Hypoxia-Activated Theragnostic Prodrugs (HATPs): Current State and Future Perspectives

Hypoxic microenvironment plays a critical role in solid tumor growth, metastasis and angiogenesis. Hypoxia-inducible factors (HIFs), which are canonical transcription factors in response to hypoxia, are stabilized under hypoxia and they coordinate the process of hypoxia-induced gene expression leading to cancer progression. Increasing evidence has indicated that long noncoding RNAs (lncRNAs) which are closely associated with cancer play crucial roles in hypoxia-mediated HCC progression, while the mechanisms are largely unknown. Here, we identified a novel lncRNA SZT2-AS1 in HCC, which was induced by hypoxia in a HIF-1-dependent manner and promoted HCC growth, metastasis and angiogenesis. The clinical data indicated that SZT2-AS1 level was substantially upregulated in HCC and significantly associated with poor clinical outcomes, and acted as an independent prognostic predictor. Mechanistically, SZT2-AS1, in turn, recruited HIF-1α and HIF-1β to form the HIF-1 heterodimer. And SZT2-AS1 was required for the occupancy of HIF-1 to hypoxia response elements (HREs) and HIF target gene transcription. In addition, SZT2-AS1 was required for hypoxia-induced histone trimethylation (H3K4me3 and H3K36me3) at HREs. Through recruiting methyltransferase SMYD2, SZT2-AS1 promoted trimethylation modification of H3K4 and H3K36 in HCC cells. Taken together, our results uncovered a lncRNA-involved positive feedback mechanism under hypoxia and established the clinical value of SZT2-AS1 in prognosis and potential therapeutic strategy for HCC. Significance: LncRNA SZT2-AS1 involves in a positive feedback mechanism under hypoxia, which provides a therapeutic strategy for HCC.

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Design Principles and Applications of Fluorescent Kinase Inhibitors for Simultaneous Cancer Bioimaging and Therapy

Ganai,

Vrettos,

Kyrkou

et al. 2024

Cancers

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Kinase inhibitors are potent therapeutic agents in cancer treatment, but their effectiveness is frequently restricted by the inability to image the tumor microenvironment. To address this constraint, kinase inhibitor–fluorophore conjugates have emerged as promising theranostic agents, allowing for simultaneous cancer diagnosis and treatment. These conjugates are gaining attention for their ability to visualize malignant tissues and concurrently enhance therapeutic interventions. This review explores the design principles governing the development of multimodal inhibitors, highlighting their potential as platforms for kinase tracking and inhibition via bioimaging. The structural aspects of constructing such theranostic agents are critically analyzed. This work could shed light on this intriguing field and provide adequate impetus for developing novel theranostic compounds based on small molecule inhibitors and fluorophores.

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Hypoxia-Activated Theragnostic Prodrugs (HATPs): Current State and Future Perspectives

Cited by 3 publications

References 54 publications

A novel hypoxia-induced lncRNA, SZT2-AS1, boosts HCC progression by mediating HIF heterodimerization and histone trimethylation under a hypoxic microenvironment

A novel hypoxia-induced lncRNA, SZT2-AS1, boosts HCC progression by mediating HIF heterodimerization and histone trimethylation under a hypoxic microenvironment

Hypoxia-induced SZT2-AS1 is required for HIF-1 heterodimer formation and histone trimethylation in HCC cells under hypoxic microenvironment

Design Principles and Applications of Fluorescent Kinase Inhibitors for Simultaneous Cancer Bioimaging and Therapy

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