Novel dihydrobenzofuro[4,5-b][1,8]naphthyridin-6-one derivative, MHY-449, induces apoptosis and cell cycle arrest in HCT116 human colon cancer cells

Abstract

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.

Novel dihydrobenzofuro[4,5-b][1,8]naphthyridin-6-one derivative, MHY-449, induces cell cycle arrest and apoptosis via the downregulation of Akt in human lung cancer cells

“…Of note, the downregulation of caspases-3, -9, and -8, as well as cleavage of PARP, was observed in present study. The observed caspase-mediated properties of MHY-449 are in agreement with previous studies using colon (6) and prostate (7) cancer cells. We also demonstrated that MHY-449, in the presence of Z-VAD-FMK, prevented the degradation of PARP in these cells.…”

“…In the present study, we have determined that synthetic MHY-449 exerts potent antitumor effects in NSCLC cells. To the best of our knowledge, this is the first study describing this effect of MHY-449 on NSCLC cells, despite its documented cytotoxicity in numerous other cancer cell lines (5)(6)(7). MHY-449 can effectively induce NSCLC cells to undergo apoptosis.…”

“…The (±)-(R * )-5-methoxy-11-methyl-2-((R * )-2-methyloxiran-2-yl)-1,2-dihydrobenzofuro [4,5-b] [1,8]naphthyridin-6(11H)-one, MHY-449, is a novel synthetic compound containing xanthone and acridone components, derived from psorospermin and acronycine templates, respectively (5). MHY-449 has been shown to induce apoptosis in various human cancer cell lines, including breast (5), colon (6) and prostate (5,7). While its precise mechanism of anticancer activity has not been fully elucidated, we have previously reported that MHY-449 induces G2/M phase cell cycle arrest (5,6), inhibits Akt/forkhead box O1 (7), activates caspases (6) and extracellular signalregulated kinase (ERK) (7), modulates cell cycle regulatory proteins (6), and downregulates the anti-apoptotic protein Bcl-2 (6,7).…”

“…MHY-449 has been shown to induce apoptosis in various human cancer cell lines, including breast (5), colon (6) and prostate (5,7). While its precise mechanism of anticancer activity has not been fully elucidated, we have previously reported that MHY-449 induces G2/M phase cell cycle arrest (5,6), inhibits Akt/forkhead box O1 (7), activates caspases (6) and extracellular signalregulated kinase (ERK) (7), modulates cell cycle regulatory proteins (6), and downregulates the anti-apoptotic protein Bcl-2 (6,7). These anticancer activities make MHY-449 an attractive candidate for potential pharmaceutical development.…”

A novel hydroxamic acid derivative, MHY218, induces apoptosis and cell cycle arrest through downregulation of NF-κB in HCT116 human colon cancer cells

“…CRC is the fourth most common cancer in the world, but it is more common in developed countries. CRC is the third most common cancer and the fourth leading cause of cancer-related death in Korea and the incidence of CRC have been increased rapidly over the past few decades (1,2). While surgical resection cures >50% of CRC patients, 40-50% of these subjects eventually experience recurrences, leaving only a minority amenable to re-operation (3).…”