Vascular disrupting agents in cancer therapy

Smolarczyk, Ryszard; Czapla, Justyna; Jarosz-Biej, Magdalena; Czerwinski, Kyle; Cichoń, Tomasz

doi:10.1016/j.ejphar.2020.173692

Cited by 55 publications

(50 citation statements)

References 158 publications

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“…The lymphatic vessels that support the tumor at the secondary site are lined with loosely-connected lymphatic endothelial cells (LECs) that may also promote metastasis [ 59 , 60 ]. LECs recruit tumor cells by producing chemoattractants, such as CCL21 and SDF-1, which bind to CCR7 and CXCR4 receptors expressed in cancer cells, respectively [ 61 ].…”

Section: Roles Of Cellular Tme Components In Regulating the Metastatic Cascadementioning

confidence: 99%

The Role of Tumor Microenvironment in Cancer Metastasis: Molecular Mechanisms and Therapeutic Opportunities

Neophytou

Panagi

Stylianopoulos

et al. 2021

Cancers

212

106

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The tumor microenvironment (TME) regulates essential tumor survival and promotion functions. Interactions between the cellular and structural components of the TME allow cancer cells to become invasive and disseminate from the primary site to distant locations, through a complex and multistep metastatic cascade. Tumor-associated M2-type macrophages have growth-promoting and immunosuppressive functions; mesenchymal cells mass produce exosomes that increase the migratory ability of cancer cells; cancer associated fibroblasts (CAFs) reorganize the surrounding matrix creating migration-guiding tracks for cancer cells. In addition, the tumor extracellular matrix (ECM) exerts determinant roles in disease progression and cancer cell migration and regulates therapeutic responses. The hypoxic conditions generated at the primary tumor force cancer cells to genetically and/or epigenetically adapt in order to survive and metastasize. In the circulation, cancer cells encounter platelets, immune cells, and cytokines in the blood microenvironment that facilitate their survival and transit. This review discusses the roles of different cellular and structural tumor components in regulating the metastatic process, targeting approaches using small molecule inhibitors, nanoparticles, manipulated exosomes, and miRNAs to inhibit tumor invasion as well as current and future strategies to remodel the TME and enhance treatment efficacy to block the detrimental process of metastasis.

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Section: Roles Of Cellular Tme Components In Regulating the Metastatic Cascadementioning

confidence: 99%

The Role of Tumor Microenvironment in Cancer Metastasis: Molecular Mechanisms and Therapeutic Opportunities

Neophytou

Panagi

Stylianopoulos

et al. 2021

Cancers

212

106

View full text Add to dashboard Cite

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“…Given the significance of VDAs, there have been several previous reviews [ 22 ]. [ 6 , 19 , 25 , 47 , 71 , 171 , 172 ], but few have focused on the ability to examine activity non-invasively [ 5 , 132 , 173 , 174 ], the emphasis of this current review.…”

Section: Introductionmentioning

confidence: 99%

Non-Invasive Evaluation of Acute Effects of Tubulin Binding Agents: A Review of Imaging Vascular Disruption in Tumors

et al. 2021

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Tumor vasculature proliferates rapidly, generally lacks pericyte coverage, and is uniquely fragile making it an attractive therapeutic target. A subset of small-molecule tubulin binding agents cause disaggregation of the endothelial cytoskeleton leading to enhanced vascular permeability generating increased interstitial pressure. The resulting vascular collapse and ischemia cause downstream hypoxia, ultimately leading to cell death and necrosis. Thus, local damage generates massive amplification and tumor destruction. The tumor vasculature is readily accessed and potentially a common target irrespective of disease site in the body. Development of a therapeutic approach and particularly next generation agents benefits from effective non-invasive assays. Imaging technologies offer varying degrees of sophistication and ease of implementation. This review considers technological strengths and weaknesses with examples from our own laboratory. Methods reveal vascular extent and patency, as well as insights into tissue viability, proliferation and necrosis. Spatiotemporal resolution ranges from cellular microscopy to single slice tomography and full three-dimensional views of whole tumors and measurements can be sufficiently rapid to reveal acute changes or long-term outcomes. Since imaging is non-invasive, each tumor may serve as its own control making investigations particularly efficient and rigorous. The concept of tumor vascular disruption was proposed over 30 years ago and it remains an active area of research.

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“…Different investigations on FAA and XAA were performed in the last 20 years, and our research group was deeply involved in establishing appropriate SARs for the two related compounds aimed at identifying an effective VDA and gaining more insight into the peculiar mechanism of action of these drugs. Indeed, the biological targets involved were still unknown, and studies mainly focused on the definition of structural requirements for both immune modulation and induction of cytokines such as TNFα, also involved in vascular disrupting properties of the parent compounds [ 6 ], to gain enhanced anticancer potential.…”

Section: Sar Studies 2001–2009mentioning

confidence: 99%

“…On the other hand, VDAs can be grouped into three subclasses, namely microtubule destabilizing agents, anti-vascular-acting flavonoids and drugs directly targeting endothelial cells, all causing destruction of tumour vasculature through apoptosis or necrosis of endothelial cells. Comparing the antitumour profile of classic anticancer drugs acting on tumour cells and compounds targeting tumour blood vessels, VDAs appear the most promising, mainly due to their low induction of resistance, and their ability to reach the target blood vessels and to induce substantial necrosis of the tumour core [ 6 ]. Unfortunately, one of the main disadvantages associated with VDAs is the incomplete eradication of the tumour, due to the induction of a central necrosis that is surrounded by preserved vascularized cells, able to survive and proliferate.…”

Section: Introductionmentioning

confidence: 99%

“…A number of combretastatin-based derivatives were submitted to clinical trials, both as single agents and in combination with other anticancer drugs, giving better clinical outcomes when administrated as combinations. On the other hand, flavonoids, plant secondary metabolites found in food, mainly vegetables, fruits and cereals, showed a myriad of beneficial properties, among which were antioxidant, anti-inflammatory, anti-mutagenic and anti-carcinogenic [ 6 , 7 ] properties, and different mechanisms of action were proposed to elucidate their activity in several stages of cancer progression. In particular, they are known to play a relevant role as VDAs by inducing apoptosis.…”

Section: Introductionmentioning

confidence: 99%

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Flavonoid-Inspired Vascular Disrupting Agents: Exploring Flavone-8-Acetic Acid and Derivatives in the New Century

et al. 2021

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Naturally occurring flavonoids are found as secondary metabolites in a wide number of plants exploited for both medicine and food and have long been known to be endowed with multiple biological activities, making them useful tools for the treatment of different pathologies. Due to the versatility of the scaffolds and the vast possibilities of appropriate decoration, they have also been regarded as fruitful sources of lead compounds and excellent chemical platforms for the development of bioactive synthetic compounds. Flavone-8-acetic acid (FAA) and 5,6-dimethylxanthone acetic acid (DMXAA) emerged for their antitumour potential due to the induction of cytokines and consequent rapid haemorrhagic necrosis of murine tumour vasculature, and different series of derivatives have been designed thereafter. Although the promising DMXAA failed in phase III clinical trials because of strict species-specificity, a boost in research came from the recent identification of the stimulator of interferon genes (STING), responsible for supporting tumoural innate immune responses, as a possible biological target. Consequently, in the last decade a renewal of interest for these flavonoid-based structures was noticed, and novel derivatives have been synthesised and evaluated for a deeper understanding of the molecular features needed for affecting human cells. Undoubtedly, these natural-derived molecules deserve further investigation and still appear attractive in an anticancer perspective.

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Vascular disrupting agents in cancer therapy

Cited by 55 publications

References 158 publications

The Role of Tumor Microenvironment in Cancer Metastasis: Molecular Mechanisms and Therapeutic Opportunities

The Role of Tumor Microenvironment in Cancer Metastasis: Molecular Mechanisms and Therapeutic Opportunities

Non-Invasive Evaluation of Acute Effects of Tubulin Binding Agents: A Review of Imaging Vascular Disruption in Tumors

Flavonoid-Inspired Vascular Disrupting Agents: Exploring Flavone-8-Acetic Acid and Derivatives in the New Century

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