Sanggenon C decreases tumor cell viability associated with proteasome inhibition

Abstract

Several flavonoids have been reported to be proteasome inhibitors, but whether prenylated flavonoids are able to inhibit proteasome function remains unknown. We report for the first time that Sanggenon C, a natural prenylated flavonoid, inhibits tumor cellular proteasomal activity and cell viability. We found that (1) Sanggenon C inhibited tumor cell viability and induced cell cycle arrest at G0/G1 phase; (2) Sanggenon C inhibited the chymotrypsin-like activity of purified human 20S proteasome and 26S proteasome in H22 cell lysate, and Sanggenon C was able to dosedependently accumulate ubiquitinated proteins and proteasome substrate protein p27; (3) Sanggenon C-induced proteasome inhibition occurred prior to cell death in murine H22 and P388 cell lines; (4) Sanggenon C induced death of human K562 cancer cells and primary cells isolated from leukemic patients. We conclude that Sanggenon C inhibits tumor cell viability via induction of cell cycle arrest and cell death, which is associated with its ability to inhibit the proteasome function and that proteasome inhibition by Sanggenon C at least partially contributes to the observed tumor cell growth-inhibitory activity. Proteasome inhibition has been demonstrated as a novel therapeutic strategy in multiple disease models, including fibrosis (4), inflammation (5), ischemia-reperefusion injury (6), myocardial hypertrophy (7) and cancer (8). Proteasome inhibitor bortezomib (Valcade or PS-341) has been approved by the United States FDA to treat multiple myeloma. Other proteasome inhibitors are now under clinical trials for cancer therapy (8). However, there were some associated toxicity observed in the clinical trials using bortezomib (8). Therefore, there is a need to search for novel proteasome inhibitors with decreased side effect. It is an attractive idea to identify and isolate novel natural proteasome inhibitors from medicinal plants. Many of the reported natural proteasome inhibitors belong to the flavonoid family (3). Among all these reported natural flavonoid proteasome inhibitors, an aromatic ketone structure plays a very important role for binding to the threonine residue at the N terminus (Thr 1) of the proteasome subunits and inhibiting the proteasomal activities (3, 9, 10). KeywordsSeveral flavonoids have been isolated from the stem bark of Morus cathayana (SANGPAIPI), including Sanggenon C. Sanggenon C is a flavanone Diel-Alder adduct compound. Up to now, there are only a few reports on the biological and pharmacological effects of Sanggenon C. It has been reported that Sanggenon C has anti-oxidant and antiinflammation activities (2) and could inhibit TNF-alpha-stimulated cell adhesion and expression of VCAM-1 by suppressing the activation of NF-kappa B. It has also been proposed that Sanggenon C decreases ICAM-1 protein expression at a post-translational level (11). In addition, it was reported that Sanggenon C inhibited protein tyrosine phosphatase 1B (12) and possessed the function to decrease blood pressure. Since Sanggenon C possesses the mo...

Sanggenon C inhibits cell proliferation and induces apoptosis by regulating the MIB1/DAPK1 axis in glioblastoma

“…After MIB1 was once overexpressed, it may want to needless to say block the upregulation of DAPK1 precipitated with the aid of SC. Previous findings confirmed that SC was once in a position to accumulate proteasome substrate protein p27 in a dose‐dependent manner in general precipitated proteasome inhibition in murine H22 and P388 cell strains 15 . Similarly, our results indicated that SC therapy decreased MIB1‐mediated DAPK protein degradation in a dose‐dependent manner in GBM cells.…”

“…Interest in SC's anti‐cancer properties has grown recently as a result of in vitro and animal research showing that it slows tumor growth, including cell cycle and cell death. In human K562 cancer cells, SC displayed strong inhibitory effects by inducing cell cycle arrest and cell death via inhibiting tumor cellular proteasomal activity 15 . In addition, another study documented that SC could dose‐dependently induce cell death by activating caspase3 and caspase9 signaling 16 .…”

Synthesis, Biosynthesis, and Biological Activity of Diels–Alder Adducts from Morus Genus: An Update

“…Kuwanon Y was shown to inhibit protein kinase C (PKC) with an IC 50 value of 15 μM [ 106 ]. Sanggenon C ( 13 ) inhibited tumour cellular proteasomal activity and cell viability via induction of cell cycle arrest and cell death, but also induced necrotic cell death in cancer cells, which could limit the clinical potential of Sanggenon C [ 107 ]. Sanggenons C and O ( 13 and 14 ) and kuwanon J were evaluated using luciferase reporter assay and were found to inhibit hypoxia-induced HIF-1α accumulation in a dose-dependent manner in human hepatocellular carcinoma cell-line Hep3B cells (IC 50 = 1.03 μM, for sanggenon O ( 14 )) [ 108 ].…”

Bioactive Phytoconstituents of Morus Plants exhibiting Numerous Therapeutic Activities

“…Compounds isolated from M. alba exhibit antitumor activities by different mechanisms, where kuwanons inhibit hypoxia-induced HIF-1α accumulation [44], and inhibit protein kinase C [45]. Sanggenons also inhibit hypoxia-induced HIF-1α accumulation [44], induce internucleosomal DNA fragmentation [46], induce cell cycle arrest at G0/G1 phase, and inhibit the chymotrypsin-like activity [47].…”