Introduction Intrahepatic cholangiocarcinoma (iCCA) constitutes a rare and aggressive cancer that emerge in the biliary tree bearing a fatal prognosis (5-years relative survival rate). iCCA is characterized by intertumoral clinical-pathological and molecular heterogeneity, leading to a new histological classification approved by WHO (ICD-O-3.2), into small and large bile duct iCCA. The molecular pathogenesis of iCCA embroils multiple molecular networks: among them, Hedgehog (Hh) pathway plays a key role in many aspects of iCCA, such as tumor proliferation, survival, migration, and epithelial-mesenchymal transition. Evidence on the pathogenetic role of Hh in iCCA entails the chance of targeting this cascade for therapeutic purposes in iCCA. Aim The main purpose of this study is to test a new natural compound, named Glabrescione B (GlaB) able to selectively inhibit Gli1 (Hh downstream transcriptional factor), in vitro in established and primary cell lines. Materials and Methods Results The dose-response effect of free GlaB and hyaluronic acid (HA)-encapsulated GlaB (HA-GlaB) has been assessed by Trypan Blue Exclusion Test. The target protein expression levels have been analysed by Western blot. The cell migratory activity has been evaluated by Wound healing assay. Cell death has been explored by Flow cytometry analyses. All experiments have been conducted in N.3 experimental replicates. Results Our research illustrates a decrease in iCCA cell rate proliferation, migration and a Gli1 levels reduction in a dose- and time-dependent manner after both free GlaB and HA-GlaB treatments (p<0.05), leading to a considerable reduction of proliferation and invasiveness in cancer cells. Eventually, flow cytometry preliminary data shows cell death, as a consequence of drug administration compared to controls. Conclusion These data shed a light on a novel and putative natural therapeutic compound for the treatment of iCCA.
Targeting Hedgehog signaling pathway by a natural compound: a promising approach for anti-cancer therapeutic development in Intrahepatic Cholangiocarcinoma / Paradiso, S.; Carpino, G.; Quaglio, D.; Ghirga, F.; Di Meo, C.; Paoletti, L.; De Luca, T.; Franchitto, M.; Di Marcotullio, L.; Infante, P.; Gaudio, E.; Alvaro, D.; Cardinale, V.. - 56:(2024), pp. 23-23. (Intervento presentato al convegno 56th Annual Meeting of the Italian Association for the Study of the Liver tenutosi a Rome; Italy).
Targeting Hedgehog signaling pathway by a natural compound: a promising approach for anti-cancer therapeutic development in Intrahepatic Cholangiocarcinoma
Paradiso, S.
Primo
Investigation
;Carpino, G.;Quaglio, D.;Ghirga, F.;Di Meo, C.;Paoletti, L.;De Luca, T.;Franchitto, M.;Di Marcotullio, L.;Infante, P.;Gaudio, E.;Alvaro, D.Funding Acquisition
;Cardinale, V.
Supervision
2024
Abstract
Introduction Intrahepatic cholangiocarcinoma (iCCA) constitutes a rare and aggressive cancer that emerge in the biliary tree bearing a fatal prognosis (5-years relative survival rate). iCCA is characterized by intertumoral clinical-pathological and molecular heterogeneity, leading to a new histological classification approved by WHO (ICD-O-3.2), into small and large bile duct iCCA. The molecular pathogenesis of iCCA embroils multiple molecular networks: among them, Hedgehog (Hh) pathway plays a key role in many aspects of iCCA, such as tumor proliferation, survival, migration, and epithelial-mesenchymal transition. Evidence on the pathogenetic role of Hh in iCCA entails the chance of targeting this cascade for therapeutic purposes in iCCA. Aim The main purpose of this study is to test a new natural compound, named Glabrescione B (GlaB) able to selectively inhibit Gli1 (Hh downstream transcriptional factor), in vitro in established and primary cell lines. Materials and Methods Results The dose-response effect of free GlaB and hyaluronic acid (HA)-encapsulated GlaB (HA-GlaB) has been assessed by Trypan Blue Exclusion Test. The target protein expression levels have been analysed by Western blot. The cell migratory activity has been evaluated by Wound healing assay. Cell death has been explored by Flow cytometry analyses. All experiments have been conducted in N.3 experimental replicates. Results Our research illustrates a decrease in iCCA cell rate proliferation, migration and a Gli1 levels reduction in a dose- and time-dependent manner after both free GlaB and HA-GlaB treatments (p<0.05), leading to a considerable reduction of proliferation and invasiveness in cancer cells. Eventually, flow cytometry preliminary data shows cell death, as a consequence of drug administration compared to controls. Conclusion These data shed a light on a novel and putative natural therapeutic compound for the treatment of iCCA.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
