBBE Database (NuBBE DB ) 15 and evaluated its ability to inhibit Synthetic Analogue of the Natural Product Piperlongumine as a Potent Inhibitor of Breast Cancer Cell Line Migration J. Braz. Chem. Soc. 476 cancer cell migration using biological and target-based experiments.Piperlongumine (1, Figure 1) is an alkamide isolated from several species of Piper (Piperaceae). 16 It is described as possessing antifungal properties, 17 cytotoxicity toward several cancer cell lines, 18,19 and trypanocidal effects, 20 as well as other biological activities. 21 Furthermore, piperlongumine selectively induces cell death in cancer cells but does not reduce viability in normal cells. 22This ...

show abstract

“…[38][39][40][41][42][43][44] Microtubules are formed via a dynamic process of polymerization and depolymerization of Scheme 2. Synthesis of piperlongumine analogues 2-6.…”

Section: Tubulin Polymerization Assaymentioning

confidence: 99%

Synthetic Analogue of the Natural Product Piperlongumine as a Potent Inhibitor of Breast Cancer Cell Line Migration

Valli¹,

Altei²,

Santos³

et al. 2017

J. Braz. Chem. Soc.

View full text Add to dashboard Cite

show abstract

“…Dysfunction in cellular shape can cause subsequent vascular hyperpermeability [22] . The cytoskeleton consists of three distinct components: microtubules, actin microfilaments and intermediate filaments [23] , and the former two are associated via linking proteins, which, in turn, interact with these two cytoskeletal components for signaling [24] . As the scaffolding of the cell, the cytoskeleton plays a vital role in cell motility, division, shape maintenance, and signal transduction [24] .…”

Section: Role Of Cytoskeleton In the Regulation Of Endothelial Barriementioning

confidence: 99%

Multiparametric MRI biomarkers for measuring vascular disrupting effect on cancer

Marchal¹,

2011

WJR

View full text Add to dashboard Cite

Solid malignancies have to develop their own blood supply for their aggressive growth and metastasis; a process known as tumor angiogenesis. Angiogenesis is largely involved in tumor survival, progression and spread, which are known to be significantly attributed to treatment failures. Over the past decades, efforts have been made to understand the difference between normal and tumor vessels. It has been demonstrated that tumor vasculature is structurally immature with chaotic and leaky phenotypes, which provides opportunities for developing novel anticancer strategies. Targeting tumor vasculature is not only a unique therapeutic intervention to starve neoplastic cells, but also enhances the efficacy of conventional cancer treatments. Vascular disrupting agents (VDAs) have been developed to disrupt the already existing neovasculature in actively growing tumors, cause catastrophic vascular shutdown within short time, and induce secondary tumor necrosis. VDAs are cytostatic; they can only inhibit tumor growth, but not eradicate the tumor. This novel drug mechanism has urged us to develop multiparametric imaging biomarkers to monitor early hemodynamic alterations, cellular dysfunctions and metabolic impairments before tumor dimensional changes can be detected. In this article, we review the characteristics of tumor vessels, tubulindestabilizing mechanisms of VDAs, and in vivo effects of the VDAs that have been mostly studied in preclinical studies and clinical trials. We also compare the different tumor models adopted in the preclinical studies on VDAs. Multiparametric imaging biomarkers, mainly diffusion-weighted imaging and dynamic contrast-enhanced imaging from magnetic resonance imaging, are evaluated for their potential as morphological and functional imaging biomarkers for monitoring therapeutic effects of VDAs.

show abstract

“…The cytotoxic activities of microtubule-targeted agents results from a sustained activation of the spindle assembly checkpoint (33). Vinca alkaloids (e.g., vincristine, vinblastine, etc.)…”

Section: Combination Of Sns-314 With Spindle Toxins Compromises the Smentioning

confidence: 99%

The Aurora kinase inhibitor SNS-314 shows broad therapeutic potential with chemotherapeutics and synergy with microtubule-targeted agents in a colon carcinoma model

VanderPorten

Taverna

Hogan

et al. 2009

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Aurora kinases play key roles in regulating centrosome maturation, mitotic spindle formation, and cytokinesis during cell division, and are considered promising drug targets due to their frequent overexpression in a variety of human cancers. SNS-314 is a selective and potent pan Aurora inhibitor currently in a dose escalation phase 1 clinical trial for the treatment of patients with advanced solid tumors. Here, we report the antiproliferative effects of SNS-314 in combination with common chemotherapeutics in cell culture and xenograft models. The HCT116 colorectal carcinoma cell line, with intact or depleted p53 protein levels, was treated with SNS-314 and a cytotoxic chemotherapeutic from a panel comprised of gemcitabine, 5-fluorouracil (5-FU), carboplatin, daunomycin, SN-38 (the active metabolite of irinotecan), docetaxel, and vincristine. Combinations were administered under either concurrent or sequential schedules. SNS-314 has predominantly additive effects when administered concurrently with commonly used anticancer agents. Sequential administration of SNS-314 with chemotherapeutic compounds showed additive antiproliferative effects with carboplatin, gemcitabine, 5-FU, daunomycin, and SN-38, and synergy was observed in combination with gemcitabine, docetaxel, or vincristine. The most profound antiproliferative effects were observed with sequential administration of SNS-314 followed by docetaxel or vincristine. In vivo, SNS-314 potentiated the antitumor activity of docetaxel in xenografts. Both the in vitro synergies observed between SNS-314 and agents that target the mitotic spindle and the potentiation seen with docetaxel in vivo are consistent with a mechanism of action in which Aurora inhibition bypasses the mitotic spindle assembly checkpoint and prevents cytokinesis, augmenting subsequent spindle toxinmediated mitotic catastrophe and cell death. [Mol Cancer Ther 2009;8(4):930-9]

show abstract

Microtubules: A dynamic target in cancer therapy

Cited by 175 publications

References 29 publications

Synthetic Analogue of the Natural Product Piperlongumine as a Potent Inhibitor of Breast Cancer Cell Line Migration

Synthetic Analogue of the Natural Product Piperlongumine as a Potent Inhibitor of Breast Cancer Cell Line Migration

Multiparametric MRI biomarkers for measuring vascular disrupting effect on cancer

The Aurora kinase inhibitor SNS-314 shows broad therapeutic potential with chemotherapeutics and synergy with microtubule-targeted agents in a colon carcinoma model

Contact Info

Product

Resources

About