Executive Summary : | Colorectal cancer (CRC) contributes to the second leading cause of cancer-related mortality, with 1.9 million new cases and 0.9 million deaths worldwide in 2020 1. Three-fourths of CRC cases develop via conventional adenomatous polyps to ultimately invasive and metastatic disease. The adenomatous polyposis coli (APC), a housekeeping gene, modulates cell proliferation, adhesion, apoptosis, migration, and DNA repair 2,3. Mutated and inactivated APC gene initiates the tumorigenesis in most (~90%) sporadically occurring CRC. APC functions as a Wnt-signal antagonist, forms β-catenin destruction complex (DC) with Axin, glycogen synthase kinase-3 (GSK3), and casein kinase 1 α (CK1α), and regulates the phosphorylation and ubiquitin-mediated proteolytic degradation of oncoprotein β-catenin. Predisposed genetic alterations (APC mutations) result in the truncated APC proteins leaving most of the C-terminal portion and activating the aberrant Wnt/β-catenin signaling pathway, causing the destruction complex disassembly and β-catenin accumulation in the cytoplasm 4. Accumulated β-catenin translocates to the nucleus, binds to lymphoid enhancer factor/T-cell factor (LEF/TCF) family of transcription factors and co-factors, and activates expression of downstream target genes such as c-myc and cyclin D1 5,6. β-catenin remains an easy target for cancer therapy to identify druggable vulnerabilities for CRC cancers. Also, most small molecules that target only β-catenin/Tcf4 protein complex/PORCN/Tankyrase are in clinical trials, which include natural compounds and repurposed drugs for treating CRC 7-10. Sesquiterpene lactones (SLs) are plant-based terpenoid classes employed in cancer clinical trials 11. Guaianolides represent the most biologically potent SLs attributed to the α-methylene-γ-lactone group and are mostly isolated from the genus Centaurea 12. Centaurea depressa is commonly prescribed in the Amchi system of medicine in Ladakh regions for treating chest pain, abdominal pain, cold, cough, and fever in Ladakh regions 13. In our proof of concept, CPS-2, a 6,12-guaianolide type from C. depressa ethanolic extract, expressed potent anticancer activities with colon cancer cell lines, HCT-116 and SW-620 at 1.58 and 0.73 µM, respectively. Low expression of β-catenin and cyclin D1 was observed in the treated group through in vitro western blotting analysis, indicating the proteasomal degradation of β-catenin and block of downstream target genes. Also, the bioactive compounds from other extracts are under exploration. The potential candidate(s) will be studied for in-vivo efficacy using ApcMin/+ mice and for non-GLP safety and toxicity profiles in-house with good laboratory practices (GLP) principles following respective OECD guidelines. |