<p>Isobavachalcone isolated from <em>Psoralea corylifolia</em> inhibits cell proliferation and induces apoptosis via inhibiting the AKT/GSK-3&beta;/&beta;-catenin pathway in colorectal cancer cells</p>

Abstract

Background: Colorectal cancer (CRC) is a common form of cancer associated with a high mortality rate and poor prognosis. Given the limited efficacy of current therapies for CRC, interest in novel therapeutic agents isolated from natural sources has increased. We studied the anticancer properties of isobavachalcone (IBC), a flavonoid isolated from the herb Psoralea corylifolia , which is used in traditional Chinese medicine, in an in vitro model of CRC. Materials and methods: Cell viability and growth of CRC cells were determined by Cell Counting Kit-8 and colony formation assays following treatment with varying concentrations of IBC, respectively. Apoptosis was examined by 4′,6-diamidino-2-phenylindole staining and flow cytometry with Annexin V/propidium iodide double staining. Western blot analysis was used to analyze expression of apoptosis-associated protein pathway and the AKT/GSK-3β/β-catenin signaling pathway. Results: Initial experiments showed that IBC inhibited proliferation and colony formation of human CRC cell lines in dose- and time-dependent manners. The antiproliferative effect of IBC resulted from induction of apoptosis, as evidenced by morphological changes in the nucleus, flow cytometry analysis, upregulation of cleaved caspase-3 and cleaved PARP, changes in the ratio of the anti-apoptotic protein Bcl-2 and the pro-apoptotic protein Bax, translocation of Bax from the cytosol to the mitochondria, and decreased expression of two inhibitors of apoptosis family proteins, XIAP, and survivin. Western blot analysis of signaling pathway proteins demonstrated that IBC downregulated Wnt/β-catenin signaling, which has previously been associated with CRC, by inhibiting the AKT/GSK-3β signaling pathway. Conclusion: This study demonstrated that IBC inhibited cell proliferation and induced apoptosis through inhibition of the AKT/GSK-3β/β-catenin pathway in CRC. These results suggest the potential of IBC as a novel therapeutic agent for the treatment of CRC.

Chalcone Derivatives: Role in Anticancer Therapy

“…Moreover, IBC has been found to induce ROS-mediated apoptosis by targeting thioredoxin reductase 1 (TrxR1) in human prostate cancer [ 42 ]. IBC has also been demonstrated to inhibit cell proliferation and induce apoptosis by suppressing the AKT/glycogen synthase kinase 3β (GSK3β)/β-catenin pathway in colorectal cancer cells [ 43 ]. Additionally, IBC can inhibit estrogen receptor alpha (ERα) and decrease CD44 antigen expression, which leads to decreased paclitaxel resistance in ER+ breast cancer [ 44 ].…”

Molecular Mechanisms of Antiproliferative Effects of Natural Chalcones

“…Treatment of colorectal cancer cells with IBC initiated several processes resulting in the mitochondrial apoptosis pathway as documented by changes in Bcl-2/Bax ratio, translocation of Bax to the mitochondria, activation of caspase-3, as well as PARP cleavage. Moreover, the expression of the inhibitors of apoptosis, XIAP and survivin, has been downregulated [ 63 ]. Additionally, the propapototic effect of IBC can be also related to the downregulation of ERKs/RSK2 or Akt signaling pathways [ 64 , 65 , 66 ].…”

Emerging Roles of Wnt Ligands in Human Colorectal Cancer

“…Interestingly, the effect of EGCG on CRC could be attributed to the inhibition on CRC stem cells by suppressing the canonical Wnt signaling (155). Furthermore, other natural compounds such as calycosin, isobavachalcone, resveratrol, etc., were also proved to suppress the malignant phenotypes of CRC via inhibiting the Wnt signaling pathways (156)(157)(158), providing more feasible therapeutic options for CRC treatment. However, few natural compounds have been proven to suppress the development of CRC by directly targeting Wnts, and none of them is currently undergoing clinical testing.…”