Transcatheter arterial chemoembolization (TACE), aiming to block the hepatic artery for inhibiting tumor blood supply, became a popular therapy for hepatocellular carcinoma (HCC) patients. Traditional TACE formulation of anticancer drug emulsion in ethiodized oil (i.e., Lipiodol ® ) and gelatin sponge (i.e., Gelfoam ® ) had drawbacks on patient tolerance and resulted in undesired systemic toxicity, which were both significantly improved by polymeric beads, microparticles, or hydrogels by taking advantage of the elegant design of biocompatible or biodegradable polymers, especially amphiphilic polymers or polymers with both hydrophilic and hydrophobic chains, which could self-assemble into proposed microspheres or hydrogels. In this review, we aimed to summarize recent advances on polymeric embolization beads or hydrogels as TACE agents, with emphasis on their material basis of polymer architectures, which are important but have not yet been comprehensively summarized.

The M2 splice isoform of pyruvate kinase (PKM2) is a key enzyme for generating pyruvate and ATP in the glycolytic pathway, whereas the role of PKM2 in tumorigenesis remains a subject of debate. In our study, we found PKM2 is highly expressed in melanoma patients and the malignance is positively correlated with high PKM2 activity and glycolytic capability in melanoma cells. Suppression of PKM2 expression by knocking down markedly attenuated malignant phenotype both in vitro and in vivo, and restoration of PKM2 expression in PKM2 depleted cells could rescue melanoma cells proliferation, invasion and metastasis. With the data indicating PKM2 as a potential therapeutic target, we performed screening for PKM2 inhibitors and identified benserazide (Ben), a drug currently in clinical use. We demonstrated that Ben directly binds to and blocks PKM2 enzyme activity, leading to inhibition of aerobic glycolysis concurrent up-regulation of OXPHOS. Of note, despite PKM2 is very similar to PKM1, Ben does not affect PKM1 enzyme activity. We showed that Ben significantly inhibits cell proliferation, colony formation, invasion and migration in vitro and in vivo. The specificity of Ben was demonstrated by the findings that, suppression of PKM2 expression diminishes the efficacy of Ben in inhibition of melanoma cell growth; ectopic PKM2 expression in normal cells sensitizes cells to Ben treatment. Interestingly, PKM2 activity and aerobic glycolysis are upregulated in BRAFi-resistant melanoma cells. As a result, BRAFi-resistant cells exhibit heightened sensitivity to suppression of PKM2 expression or treatment with Ben both in vitro and in vivo.Y.Z. and Z.H. contributed equally to this work Additional Supporting Information may be found in the online version of this article.

Malignant melanoma is one of the most invasive tumours. However, effective therapeutic strategies are limited, and overall survival rates remain low. By utilizing transcriptomic profiling, tissue array and molecular biology, we revealed that two key ubiquitin-specific proteases (USPs), ubiquitin-specific peptidase10 (USP10) and ubiquitin-specific peptidase10 (USP13), were significantly elevated in melanoma at the mRNA and protein levels. Spautin-1 has been reported as a USP10 and USP13 antagonist, and we demonstrated that spautin-1 has potent anti-tumour effects as reflected by MTS and the colony formation assays in various melanoma cell lines without cytotoxic effects in HaCaT and JB6 cell lines. Mechanistically, we identified apoptosis and ROS-mediated DNA damage as critical mechanisms underlying the spautin-1-mediated anti-tumour effect by utilizing transcriptomics, qRT-PCR validation, flow cytometry, Western blotting and immunofluorescence staining. Importantly, by screening spautin-1 with targeted or chemotherapeutic drugs, we showed that spautin-1 exhibited synergy with cisplatin in the treatment of melanoma. Pre-clinically, we demonstrated that spautin-1 significantly attenuated tumour growth in a cell line-derived xenograft mouse model, and its anti-tumour effect was further enhanced by cotreatment with cisplatin. Taken together, our study revealed | 4325 GUO et al.

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