Anti-cancer activity of benzoxazinone derivatives via targeting c-Myc G-quadruplex structure.

AIMS: This study aimed to analyze the impact of four synthesized benzoxazinone derivatives as screening drugs on c-Myc-overexpressed cancer cells (H7402, HeLa, SK-RC-42, SGC7901, and A549) and to explore their interaction mechanisms in detail. MATERIALS AND METHODS: Using morphological analysis, real-time cytotoxicity analysis, wound healing assay, reverse transcription PCR, electrophoretic mobility shift assay, and circular dichroism spectroscopy techniques. KEY FINDINGS: Results revealed that these four compounds could inhibit proliferation of SK-RC-42, SGC7901, and A549 cells in five cancer cell lines to varying degrees and significantly hinder migration. More importantly, the RT-PCR assay showed that the compounds could surprisingly downregulate the expression of c-Myc mRNA in a dose-dependent manner in the five cancer cells, which may be one of the causes of cancer cell proliferation in vitro inhibition. Further EMSA assays demonstrated that at the molecular level of DNA, four compounds can induce the formation of G-quadruplexes (G4-DNAs) in the c-Myc gene promoter. In addition, the CD result of compound 1 clearly indicates that it specifically induces a c-Myc GC-rich 36mer double-stranded DNA in the c-Myc promoter to form a G-quadruplex hybrid configuration. In conclusion, the compounds studied could dose-dependently inhibit the growth and migration of the cancer cells being investigated. This is positively associated with the reduction of overexpression of the c-Myc gene, which may be significantly regulated by the association of compounds with the G-quadruplexes produced in the c-Myc gene promoter region. SIGNIFICANCE: We conclude that three compounds merit further study, particularly against non-small-cell lung cancer, as leading compounds of anticancer drugs.

γδ T cells and their potential for immunotherapy.

Vγ9Vδ2 (also termed Vγ2Vδ2) T cells, a major human peripheral blood γδ T cell subset, recognize microbial (E)-4-hydroxy-3-methylbut-2-enyl diphosphate and endogenous isopentenyl diphosphate in a TCR-dependent manner. The recognition does not require specific accessory cells, antigen uptake, antigen processing, or MHC class I, class II, or class Ib expression. This subset of T cells plays important roles in mediating innate immunity against a wide variety of infections and displays potent and broad cytotoxic activity against human tumor cells. Because γδT cells express both natural killer receptors such as NKG2D and γδ T cell receptors, they are considered to represent a link between innate and adaptive immunity. In addition, activated γδ T cells express a high level of antigen-presenting cell-related molecules and can present peptide antigens derived from destructed cells to αß T cells. Utilizing these antimicrobial and anti-tumor properties of γδ T cells, preclinical and clinical trials have been conducted to develop novel immunotherapies for infections and malignancies. Here, we review the immunological properties of γδ T cells including the underlying recognition mechanism of nonpeptitde antigens and summarize the results of γδ T cell-based therapies so far performed. Based on the results of the reported trials, γδ T cells appear to be a promising tool for novel immunotherapies against certain types of diseases.