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Pentamidine niosomes thwart S100B effects in human colon carcinoma biopsies favouring wtp53 rescue.

ABSTRACT: S100B protein bridges chronic mucosal inflammation and colorectal cancer given its ability to activate NF-kappaB transcription via RAGE signalling and sequestrate pro-apoptotic wtp53. Being an S100B inhibitor, pentamidine antagonizes S100B-wtp53 interaction, restoring wtp53-mediated pro-apoptotic control in cancer cells in several types of tumours. The expression of S100B, pro-inflammatory molecules and wtp53 protein was evaluated in human biopsies deriving from controls, ulcerative colitis and colon cancer patients at baseline (a) and (b) following S100B targeting with niosomal PENtamidine VEhiculation (PENVE), to maximize drug permeabilization in the tissue. Cultured biopsies underwent immunoblot, EMSA, ELISA and biochemical assays for S100B and related pro-inflammatory/pro-apoptotic proteins. Exogenous S100B (0.005-5 ?mol/L) alone, or in the presence of PENVE (0.005-5 ?mol/L), was tested in control biopsies while PENVE (5 ?mol/L) was evaluated on control, peritumoral, ulcerative colitis and colon cancer biopsies. Our data show that S100B level progressively increases in control, peritumoral, ulcerative colitis and colon cancer enabling a pro-inflammatory/angiogenic and antiapoptotic environment, featured by iNOS, VEGF and IL-6 up-regulation and wtp53 and Bax inhibition. PENVE inhibited S100B activity, reducing its capability to activate RAGE/phosphor-p38 MAPK/NF-kappaB and favouring its disengagement with wtp53. PENVE blocks S100B activity and rescues wtp53 expression determining pro-apoptotic control in colon cancer, suggesting pentamidine as a potential anticancer drug.

SUBMITTER: Seguella L

PROVIDER: S-EPMC7077541 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Pentamidine niosomes thwart S100B effects in human colon carcinoma biopsies favouring wtp53 rescue.

Seguella Luisa L Rinaldi Federica F Marianecci Carlotta C Capuano Riccardo R Pesce Mirella M Annunziata Giuseppe G Casano Fabrizio F Bassotti Gabrio G Sidoni Angelo A Milone Marco M Aprea Giovanni G de Palma Giovanni Domenico GD Carafa Maria M Pesce Marcella M Esposito Giuseppe G Sarnelli Giovanni G

Journal of cellular and molecular medicine 20200205 5

S100B protein bridges chronic mucosal inflammation and colorectal cancer given its ability to activate NF-kappaB transcription via RAGE signalling and sequestrate pro-apoptotic wtp53. Being an S100B inhibitor, pentamidine antagonizes S100B-wtp53 interaction, restoring wtp53-mediated pro-apoptotic control in cancer cells in several types of tumours. The expression of S100B, pro-inflammatory molecules and wtp53 protein was evaluated in human biopsies deriving from controls, ulcerative colitis and ...[more]

PMID: 32022398

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Project description:S100 calcium-binding protein B (S100B) is highly expressed in glioma cells and promotes cancer cell survival via inhibition of the p53 protein. In melanoma cells, this S100B-p53 interaction is known to be inhibited by pentamidine isethionate, an antiprotozoal agent. Thus, the aim of the present study was to evaluate the effect of pentamidine on rat C6 glioma cell proliferation, migration and apoptosis in vitro. The change in C6 cell proliferation following treatment with pentamidine was determined by performing a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide-formazan assay. Significant dose-dependent decreases in proliferation were observed at pentamidine concentrations of 0.05 µM (58.5±5%; P<0.05), 0.5 µM (40.6±7%; P<0.01) and 5 µM (13±4%; P<0.001) compared with the control (100% viability). Furthermore, treatment with 0.05, 0.5 and 5 µM pentamidine was associated with a significant increase in apoptosis versus the untreated cells, as determined by DNA fragmentation assays, immunofluorescence analysis of C6 chromatin using Hoechst staining, and immunoblot analysis of B-cell lymphoma-2 (Bcl-2)-associated X protein (100%, P<0.05; 453%, P<0.01; and 1000%, P<0.001, respectively) and Bcl-2 (-60%, P<0.001; -80.13%, P<0.001; -95%, P<0.001, respectively). In addition, the administration of 0.05, 0.5 and 5 µM pentamidine significantly upregulated the protein expression levels of p53 (681±87.5%, P<0.05; 1244±94.3%, P<0.01; and 2244±111%, P<0.001, respectively), and significantly downregulated the expression levels of matrix metalloproteinase-2 (42±2.3%, P<0.05; 71±2.5%, P<0.01; and 95.8±3.3%, P<0.001, respectively) and aquaporin 4 (38±2.5%, P<0.05; 69±2.6%, P<0.01; and 88±3.0%, P<0.001, respectively), compared with the untreated cells. The wound healing assay demonstrated that cell migration was significantly impaired by treatment with 0.05, 0.5 and 5 µM pentamidine compared with untreated cells (88±4.2%, P<0.05; 64±2%, P<0.01; and 42±3.1%, P<0.001, respectively). Although additional in vivo studies are required to clarify the current in vitro data, the present study indicates that pentamidine and S100B-p53 inhibitors may represent a novel approach for the treatment of glioma.

Project description:A number of molecular biofactors have been documented in pathogenesis and poor prognosis of colorectal cancer (CRC). Among them, the Hypoxia-Inducible Factor (HIF-1a) is frequently reported to become over-expressed, and its targeting could restrict and control a variety of essential hallmarks of CRC. Niosomes are innovative drug delivery vehicles with the encapsulating capacity for co-loading both hydrophilic and hydrophobic drugs at the same time. Also, they can enhance the local accumulation while minimizing the dose and side effects of drugs. YC-1 and PX-12 are two inhibitors of HIF-1a. The purpose of this work was to synthesize dual-loaded YC-1 and PX-12 niosomes to efficiently target HIF-1α in CRC, HT-29 cells. The niosomes were prepared by the thin-film hydration method, then the niosomal formulation of YC-1 and PX-12 (NIO/PX-YC) was developed and optimized by the central composition method (CCD) using the Box-Behnken design in terms of size, polydispersity index (PDI), entrapment efficiency (EE). Also, they are characterized by DLS, FESEM, and TEM microscopy, as well as FTIR spectroscopy. Additionally, entrapment efficiency, in vitro drug release kinetics, and stability were assessed. Cytotoxicity, apoptosis, and cell cycle studies were performed after the treatment of HT-29 cells with NIO/PX-YC. The expression of HIF-1αat both mRNA and protein levels were studied after NIO/PX-YC treatment. The prepared NIO/PX-YC showed a mean particle size of 185 nm with a zeta potential of about-7.10 mv and a spherical morphology. Also, PX-12 and YC-1 represented the entrapment efficiency of about %78 and %91, respectively, with a sustainable and controllable release. The greater effect of NIO/PX-YC than the free state of PX-YC on the cell survival rate, cell apoptosis, and HIF-1α gene/protein expression were detected (p < 0.05). In conclusion, dual loading of niosomes with YC-1 and PX-12 enhanced the effect of drugs on HIF-1α inhibition, thus boosting their anticancer effects.

Dataset Information

Pentamidine niosomes thwart S100B effects in human colon carcinoma biopsies favouring wtp53 rescue.

Publications

Pentamidine niosomes thwart S100B effects in human colon carcinoma biopsies favouring wtp53 rescue.

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