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The effects of sulforaphane (a natural product commonly found in broccoli) was investigated on hypoxia inducible factor-1α (HIF-1α) expression in HCT116 human colon cancer cells and AGS human gastric cancer cells. We found that hypoxia-induced HIF-1α protein expression in HCT116 and AGS cells, while treatment with sulforaphane markedly and concentration-dependently inhibited HIF-1α expression in both cell lines. Treatment with sulforaphane inhibited hypoxia-induced vascular endothelial growth factor (VEGF) expression in HCT116 cells. Treatment with sulforaphane modulated the effect of hypoxia on HIF-1α stability. However, degradation of HIF-1α by sulforaphane was not mediated through the 26S proteasome pathway. We also found that the inhibition of HIF-1α by sulforaphane was not mediated through AKT and extracellular signal-regulated kinase phosphorylation under hypoxic conditions. Finally, hypoxia-induced HCT116 cell migration was inhibited by sulforaphane. These data suggest that sulforaphane may inhibit human colon cancer progression and cancer cell angiogenesis by inhibiting HIF-1α and VEGF expression. Taken together, these results indicate that sulforaphane is a new and potent chemopreventive drug candidate for treating patients with human colon cancer.

Betaine is an important human nutrient obtained from various foods and studies in animals and humans have provided results suggesting their pathogenesis of various chronic diseases and points to a role in risk assessment and disease prevention. However, the molecular mechanisms of its activity remain poorly understood and warrant further investigation. This study was performed to investigate the anti-inflammation and tumor preventing capacity of betaine on colitis-associated cancer in mice. In in vivo experiments, we induced colon tumors in mice by azoxymethane (AOM) and dextran sulfate sodium (DSS) and evaluated the effects of betaine on tumor growth. Administration with betaine significantly decreased the incidence of tumor formation with downregulation of inflammation. Treatment with betaine inhibited ROS generation and GSSG concentration in colonic mucosa. Based on the qPCR data, administration of betaine inhibited inflammatory cytokines such TNF-α, IL-6, iNOS and COX-2. In in vitro experiments, LPS-induced NF-κB and inflammatory-related cytokines were inhibited by betaine treatment in RAW 264.7 murine macrophage cells. Our findings suggest that betaine is one of the candidates for the prevention of inflammation-associated colon carcinogenesis.

Corosolic acid (CA), a pentacyclic triterpene isolated from Lagerstroemia speciosa L. (also known as Banaba), has been shown to exhibit anticancer properties in various cancer cell lines. However, the anticancer activity of CA on human colorectal cancer cells and the underlying mechanisms remain to be elucidated. In this study, we investigated the effects of CA on cell viability and apoptosis in HCT116 human colon cancer cells. CA dose-dependently inhibited the viability of HCT116 cells. The typical hallmarks of apoptosis, such as chromatin condensation, a sub-G1 peak and phosphatidylserine externalization were detected by Hoechst 33342 staining, flow cytometry and Annexin V staining following treatment with CA. Western blot analysis revealed that CA induced a decrease in the levels of procaspase-8, -9 and -3 and the cleavage of poly(ADP-ribose) polymerase (PARP). The apoptotic cell death induced by CA was accompanied by the activation of caspase-8, -9 and -3, which was completely abrogated by the pan-caspase inhibitor, z-VAD‑FMK. Furthermore, CA upregulated the levels of pro-apoptotic proteins, such as Bax, Fas and FasL and downregulated the levels of anti-apoptotic proteins, such as Bcl-2 and survivin. Taken together, our data provide insight into the molecular mechanisms of CA-induced apoptosis in colorectal cancer (CRC), rendering this compound a potential anticancer agent for the treatment of CRC.

In this study, we compared cytotoxicity, cell cycle distribution, and apoptosis on MHY336 treatment in three human colorectal carcinoma HCT116 cells: p53+/+ (p53‑wt), p53-/- (p53-null), and p21-/- (p21-null), as well as investigated the roles of p53 and p21 in cell death. Using these three isogenic variants, the roles of p53 and p21 in the cellular response to treatment with MHY336, a novel topoisomerase IIα inhibitor, were investigated. Our results showed that MHY336 treatment increased the expression of p53 over time in cells with wild-type p53 status. This elevated levels of p53 is associated with increased DNA fragmentation, and cleavage of poly(ADP-ribose) polymerase, consistent with increased sensitivity of these cells to apoptotic stimuli. However, p53-null and p21-null cells were more resistant to the antiproliferative and apoptotic effects of MHY336 than p53-wt cells. The same result was achieved by knocking down p53 and p21 with siRNA in p53-wt cells, indicating that p53 and p21 play a crucial role in MHY336-induced cell cycle arrest and apoptosis. Taken together, these results suggest that MHY336 could be a potential candidate to be used in chemoprevention and/or treatment of colon cancer.

Colorectal cancer (CRC) is one of the most common malignant diseases and frequent cause of cancer deaths in the world. In spite of the significant advances in conventional therapeutic approaches to CRC, most patients ultimately die of their disease. There is a need to develop novel preventive approaches for this malignancy. This study was carried out to investigate the anticancer effect of MHY218, a hydroxamic acid derivative, in HCT116 human colon cancer cells. Treatment of cells with MHY218 resulted in growth inhibition and induction of apoptosis in a concentration-dependent manner. MHY218 induced G2/M phase arrest in the cell cycle progression which was observed by flow cytometry analysis, and a decrease in the protein expression of cyclin B1 and its activating partners Cdc25C and Cdc2. MHY218 also caused an increase in the expression levels of p21(WAF1/CIP1), a G2/M phase inhibitor, in a p53-independent pathway. The induction of apoptosis was observed by decreased viability, DNA fragmentation, cleavage of poly(ADP-ribose) polymerase, alteration in the ratio of Bax/Bcl-2 protein expression, and activation of caspase-3, -8 and -9. In addition, MHY218 treatment showed downregulation of the expression levels of the transcription factor nuclear factor-kappa B (NF-κB) in the nucleus, which has been reported to be implicated in the apoptotic cell death of several types of cancer cells, suppression of TNF-α-induced NF-κB activation, inhibition of cyclooxygenase-2 expression, repression of matrix metalloproteinase-9 activation and decrease of 5-lipoxygenase in a concentration-dependent manner. These results suggest that MHY218 may be a useful candidate to be used in the chemoprevention and/or treatment of colon cancer.

Flavonoids have been demonstrated to provide health benefits in humans. Baicalein (5,6,7-trihydroxyflavone) is a phenolic flavonoid compound derived mainly from the root of Scutellaria baicalensis Georgi, a medicinal plant traditionally used in oriental medicine. Baicalein is widely used in Korean and Chinese herbal medicines as anti-inflammatory and anticancer therapy. However, the molecular mechanisms of its activity remain poorly understood and warrant further investigation. This study was performed to investigate the anticancer effect of baicalein on HCT116 human colon cancer cells and the tumor preventing capacity of baicalein on colitis-associated cancer in mice. In in vivo experiments, we induced colon tumors in mice by azoxymethane (AOM) and dextran sulfate sodium (DSS) and evaluated the effects of baicalein on tumor growth. Baicalein treatment on HCT116 cells resulted in a concentration-dependent inhibition of cell growth and induction of apoptotic cell death. The induction of apoptosis was determined by morphological changes and cleavage of poly(ADP-ribose) polymerase. Baicalein also suppressed the activation of NF-κB through PPARγ activation. These results indicate that the anti-inflammatory effects of baicalein may be mediated through PPARγ activation. Finally, administration with baicalein significantly decreased the incidence of tumor formation with inflammation. Our findings suggest that baicalein is one of the candidates for the prevention of inflammation-associated colon carcinogenesis.

Colorectal cancer (CRC) is the second most frequent cancer in men and the third most common cancer in women in Korea. In spite of the significant advances in conventional therapeutic approaches to CRC, most patients ultimately die of their disease. There is a need to develop novel preventive approaches for this malignancy. This study was carried out to investigate the anticancer effect of the diastereoisomeric compounds, MHY-449 and MHY-450, novel dihydrobenzofuro[4,5-b][1,8]naphthyridin-6-one derivatives, on HCT116 human colon cancer cells. MHY-449 exhibited more potent cytotoxicity than MHY-450, against HCT116 cells. Treatment of cells with MHY-449 resulted in growth inhibition and induction of apoptosis in a concentration-dependent manner, and inhibition of proliferation in a time-dependent manner. The induction of apoptosis was observed by decreased cell viability, DNA fragmentation, activation of protein levels involved in death receptors. Moreover, activation of caspase-3, -8 and -9 and cleavage of poly(ADP-ribose) polymerase and alteration in the ratio of Bax/Bcl-2 protein expression was observed. MHY-449 induced G2/M phase arrest in the cell cycle progression which was observed by flow cytometry analysis, and a decrease in the protein expression of cyclin B1 and its activating partners Cdc25c and Cdc2. MHY-449 also caused increase in the expression levels of p53, a tumor suppressor gene, and p21WAF1/CIP and p27KIP, G2/M phase inhibitors. These results suggest that MHY-449 may be a useful candidate for chemo-prevention and/or treatment of colon cancer.