Dong Cho Han

Antitumor effect of the cinnamaldehyde derivative CB403 through the arrest of cell cycle progression in the G2/M phase.

Cinnamaldehydes have been shown to have inhibitory effects on farnesyl protein transferase (FPTase; EC 2.5.1.29) in vitro, angiogenesis, cell-cell adhesion, and tumor cell growth and to be immunomodulators. However, the mechanisms responsible for these effects remain unknown. To elucidate the molecular mechanism of the cinnamaldehyde derivative CB403 for growth inhibition, CB403 was synthesized from 2-hydroxycinnamaldehyde. CB403-treated cells were weakly adherent to the culture dishes. In addition, CB403 inhibited tumor growth in these cells in a concentration-dependent manner. FACS analysis using human cancer cells treated with this compound showed cell cycle arrest in mitosis, which was correlated with a marked increase in the amount of cyclin B1. Furthermore, CB403 blocked in vivo growth of human colon and breast tumor xenografts without loss of body weight in nude mice. These results support the hypothesis that the cinnamaldehyde derivative CB403 exerts cytostatic properties by inducing mitotic arrest in cancer cells.

Biflavonoids inhibited phosphatase of regenerating liver-3 (PRL-3)

Two biflavonoids, ginkgetin (1) and sciadopitysin (2), were isolated from the MeOH extract of the young branches of Taxus cuspidata, which inhibited phosphatase of regenerating liver-3 (PRL-3) with IC50 values of 25.8 and 46.2u2009μM, respectively. This is the first report on PRL-3 inhibitors, isolated from natural sources.

Obovatol inhibits colorectal cancer growth by inhibiting tumor cell proliferation and inducing apoptosis.

Neolignans such as obovatol, honokiol, and magnolol have been previously reported to show various biological activities including anti-inflammation and antitumor effects. This is the first demonstration on the in vivo antitumor effect of obovatol on human colorectal carcinoma SW620 cells. Nude mice were implanted with SW620 cells and fed with vehicle or 5mg/kg/d dose of obovatol for 20 days. Obovatol inhibited tumor growth that accounted for 50% decrease in tumor volume and 44.6% decrease in tumor weight at the end of the experiment without any adverse health effect. In nude mice bearing SW620-incubated tumor, obovatol exhibited more potent antitumor activity than honolkiol. In addition, DNA flow cytometric analysis shows that obovatol progresses to apoptosis as detected by flow cytometry after double staining with annexin V and propidium iodide. Thus, we suggest that obovatol is a potent inducer of cell apoptosis in SW620 cells, and a potent antitumor agent.

Phosphatase of regenerating liver-3 promotes migration and invasion by upregulating matrix metalloproteinases-7 in human colorectal cancer cells

Phosphatase of regenerating liver (PRL)‐3, a member of a subgroup of protein tyrosine phosphatases that can stimulate the degradation of the extracellular matrix, is over‐expressed in metastatic colorectal cancer (CRC) relative to primary tumors. To determine whether PRL‐3‐induced enhancement of migration and invasion is dependent on the expression of matrix metalloproteinases (MMPs), PRL‐3 was expressed in DLD‐1 human CRC cells. The motility, migration and invasion characteristics of the cells were examined, and metastasis to the lung was confirmed in a nude mouse using PRL‐3‐overexpressing DLD‐1 cells [DLD‐1 (PRL‐3)]. Migration and invasion of the cells were inhibited by phosphatase and farnesyltransferase inhibitors. Expression of MMPs was enhanced 3‐ to 10‐fold in comparison to control cells, and migration and invasion were partially inhibited by small interfering RNA (siRNA) knockdown of MMP‐2, ‐13 or ‐14. Importantly, siRNA knockdown of MMP‐7 completely inhibited the migration and invasion of DLD‐1 (PRL‐3) cells, whereas overexpression of MMP‐7 increased migration. The expression of MMP‐7 was also downregulated by phosphatase and farnesyltransferase inhibitors. It was found that PRL‐3 induced MMP‐7 through oncogenic pathways including PI3K/AKT and ERK and that there is a relationship between the expression of PRL‐3 and MMP‐7 in human tumor cell lines. The expression of MMP‐13 and ‐14 was very sensitive to the inhibition of farnesyltransferase; however, the migration and invasion of DLD‐1 (PRL‐3) cells did not strongly depend on the expression of MMP‐13 or ‐14. These results suggest that the migration and invasion of PRL‐3‐expressing CRC cells depends primarily on the expression of MMP‐7.

Emodin inhibits migration and invasion of DLD-1 (PRL-3) cells via inhibition of PRL-3 phosphatase activity.

Anthraquinones have been reported as phosphatase inhibitors. Therefore, anthraquinone derivatives were screened to identify a potent phosphatase inhibitor against the phosphatase of regenerating liver-3 (PRL-3). Emodin strongly inhibited phosphatase activity of PRL-3 with IC(50) values of 3.5μM and blocked PRL-3-induced tumor cell migration and invasion in a dose-dependent manner. Emodin rescued the phosphorylation of ezrin, which is a known PRL-3 substrate. The results of this study reveal that emodin is a PRL-3 inhibitor and a good lead molecule for obtaining a selective PRL-3 inhibitor.

2-Hydroxycurcuminoid induces apoptosis of human tumor cells through the reactive oxygen species–mitochondria pathway

2-Hydroxycinnamaldehyde (HCA) and curcumin have been reported to have antitumor effects against various human tumor cells in vitro and in vivo by generation of ROS. Aldehyde-free HCA analogs were synthesized based on the structure of curcumin, which we have called 2-hydroxycurcuminoids. The hydroxyl group of curcuminoids enhances the ability to generate ROS. 2-Hydroxycurcuminoid (HCC-7) strongly inhibited the growth of SW620 colon tumor cells with a GI(50) value of 7μM, while the parent compounds, HCA and curcumin, displayed GI(50) values of 12 and 30μM, respectively. HCC-7 was found to induce apoptosis through the reactive oxygen species-mitochondria pathway and cell cycle arrest at G2/M phase.

Cinnamaldehydes in Cancer Chemotherapy.

Cinnamaldehyde and cinnamaldehyde‐derived compounds are candidates for the development of anticancer drugs that have received extensive research attention. In this review, we summarize recent findings detailing the positive and negative aspects of cinnamaldehyde and its derivatives as potential anticancer drug candidates. Furthermore, we describe the in vivo pharmacokinetics and metabolism of cinnamaldehydes. The oxidative and antioxidative properties of cinnamaldehydes, which contribute to their potential in chemotherapy, have also been discussed. Moreover, the mechanism(s) by which cinnamaldehydes induce apoptosis in cancer cells have been explored. In addition, evidence of the regulatory effects of cinnamaldehydes on cancer cell invasion and metastasis has been described. Finally, the application of cinnamaldehydes in treating various types of cancer, including breast, prostate, and colon cancers, has been discussed in detail. The effects of cinnamaldehydes on leukemia, hepatocellular carcinoma, and oral cancer have been summarized briefly. Copyright

Biological effects of G1 phase arrest compound, sesquicillin, in human breast cancer cell lines.

Sesquicillin, isolated from fungal fermentation broth, strongly induced G1 phase arrest in human breast cancer cells. During G1 phase arrest, the expression level of cyclin D1, cyclin A, and cyclin E was decreased, and the expression of CDK (cyclin-dependent-kinase) inhibitor, protein p21(Waf1/Cip1), was increased in a time-dependent manner in a breast cancer cell MCF-7. Interestingly, the G1 phase arrest induced by sesquicillin also occurred independently of the tumor suppressor protein, p53. Sesquicillin inhibits the proliferation of MCF-7 via G1 phase arrest in association with the induction of CDK inhibitor protein, p21(Waf1/Cip1), and the reduction of G1 phase related-cyclin proteins.

Confirmation of a linkage between H-Ras and MMP-13 expression as well as MMP-9 by chemical genomic approach.

As farnesylation of the Ras protein by farnesyl transferase is a critical step for the Ras functional activity, the farnesyl transferase inhibitor could affect H‐Ras functions and the inhibitors such as arteminolide, SCH66336 and LB42908 completely inhibited Ras‐farnesylation. However, they did not induce apoptosis of H‐Ras‐transformed cells with concentration for blocking H‐Ras farnesylation. To determine the antitumor effects of the inhibitors, it was analyzed through the expression profile of genes, regulated by activated H‐Ras or FTIs by using cDNA microarray. On the basis of the results, the relationship between H‐Ras and MMPs expression was confirmed by RT‐PCR, Western bolt, zymographic analysis and angiogenesis assay. Our results suggested that activation of MMP‐13 as well as MMP‐9 induced by H‐Ras is involved in angiogenesis and with farnesyl transferase inhibitors, in part, exerts their anticancer effects. We confirmed that MMP‐13 is a critical H‐Ras target gene through chemical genomic approaches with farnesyl transferase inhibitors.

Cosmomycin C inhibits signal transducer and activator of transcription 3 (STAT3) pathways in MDA-MB-468 breast cancer cell.

The signal transducer and activator of transcription 3 (STAT3) is constitutively activated in cancer cells. Therefore, blocking the aberrant activity of STAT3 in tumor cells is a validated therapeutic strategy. To discover novel inhibitors of STAT3 activity, we screened against microbial natural products using a dual-luciferase assay. Using the microbial metabolome library, we identified cosmomycin C (CosC), which was isolated from the mycelium extract of Streptomyces sp. KCTC19769, as a STAT3 pathway inhibitor. CosC inhibited STAT3 (Tyr705) phosphorylation and subsequent nuclear translocation in MDA-MB-468 breast cancer cells. CosC-mediated inhibition of STAT3 signaling pathway was confirmed by suppressed expression of STAT3 downstream target proteins including cyclin D1, Bcl-xL, survivin, Mcl-1, and VEGF in CosC-treated MDA-MB-468 cells. Flow cytometry showed that CosC caused accumulation in the G(0)-G(1) phase of the cell cycle and induced apoptosis via PARP cleavage and caspase-3 activation. Based on these findings, CosC may be a potential candidate for modulation of STAT3 pathway.