Re-Use of Established Drugs for Anti-Metastatic Indications

Entschladen, Frank; D, Thyssen; Drell, David W.

doi:10.3390/cells5010002

Cited by 7 publications

(6 citation statements)

References 44 publications

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“…Conversely, paclitaxel at small doses did not affect cell viability or cytoskeletal integrity, but strongly reduced the nuclear import of S100A4 (through inhibition of its SUMOylation) and, more importantly, the invasive properties of CCA cells 101 . If confirmed in clinical studies, these observations may suggest the use of low-dose paclitaxel as an adjuvant therapy to prevent the metastatic spread of CCA after surgery, an exemplary case of drug repositioning 187 .…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 73%

Molecular Mechanisms Driving Cholangiocarcinoma Invasiveness: An Overview

et al. 2018

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The acquisition of invasive functions by tumor cells is a first and crucial step towards the development of metastasis, which nowadays represents the main cause of cancer-related death. Cholangiocarcinoma (CCA), a primary liver cancer originating from the biliary epithelium, typically develops intrahepatic or lymph node metastases at early stages, thus preventing the majority of patients from undergoing curative treatments, consistent with their very poor prognosis. As in most carcinomas, CCA cells gradually adopt a motile, mesenchymal-like phenotype, enabling them to cross the basement membrane, detach from the primary tumor, and invade the surrounding stroma. Unfortunately, little is known about the molecular mechanisms that synergistically orchestrate this pro-invasive phenotypic switch. Autocrine and paracrine signals (cyto/chemokines, growth factors, morphogens) permeating the tumor microenvironment undoubtedly play a prominent role in this context. Moreover, a number of recently identified signaling systems are currently drawing attention as putative mechanistic determinants of CCA cell invasion. They encompass transcription factors, protein kinases and phosphatases, ubiquitin ligases, adaptor proteins, and miRNAs, whose aberrant expression may result from either stochastic mutations or the abnormal activation of upstream pro-oncogenic pathways. Herein, we sought to summarize the most relevant molecules in this field, and to discuss their mechanism of action and potential prognostic relevance in CCA. Hopefully, a deeper knowledge of the molecular determinants of CCA invasiveness will help to identify clinically useful biomarkers and novel druggable targets, with the ultimate goal to develop innovative approaches to the management of this devastating malignancy.

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Section: Conclusion and Future Perspectivesmentioning

confidence: 73%

Molecular Mechanisms Driving Cholangiocarcinoma Invasiveness: An Overview

et al. 2018

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“…Moreover, several triggers, like hypoxia, may promote cell dissemination in one tumour type and inhibit it in others [ 6 ]. A consequence of this is that therapies targeting tumour cell dissemination and metastasis formation are largely under-represented [ 7 ]. A better understanding of the general principles underlying the triggers of tumour cell dissemination is therefore a key step in developing effective cancer treatments.…”

Section: Introductionmentioning

confidence: 99%

Cell adhesion heterogeneity reinforces tumour cell dissemination: novel insights from a mathematical model

et al. 2017

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BackgroundCancer cell invasion, dissemination, and metastasis have been linked to an epithelial-mesenchymal transition (EMT) of individual tumour cells. During EMT, adhesion molecules like E-cadherin are downregulated and the decrease of cell-cell adhesion allows tumour cells to dissociate from the primary tumour mass. This complex process depends on intracellular cues that are subject to genetic and epigenetic variability, as well as extrinsic cues from the local environment resulting in a spatial heterogeneity in the adhesive phenotype of individual tumour cells. Here, we use a novel mathematical model to study how adhesion heterogeneity, influenced by intrinsic and extrinsic factors, affects the dissemination of tumour cells from an epithelial cell population. The model is a multiscale cellular automaton that couples intracellular adhesion receptor regulation with cell-cell adhesion.ResultsSimulations of our mathematical model indicate profound effects of adhesion heterogeneity on tumour cell dissemination. In particular, we show that a large variation of intracellular adhesion receptor concentrations in a cell population reinforces cell dissemination, regardless of extrinsic cues mediated through the local cell density. However, additional control of adhesion receptor concentration through the local cell density, which can be assumed in healthy cells, weakens the effect. Furthermore, we provide evidence that adhesion heterogeneity can explain the remarkable differences in adhesion receptor concentrations of epithelial and mesenchymal phenotypes observed during EMT and might drive early dissemination of tumour cells.ConclusionsOur results suggest that adhesion heterogeneity may be a universal trigger to reinforce cell dissemination in epithelial cell populations. This effect can be at least partially compensated by a control of adhesion receptor regulation through neighbouring cells. Accordingly, our findings explain how both an increase in intra-tumour adhesion heterogeneity and the loss of control through the local environment can promote tumour cell dissemination.ReviewersThis article was reviewed by Hanspeter Herzel, Thomas Dandekar and Marek Kimmel.Electronic supplementary materialThe online version of this article (doi:10.1186/s13062-017-0188-z) contains supplementary material, which is available to authorized users.

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“…Although metastasis leads to therapeutic failure and increased disease mortality in cancer patients, the current oncologic drug development approach targets only the primary tumor, and until now, there are no approved antimetastatic drugs especially targeting anoikis. The dismal results of current therapy necessitate the search for novel therapeutic agents. , The failure of standard therapies to address metastasis has brought on a resurgence of research interest in drug leads from natural resources. The discovery of highly potent marine bioactive compounds with novel mechanisms of action may mark a new era for cancer management. , Jorunnamycin A (Figure ), a promising anticancer compound, is a bistetrahydroisoquinolinequinone alkaloid that has been isolated from the Thai blue sponge Xestospongia sp.…”

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confidence: 99%

Jorunnamycin A from Xestospongia sp. Suppresses Epithelial to Mesenchymal Transition and Sensitizes Anoikis in Human Lung Cancer Cells

et al. 2019

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Metastasis is a key driving force behind the high mortality rate associated with lung cancer. Herein, we report the first study revealing the antimetastasis activity of jorunnamycin A, a bistetrahydroisoquinolinequinone isolated from a Thai blue sponge Xestospongia sp. evidenced by its inhibition of epithelial to mesenchymal transition (EMT), sensitization of anoikis, and suppression of anchorage-independent survival in human lung cancer cells. Treatment with jorunnamycin A (0.05–0.5 μM) altered the expression of p53 and Bcl-2 family proteins, particularly causing the down-regulation of antiapoptosis Bcl-2 and Mcl-1 proteins. Under detachment conditions for 12 h, jorunnamycin A-treated cells exhibited diminution of pro-survival proteins p-Akt and p-Erk as well as the survival-promoting factor caveolin-1. Corresponding with the inhibition on the Akt and Erk pathway as well as activation of p53, there was an increase in the epithelial marker E-cadherin and a remarkable decrease of EMT markers and associated proteins including vimentin, snail, and claudin-1. As the loss of anchorage dependence is an important barrier to metastasis, the observed inhibitory effects of jorunnamycin A on the coordinating networks of EMT and anchorage-independent growth emphasize the potential development of jorunnamycin A as an effective agent against lung cancer metastasis.

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Re-Use of Established Drugs for Anti-Metastatic Indications

Cited by 7 publications

References 44 publications

Molecular Mechanisms Driving Cholangiocarcinoma Invasiveness: An Overview

Molecular Mechanisms Driving Cholangiocarcinoma Invasiveness: An Overview

Cell adhesion heterogeneity reinforces tumour cell dissemination: novel insights from a mathematical model

Jorunnamycin A from Xestospongia sp. Suppresses Epithelial to Mesenchymal Transition and Sensitizes Anoikis in Human Lung Cancer Cells

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