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o‐Aminoazotoluene (OAT), capable of photoisomerization, and o‐vanillin, a potent comutagen, have been used to synthesize a new ligand, HL, [C6H4(CH3)N=NC6H3(CH3)N=CHC6H3(OH)(OCH3)], which, upon complexation with copper(II), results in a new copper(II) complex‐Cu(L)2, [Cu{C6H4(CH3)N=NC6H3(CH3)N=CHC6H3(OCH3)O}2]. Both HL and Cu(L)2 have been characterized by single‐crystal X‐ray diffraction measurements along with other analytical techniques, for example, IR spectroscopy, NMR spectroscopy, UV–Vis spectroscopy, elemental analysis and mass spectrometry. These compounds were tested with different in vitro anticancer assay as well as with in silico studies. A comparative study has been demonstrated on anticancer activity of HL and Cu(L)2 with the ligand HAZ, {C6H5N=NC6H4N=CHC6H3(OH)(OCH3)} and its Cu‐complex, [Cu(AZ)2, Cu{C6H5N=NC6H4N=CHC6H3(OCH3)O}2]. The sensing properties of HAZ, along with the synthesis and structural properties of both HAZ and Cu(AZ)2, have been reported by our group earlier. Cytotoxicity measurements on MCF7 cell lines show that Cu(L)2 and Cu(AZ)2 have higher anticancer activity than their corresponding ligands. The apoptotic effect of Cu‐complex was studied through nuclear fragmentation assay and AO/EB dual‐staining assay on MCF7 cell line. The IC50 value of Cu(L)2 in 0.01% DMSO/water after 24‐h treatment was found 4.2 μM, which is one of the lowest values with this response time compared to the other analogous anticancer compounds. Finally, we have evaluated the expression of hERα protein with respect to Cu‐complexes, and it was observed that Cu(L)2 caused more down‐regulation of hERα as compared to Cu(AZ)2. [ABSTRACT FROM AUTHOR]

A phenylazo appended ortho‐vanillin Schiff base scaffold (HAZ) has been used for selective colorimetric sensing of Cu2+ in semi‐aqueous medium (methanol–water, 1:1, v/v) in the presence of 16 cations and 20 anions, and the limit of detection is 1.8 × 10−7 M. The structures of HAZ and Cu (II) complex, [Cu(AZ)2], have been characterised by spectroscopic data (UV–Vis, Fourier transform infrared and electron paramagnetic resonance) and established by the single crystal X‐ray diffraction measurement. The Job's plot from the absorption studies has also confirmed the 1:2 stoichiometry of Cu2+:HAZ. The absorption spectrum of [Cu (AZ)2] has returned to the spectrum of HAZ on the addition of Na2EDTA solution which is again recovered upon the addition of Cu2+ solution. Discrete Fourier transform computations were carried out using the coordinates of the X‐ray structures of the compounds, and the molecular functions were used to correlate the solution spectroscopic properties. In addition to this, the probe is treated on MDA‐MB 231 breast cancer cells to check the cytotoxicity. The probe is used for the detection of trace quantity of Cu2+ in the cancer cell. [ABSTRACT FROM AUTHOR]

Vasculogenic mimicry (VM), an endothelial cell–independent alternative mechanism of blood supply to the malignant tumour, has long been considered as an adverse prognostic factor in many cancers. The correlation of VM with laminin‐5γ2 and the assessment of their harmonized expression as an independent risk factor have not been elucidated yet in oral squamous cell carcinoma (OSCC). CD31/PAS staining stratified 116 clinically diagnosed OSCC specimens into VM+ and VM− cohorts. The expression pattern of laminin‐5γ2 and its upstream modulator MMP2 was evaluated by immunohistochemistry and Western blot. The Kaplan–Meier and Cox regression analyses were performed to assess the survival and prognostic implications. The presence of VM demonstrated a significant correlation with the expression of laminin‐5γ2 (p <.001) and MMP2 (p <.001). This pattern was mirrored by the significant upregulation of laminin‐5γ2 and MMP2 in VM+ cohorts compared with the VM− ones. Furthermore, co‐expression of VM and laminin‐5γ2 was significantly associated with tumour grade (p =.010), primary tumour size (p <.001), lymph node metastasis (p =.001) and TNM stages (p <.001) but not with patients' age, gender, tobacco and alcohol consumption habit. Vasculogenic mimicry and laminin‐5γ2 double‐positive cohort displayed a significantly poorer disease‐free survival (DFS) and overall survival (OS). Vasculogenic mimicry, laminin‐5γ2 and their subsequent dual expression underlie a significant prognostic value for DFS [hazard ratio (HR) = 9.896, p =.028] and OS [HR = 21.401, p =.033] in OSCC patients. Together, our findings imply that VM along with laminin‐5γ2 is strongly linked to the malignant progression in OSCC and VM and laminin‐5γ2 coordination emerges as a critical prognostic biomarker for OSCC. [ABSTRACT FROM AUTHOR]

Vasculogenic mimicry (VM), defined as an endothelial cell independent alternative mechanism of blood and nutrient supply by dysregulated tumor cells, is associated with poor prognosis in oral squamous cell carcinoma (OSCC). Here we aim to investigate the underlying molecular mechanism of the synergistic effect of phytochemical Lupeol and standard microtubule inhibitor Paclitaxel in reversing the hypoxia induced VM formation in OSCC. The results demonstrated that the hypoxia induced upregulation of HIF-1α led to augmentation of signaling cascade associated with extracellular matrix remodeling and EMT phenotypes that are mechanistically linked to VM. Induction of HIF-1α altered the expression of EMT/CSC markers (E-Cadherin, Vimentin, Snail, Twist and CD133) and enhanced the ability of cell migration/invasion and spheroid formation. Subsequently, the targeted knockdown of HIF-1α by siRNA led to the perturbation of matrigel mediated tube formation as well as of Laminin-5γ2 expression with the down-regulation of VE-Cadherin, total and phosphorylated (S-897) EphA2, pERK1/2 and MMP2. We also observed that Lupeol in association with Paclitaxel resulted to apoptosis and the disruption of VM associated phenotypes in vitro. We further validated the impact of this novel interventional approach in a patient derived tumor explant culture model of oral malignancy. The ex vivo tumor model mimicked the in vitro anti-VM potential of Lupeol-Paclitaxel combination through down-regulating HIF-1α/EphA2/Laminin-5γ2 cascade. Together, our findings elucidated mechanistic underpinning of hypoxia induced Laminin-5γ2 driven VM formation highlighting that Lupeol-Paclitaxel combination may serve as novel therapeutic intervention in perturbation of VM in human OSCC., (© 2022. The International CCN Society.)