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 μmol/L) alone, or in the presence of PENVE (0.005‐5 μmol/L), was tested in control biopsies while PENVE (5 μmol/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.
Highlights
By promoting the release of cytokines, interleukins and other pro-inflammatory signalling molecules, chronic intestinal inflammation significantly contributes to the carcinogenic microenvironment[1,2] and genomic instability able to escape the control of tumour suppressor factors, such as wtp53.3,4 In this context, enteric glial S100B protein overexpression has been linked to the typical features of reactive gliosis, driving the progression from chronic intestinal inflammation to colonic neoplastic lesions
Our results have shown a progressive increase in S100B levels human peritumoral, ulcerative colitis (UC) and tumour mucosal biopsies, which was correlated with the downstream activation of the proliferative signalling pathway receptor for advanced glycation end products (RAGE)/mitogen-activated protein kinase (MAPK)/NF-kappaB and a parallel reduction of proapoptotic protein wtp[53] expression
We demonstrated that pentamidine is able of inhibiting the S100B-mediated sequestration of wtp[53], restoring its ‘genome guardian’ functions in cancer tissue and promoting apoptosis, guarantee prevention of tumorigenic drift through its delivery by PENtamidine loaded VEsicles (PENVE)
Summary
By promoting the release of cytokines, interleukins and other pro-inflammatory signalling molecules, chronic intestinal inflammation significantly contributes to the carcinogenic microenvironment[1,2] and genomic instability able to escape the control of tumour suppressor factors, such as wtp53.3,4 In this context, enteric glial S100B protein overexpression has been linked to the typical features of reactive gliosis, driving the progression from chronic intestinal inflammation to colonic neoplastic lesions. By interacting with the C-terminus of wtp[53], S100B prevents its tetramerization and protein kinase C-mediated phosphorylation, inhibiting the transcriptional and tumour suppressor activity of wtp53.15,16 The targeting of enteric glial S100B protein and wtp53/S100B interaction might represent a new strategy in colorectal carcinoma therapy.[13] In this context, the well-known anti-protozoal drug pentamidine[17] has been shown to disrupt S100B-wtp[53] interaction in melanoma and glioma cells, acting as an inhibitor of S100B pro-cancerogenic activity.[8,18,19] This evidence has clinically translated into ongoing clinical trials, aiming at testing the efficacy of pentamidine as an anticancer drug, in melanoma patients and in patients with metastatic colon cancer undergoing standard chemotherapy as second-line and/or third-line treatment (ClinicalTrials.gov Identifier: NCT00729807 and NCT00809796, respectively). We investigated (d) whether pentamidine vehiculation by PENVE (5 μmol/L) was able to rescue mucosal pro-inflammatory markers and pro-apoptotic factors in order to evaluate whether S100B/wtp[53] targeting by PENVE might potentially represent an alternative strategy to the current colon cancer chemotherapy
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
