Synthesis and Biological Investigation of Bile Acid-Paclitaxel Hybrids

Chenodeoxycholic acid and ursodeoxycholic acid (CDCA and UDCA, respectively) have been conjugated with paclitaxel (PTX) anticancer drugs through a high-yield condensation reaction. Bile acid-PTX hybrids (BA-PTX) have been investigated for their pro-apoptotic activity towards a selection of cancer cell lines as well as healthy fibroblast cells. Chenodeoxycholic-PTX hybrid (CDC-PTX) displayed cytotoxicity and cytoselectivity similar to PTX, whereas ursodeoxycholic-PTX hybrid (UDC-PTX) displayed some anticancer activity only towards HCT116 colon carcinoma cells. Pacific Blue (PB) conjugated derivatives of CDC-PTX and UDC-PTX (CDC-PTX-PB and UDC-PTX-PB, respectively) were also prepared via a multistep synthesis for evaluating their ability to enter tumor cells. CDC-PTX-PB and UDC-PTX-PB flow cytometry clearly showed that both CDCA and UDCA conjugation to PTX improved its incoming into HCT116 cells, allowing the derivatives to enter the cells up to 99.9%, respect to 35% in the case of PTX. Mean fluorescence intensity analysis of cell populations treated with CDC-PTX-PB and UDC-PTX-PB also suggested that CDC-PTX-PB could have a greater ability to pass the plasmatic membrane than UDC-PTX-PB. Both hybrids showed significant lower toxicity with respect to PTX on the NIH-3T3 cell line.

Download Full-text

Chemerin, a Novel Peroxisome Proliferator-activated Receptor γ (PPARγ) Target Gene That Promotes Mesenchymal Stem Cell Adipogenesis

Journal of Biological Chemistry ◽

10.1074/jbc.m111.220491 ◽

2011 ◽

Vol 286 (27) ◽

pp. 23982-23995 ◽

Cited By ~ 79

Author(s):

Shanmugam Muruganandan ◽

Sebastian D. Parlee ◽

Jillian L. Rourke ◽

Matthew C. Ernst ◽

Kerry B. Goralski ◽

...

Keyword(s):

Bone Marrow ◽

Cell Types ◽

Clonal Expansion ◽

Carcinoma Cells ◽

Peroxisome Proliferator ◽

Mrna Levels ◽

Peroxisome Proliferator Activated Receptor ◽

Colon Carcinoma Cells ◽

Marrow Mesenchymal Stem Cells ◽

Nih 3T3

Chemerin is an adipocyte-secreted protein that regulates adipogenesis and the metabolic function of mature adipocytes via activation of chemokine-like receptor 1 (CMKLR1). Herein we report the interaction of peroxisome proliferator-activated receptor γ (PPARγ) and chemerin in the context of adipogenesis. Knockdown of chemerin or CMKLR1 expression or antibody neutralization of secreted chemerin protein arrested adipogenic clonal expansion of bone marrow mesenchymal stem cells (BMSCs) by inducing a loss of G2/M cyclins (cyclin A2/B2) but not the G1/S cyclin D2. Forced expression of PPARγ in BMSCs did not completely rescue this loss of clonal expansion and adipogenesis following chemerin or CMKLR1 knockdown. However, forced expression and/or activation of PPARγ in BMSCs as well as non-adipogenic cell types such as NIH-3T3 embryonic fibroblasts and MCA38 colon carcinoma cells significantly induced chemerin expression and secretion. Sequence analysis revealed a putative PPARγ response element (PPRE) sequence within the chemerin promoter. This PPRE was able to confer PPARγ responsiveness on a heterologous promoter, and mutation of this sequence abolished activation of the chemerin promoter by PPARγ. Chromatin immunoprecipitation confirmed the direct association of PPARγ with this PPRE. Treatment of mice with rosiglitazone elevated chemerin mRNA levels in adipose tissue and bone marrow coincident with an increase in circulating chemerin levels. Together, these findings support a fundamental role for chemerin/CMKLR1 signaling in clonal expansion during adipocyte differentiation as well as a role for PPARγ in regulating chemerin expression.

Download Full-text

Bile Acid Dysregulation Is Intrinsically Related to Cachexia in Tumor-Bearing Mice

Cancers ◽

10.3390/cancers13246389 ◽

2021 ◽

Vol 13 (24) ◽

pp. 6389

Author(s):

Morgane M. Thibaut ◽

Justine Gillard ◽

Adeline Dolly ◽

Martin Roumain ◽

Isabelle A. Leclercq ◽

...

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Cancer Cachexia ◽

Carcinoma Cells ◽

Hepatic Inflammation ◽

Colon Carcinoma Cells ◽

Pathological Conditions ◽

Host Metabolism ◽

G Protein Coupled ◽

Bile Acid Secretion

Bile acids exert diverse actions on host metabolism and immunity through bile acid-activated receptors, including Takeda G protein-coupled receptor 5 (TGR5). We have recently evidenced an alteration in bile acids in cancer cachexia, an inflammatory and metabolic syndrome contributing to cancer death. This current study aims to further explore the links emerging between bile acids and cancer cachexia. First, we showed that bile flow is reduced in cachectic mice. Next, comparing mice inoculated with cachexia-inducing and with non-cachexia-inducing C26 colon carcinoma cells, we demonstrated that alterations in the bile acid pathways and profile are directly associated with cachexia. Finally, we performed an interventional study using ursodeoxycholic acid (UDCA), a compound commonly used in hepatobiliary disorders, to induce bile acid secretion and decrease inflammation. We found that UDCA does not improve hepatic inflammation and worsens muscle atrophy in cachectic mice. This exacerbation of the cachectic phenotype upon UDCA was accompanied by a decreased TGR5 activity, suggesting that TGR5 agonists, known to reduce inflammation in several pathological conditions, could potentially counteract cachectic features. This work brings to light major evidence sustaining the emerging links between bile acids and cancer cachexia and reinforces the interest in studying bile acid-activated receptors in this context.

Download Full-text

Synthesis, Characterization, and Cytotoxicity of Binuclear Cooper(II)-Complexes with some S-Alkenyl Derivatives of Thiosalicyclic Acid

Serbian Journal of Experimental and Clinical Research ◽

10.1515/sjecr-2016-0071 ◽

2017 ◽

Vol 18 (1) ◽

pp. 13-18 ◽

Cited By ~ 2

Author(s):

Dusan Lj. Tomovic ◽

Andriana M. Bukonjic ◽

Aleksandar Kocovic ◽

Milos V. Nikolic ◽

Marina Z. Mijajlovic ◽

...

Keyword(s):

Cytotoxic Effect ◽

Magnetic Measurements ◽

Human Colon ◽

Carcinoma Cells ◽

Thiosalicylic Acid ◽

Colon Carcinoma Cells ◽

Human Colon Carcinoma ◽

Hct 116 ◽

Hct 116 Cells ◽

Derivatives Of

Abstract New complexes of copper(II) with S-alkenyl derivatives of thiosalicylic acid (alkenyl = propenyl-(L1), isobutenyl-(L2)) have been synthesized and characterized by microanalysis, infrared spectra, magnetic measurements, and by NMR spectra. The cytotoxic activity of two newly synthesized precursor S-alkenyl derivatives of thiosalicylic acid were tested using an MTT colorimetric technique on HCT-116 human colon carcinoma cells. The cytotoxic effect of the copper(II)- complexes were higher compared to the cytotoxicity of the corresponding ligand (for concentrations from 31.25 to 250 μM). Copper(II)-complexes showed a slightly lower cytotoxicity compared to cisplatin. Complexes of copper(II) with S-alkenyl derivatives of thiosalicylic acid (at concentrations from 250 to 1000 μM) had a cytotoxic effect on HCT-116 cells compared to cisplatin.

Download Full-text