Gelation, self-assembly, and acid responsive properties of an unsymmetrical 1,3,4-oxadiazole derivative

A novel unsymmetrical 1,3,4-oxadiazole derivative (2-POXD-B8) was synthesized. 2-POXD-B8 can form organogel in methanol. The gelation and self-assembly behavior of 2-POXD-B8 were researched by SEM, XRD, UV–vis, and temperature-dependent FT-IR, etc. π–π interaction and van der Waals force are viewed as the main driving forces in the self-assembly process. In addition, 2-POXD-B8 showed acid-responsive properties in different states, including gel state and film state. A dual-channel acid response by reversible solution–gel transition and fluorescence changes was observed in the methanol gel system. The protonation of 2-POXD-B8 is the reason for its acid-responsive property.</p

Bcl-xL/Bcl-2 inhibition sensitizes VS-5584-mediated activity in melanoma cells-A375 cells (A and B), primary human melanoma cells (F), B10BR murine melanocytes (G) or primary human keratinocytes (“Kera”) (G) were treated with VS-5584 (“VS”, 10 nM) or plus ABT-737 (“ABT”, 25 nM) for 72 hours, cell viability (MTT assay) and apoptosis (ELISA assay, for A375 cells) were tested.

<p>A375 cells, transfected with scramble control siRNA (sc-RNAi), Bcl-2 siRNA or Bcl-xL siRNA, were treated with VS-5584 (VS, 10 nM) for 72 hours, expression of Bcl-2, Bcl-xL and GAPDH was tested by Western blots (C, their expressions were quantified), cell survival (D) and apoptosis (E) were also tested. Data were expressed as mean ± SD, experiments were repeated three times. “C” stands for vehicle control (0.1% of DMSO). *<i>p</i><0.05 vs group “C”. **<i>p</i><0.05 vs “VS” only group (A, B and F). **<i>p</i><0.05 vs sc-RNAi group (D and E).</p

VS-5584 inhibits melanoma cell survival and proliferation-Established melanoma cell lines (A375, A-2058 and SK-MEL-3), patient-derived primary melanoma cells, B10BR melanocytes and primary human keratinocytes (“Kera”) were treated with applied concentration of VS-5585 (“VS”) or vehicle control (“C”, 0.1% of DMSO), cell survival was tested by MTT assay (A, E and F) and trypan blue exclusion assay (B, for A375 cells); Cell proliferation was analyzed by through [H³] Thymidine incorporation assay (C, for A375 cells) and clonogenicity assay (D, for A375 cells).

<p>Data were expressed as mean ± SD, experiments were repeated three times. *<i>p</i><0.05 vs group “C”.</p

VS-5584 and ABT-737 synergistically inhibits A375 xenograft growth <i>in vivo</i>-A375 bearing nude mice (n = 10 for each group) were treated with vehicle control (SX-1292, “C”), VS-5584 (“VS”, oral, 25 mg/kg/d for 21 days), ABT-737 (“ABT”, oral, 25 mg/kg/d for 21 days), or VS-5584 plus ABT-737 combo (“Com”), tumor volumes (A and B) and mice body weights (C) were recorded.

<p>Two weeks after initial drug administration, xenografted tumors of two mice per group were isolated, expressions of listed proteins in the tumor lysates were tested and quantified (D). Data were expressed as mean ± SD, experiments were repeated twice. *<i>p</i><0.05 vs group “C”. **<i>p</i><0.05 vs “VS-5584” only group. ***<i>p</i><0.05 vs “ABT-737” only group.</p

VS-5584, a Novel PI3K-mTOR Dual Inhibitor, Inhibits Melanoma Cell Growth <i>In Vitro</i> and <i>In Vivo</i>

<div><p>Melanomas cause over 76% of skin cancer deaths annually. Phosphatidylinositol 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) signaling pathway is important for melanoma initiation and progression. In the current study, we evaluated the potential anti-melanoma effect of VS-5584, a novel and highly potent PI3K-mTOR dual inhibitor. We demonstrated that VS-5584 potently inhibited survival and proliferation of established (A375, A-2058 and SK-MEL-3 lines) and primary human melanoma cells, but was non-cytotoxic to non-cancerous human skin keratinocytes and B10BR murine melanocytes. At the meantime, VS-5584 induced caspase-dependent apoptotic death in melanoma cells, and its cytotoxicity was alleviated by the caspase inhibitors. At the molecular level, VS-5584 blocked AKT-mTOR activation and downregulated cyclin D1 expression in melanoma cells, while the expressions of Bcl-xL and Bcl-2 were not affected by VS-5584 treatment. On the other hand, a BH-3 mimetic Bcl-xL/Bcl-2 inhibitor ABT-737, as well as siRNA-mediated knockdown of Bcl-xL or Bcl-2, enhanced the activity of VS-5584 in melanoma cells. <i>In vivo</i>, oral administration of VS-5584 suppressed A375 melanoma xenograft growth in nude mice, and its activity was further enhanced by co-administration of ABT-737. These results provide the rationale for the clinical assessment of VS-5584 in melanoma patients and development of ABT-737 and other Bcl-xL/Bcl-2 inhibitors as the possible adjuvants.</p></div

Image_4_Predictors based on cuproptosis closely related to angiogenesis predict colorectal cancer recurrence.tif

Up to one-third of colorectal cancer (CRC) patients experience recurrence after radical surgery, and it is still very difficult to assess and predict the risk of recurrence. Angiogenesis is the key factor of recurrence as metastasis of CRC is closely related to copper metabolism. Expression profiling by microarray from two datasets in Gene Expression Omnibus (GEO) was selected for quality control, genome annotation, normalization, etc. The identified angiogenesis-derived and cuproptosis-related Long non-coding RNAs (lncRNAs) and clinical data were screened and used as predictors to construct a Cox regression model. The stability of the model was evaluated, and a nomogram was drawn. The samples were divided into high-risk and low-risk groups according to the linear prediction of the model, and a Kaplan–Meier survival analysis was performed. In this study, a model was established to predict the postoperative recurrence of colon cancer, which exhibits a high prediction accuracy. Furthermore, the negative correlation between cuproptosis and angiogenesis was validated in colorectal cancer cell lines and the expression of lncRNAs in vitro was examined.</p

Signaling changes by VS-5584 in melanoma cells-A375 and A-2058 cells were treated with VS-5584 (“VS”, 25 nM) or the vehicle control (1% DMSO, “C”) for 6 hours (for A and B) or 24 hours (for C), expression of listed proteins was tested by Western blots.

<p>Relative intensity of kinase phosphorylations (vs. non-phosphorylated kinases) as well as cyclin D1 and Bcl-2 expression (vs. GAPDH) of three independent experiments were shown (A-C, lower panels). Data were expressed as mean ± SD, experiments were repeated three times. *<i>p</i><0.05 vs group “C”.</p

Image_5_Predictors based on cuproptosis closely related to angiogenesis predict colorectal cancer recurrence.tif

Up to one-third of colorectal cancer (CRC) patients experience recurrence after radical surgery, and it is still very difficult to assess and predict the risk of recurrence. Angiogenesis is the key factor of recurrence as metastasis of CRC is closely related to copper metabolism. Expression profiling by microarray from two datasets in Gene Expression Omnibus (GEO) was selected for quality control, genome annotation, normalization, etc. The identified angiogenesis-derived and cuproptosis-related Long non-coding RNAs (lncRNAs) and clinical data were screened and used as predictors to construct a Cox regression model. The stability of the model was evaluated, and a nomogram was drawn. The samples were divided into high-risk and low-risk groups according to the linear prediction of the model, and a Kaplan–Meier survival analysis was performed. In this study, a model was established to predict the postoperative recurrence of colon cancer, which exhibits a high prediction accuracy. Furthermore, the negative correlation between cuproptosis and angiogenesis was validated in colorectal cancer cell lines and the expression of lncRNAs in vitro was examined.</p

Image_1_Predictors based on cuproptosis closely related to angiogenesis predict colorectal cancer recurrence.tif

Up to one-third of colorectal cancer (CRC) patients experience recurrence after radical surgery, and it is still very difficult to assess and predict the risk of recurrence. Angiogenesis is the key factor of recurrence as metastasis of CRC is closely related to copper metabolism. Expression profiling by microarray from two datasets in Gene Expression Omnibus (GEO) was selected for quality control, genome annotation, normalization, etc. The identified angiogenesis-derived and cuproptosis-related Long non-coding RNAs (lncRNAs) and clinical data were screened and used as predictors to construct a Cox regression model. The stability of the model was evaluated, and a nomogram was drawn. The samples were divided into high-risk and low-risk groups according to the linear prediction of the model, and a Kaplan–Meier survival analysis was performed. In this study, a model was established to predict the postoperative recurrence of colon cancer, which exhibits a high prediction accuracy. Furthermore, the negative correlation between cuproptosis and angiogenesis was validated in colorectal cancer cell lines and the expression of lncRNAs in vitro was examined.</p

Image_3_Predictors based on cuproptosis closely related to angiogenesis predict colorectal cancer recurrence.tif

Up to one-third of colorectal cancer (CRC) patients experience recurrence after radical surgery, and it is still very difficult to assess and predict the risk of recurrence. Angiogenesis is the key factor of recurrence as metastasis of CRC is closely related to copper metabolism. Expression profiling by microarray from two datasets in Gene Expression Omnibus (GEO) was selected for quality control, genome annotation, normalization, etc. The identified angiogenesis-derived and cuproptosis-related Long non-coding RNAs (lncRNAs) and clinical data were screened and used as predictors to construct a Cox regression model. The stability of the model was evaluated, and a nomogram was drawn. The samples were divided into high-risk and low-risk groups according to the linear prediction of the model, and a Kaplan–Meier survival analysis was performed. In this study, a model was established to predict the postoperative recurrence of colon cancer, which exhibits a high prediction accuracy. Furthermore, the negative correlation between cuproptosis and angiogenesis was validated in colorectal cancer cell lines and the expression of lncRNAs in vitro was examined.</p