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

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.

Targeting Microenvironment of Melanoma and Head and Neck Cancers in Photodynamic Therapy

Background: Photodynamic therapy (PDT), in comparison to other skin cancers, is still far less effective for melanoma, due to the strong absorbance and the role of melanin in cytoprotection. The tumour microenvironment (TME) has a significant role in tumour progression, and the hypoxic TME is one of the main reasons for melanoma progression to metastasis and its resistance to PDT. Hypoxia is also a feature of solid tumours in the head and neck region that indicates a negative prognosis. Objective: The aim of this study was to individuate and describe systematically the main strategiesthe main strategies systematically in targeting the TME, especially hypoxia, in PDT against melanoma and head and neck cancers (HNC), and assess the current success in their application. Methods: PubMed, was used for searching, in MEDLINE and other databases were used for searching, for the most recent publications on PDT against melanoma and HNC in combination with the TME targeting and hypoxia. Results: In PDT for melanoma and HNC, it is very important to control hypoxia levels, and, amongst the different approaches, oxygen self-supply systems are often applied. Vascular targeting is promising, but to improve it, optimal drug-light interval, and formulation to increase the accumulation of the photosensitiser in the tumour vasculature, have to be established. On the other side, the use of angiogenesis inhibitors, such as those interfering with VEGF signalling are somewhat less successful than expected and need to be further investigated. Conclusion: Combination The combination of PDT with immunotherapy by using multifunctional nanoparticles continues to develop and seems to be the most promising for achieving a complete and lasting antitumour effect.

Disrupting tumour vasculature and recruitment of aPDL1-loaded platelets control tumour metastasis

Although therapies of cancer are advancing, it remains challenging for therapeutics to reach the sites of metastasis, which accounts for majority of cancer associated death. In this study, we have developed a strategy that guides an anti-programmed cell death-ligand 1 (aPDL1) antibody to accumulate in metastatic lesions to promote anti-tumour immune responses. Briefly, we have developed a combination in which Vadimezan disrupts tumour blood vessels of tumour metastases and facilitates the recruitment and activation of adoptively transferred aPDL1-conjugated platelets. In situ activated platelets generate aPDL1-decorated platelet-derived microparticles (PMP) that diffuse within the tumour and elicit immune responses. The proposed combination increases 10-fold aPDL1 antibody accumulation in lung metastases as compared to the intravenous administration of the antibody and enhances the magnitude of immune responses leading to improved antitumour effects.

The Tumour Vasculature as a Target to Modulate Leucocyte Trafficking

The effectiveness of immunotherapy against solid tumours is dependent on the appropriate leucocyte subsets trafficking and accumulating in the tumour microenvironment (TME) with recruitment occurring at the endothelium. Such recruitment involves interactions between the leucocytes and the endothelial cells (ECs) of the vessel and occurs through a series of steps including leucocyte capture, their rolling, adhesion, and intraluminal crawling, and finally leucocyte transendothelial migration across the endothelium. The tumour vasculature can curb the trafficking of leucocytes through influencing each step of the leucocyte recruitment process, ultimately producing an immunoresistant microenvironment. Modulation of the tumour vasculature by strategies such as vascular normalisation have proven to be efficient in facilitating leucocyte trafficking into tumours and enhancing immunotherapy. In this review, we discuss the underlying mechanisms of abnormal tumour vasculature and its impact on leucocyte trafficking, and potential strategies for overcoming the tumour vascular abnormalities to boost immunotherapy via increasing leucocyte recruitment.

Mesenchymal stem cells and cancer therapy: insights into targeting the tumour vasculature

A crosstalk established between tumor microenvironment and tumor cells leads to contribution or inhibition of tumor progression. Mesenchymal stem cells (MSCs) are critical cells that fundamentally participate in modulation of the tumor microenvironment, and have been reported to be able to regulate and determine the final destination of tumor cell. Conflicting functions have been attributed to the activity of MSCs in the tumor microenvironment; they can confer a tumorigenic or anti-tumor potential to the tumor cells. Nonetheless, MSCs have been associated with a potential to modulate the tumor microenvironment in favouring the suppression of cancer cells, and promising results have been reported from the preclinical as well as clinical studies. Among the favourable behaviours of MSCs, are releasing mediators (like exosomes) and their natural migrative potential to tumor sites, allowing efficient drug delivering and, thereby, efficient targeting of migrating tumor cells. Additionally, angiogenesis of tumor tissue has been characterized as a key feature of tumors for growth and metastasis. Upon introduction of first anti-angiogenic therapy by a monoclonal antibody, attentions have been drawn toward manipulation of angiogenesis as an attractive strategy for cancer therapy. After that, a wide effort has been put on improving the approaches for cancer therapy through interfering with tumor angiogenesis. In this article, we attempted to have an overview on recent findings with respect to promising potential of MSCs in cancer therapy and had emphasis on the implementing MSCs to improve them against the suppression of angiogenesis in tumor tissue, hence, impeding the tumor progression.

Exosomes: Critical mediators of tumour microenvironment reprogramming

: Tumour microenvironment (TME) is a resident of a variety of cells, which devoted to the heterogeneous population of the tumour. TME establishes a communication network for crosstalk and signalling between tumour cells, stroma, and other interstitial cells. The cross-communication drives the reprogramming of TME cells, which promote cancer progression and metastasis via diverse signalling pathways. Recently, TME-derived exosomes are recognized as critical communicators of TME cell reprogramming. This review addresses the role of TME-derived exosomes in the modulation of stroma, including reprogramming the stromal cells, ECM and tumour cell metabolism, as well as neoplastic transformation. Subsequently, we described the role of exosomes in pre-metastatic niche development, maintenance of stemness and tumour vasculature as well as development of drug resistance. We also explored tumour-derived exosomes in precision, including diagnosis, drug delivery, and vaccine development. We discussed the currently established bioengineered exosomes as carriers for chemotherapeutic drugs, RNAi molecules, and natural compounds. Finally, we presented tetraspanin and DNAbased precision methods for the quantification of tumour-derived exosomes. Overall, TME-derived exosome-mediated reprogramming of TME and precision strategies could illuminate the potential mechanisms for targeted therapeutic intervention.