Natural compound as anticancer agent: in vitro experimental evidence in Intrahepatic Cholangiocarcinoma (2024)

IntroductionIntrahepatic cholangiocarcinoma (iCCA) constitutes a highly aggressive and heterogeneous biliary tract cancer bearing a fatal prognosis (5-years relative survival rate). Due to its aggressiveness, there is an urgent need for therapeutic alternatives since advances in iCCA therapy represent an unfulfilled need in cancer research. Its heterogeneity is mirrored by an innovative classification into small and large bile duct iCCA. The molecular pathogenesis of iCCA is very elaborate and embroils distinct molecular networks: among them, Hedgehog (Hh) pathway plays a critical role in tumor survival, proliferation, migration and epithelial-mesenchymal transition reprogramming. Evidence on the pathogenetic role of Hh in iCCA connotes the possibility of targeting this signaling pathway for therapeutic intents in iCCA. The main purpose of this study is to shed light on 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.Material and MethodsThe 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. Colony formation has been evaluated by clonogenic formation assay. Cell death has been explored by Flow cytometry analyses. All results were confirmed in at least three independent experiments and all quantitative data were reported as the mean ± SEM. Student’s t-tests for paired samples were used to assess differences among two groups. A p-value of <0.05 was considered statistically significant (n.s., nonsignificant, p > 0.05; *p < 0.05; **p < 0.01; ***p < 0.001).Results and DiscussionsOur research illustrates a decrease in iCCA cell rate viability, migration, colony formation and a Gli1 levels depletion in a dose- and time-dependent manner after both free GlaB and HA-GlaB treatments (0.05<0.001), leading to a significant reduction of invasiveness and aggressiveness of cancer cells. Eventually, flow cytometry preliminary data shows cell death induction, as a consequence of drug administration compared to controls.ConclusionAberrant Hh pathway activation is widely known to be closely related with the development and progression of various cancers, including iCCA. These data represent the cornerstones for in vivo pre-clinical studies of HA-encapsuled GlaB in iCCA.

Natural compound as anticancer agent: in vitro experimental evidence in Intrahepatic Cholangiocarcinoma / Paradiso, S.; Carpino, G.; Botta, B.; Quaglio, D.; Di Meo, C.; Infante, P.; Di Marcotullio, L.; Gaudio, E.; Alvaro, D.; Cardinale, V.. - Volume 18:(2024), pp. 251-252. (Intervento presentato al convegno The 2024 Annual Congress of the European Association for Cancer Research: Innovative Cancer Science tenutosi a Rotterdam - Netherlands).

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