title: MHY-449, a novel dihydrobenzofuro[4,5-b][1,8] naphthyridin-6-one derivative, induces apoptotic cell death through modulation of Akt/FoxO1 and ERK signaling in PC3 human prostate cancer cells.
abstract: Previously, we reported on the anticancer effect of the diastereoisomeric compound MHY-449, a novel dihydro-benzofuro[4,5-b][1,8] naphthyridin-6-one derivative, in HCT116 human colon cancer cells. In the current study, we investigated whether MHY-449 has anticancer effect in prostate cancer cells, and if so, what the molecular mechanisms are. We examined the growth inhibitory effect of MHY-449 on p53 wild‑type (p53-wt) LNCaP (androgen‑dependent) and p53-null PC3 (androgen-independent) prostate cancer cells. MHY-449 treatment in androgen-independent and p53-null PC3 cells resulted in inhibition of cell growth and induction of apoptosis in a concentration-dependent manner. However, MHY-449 did not show any significant effects on the growth inhibition and apoptotic cell death in androgen-dependent and p53-wt LNCaP cells. Therefore, we used PC3 cells for further studies. The induction of apoptosis in PC3 cells was observed by decreased viability, DNA fragmentation, cleavage of poly (ADP-ribose) polymerase, activations of caspase-3, -8 and -9, and alteration in the ratio of Bax/Bcl-2 protein expression. In addition, MHY-449 induced increase of late apoptosis and sub-G1 DNA which were observed by flow cytometry analysis. Furthermore, MHY-449 reduced the phosphorylation of Akt and FoxO1 and induced the translocation of FoxO1 from cytoplasm to nucleus as shown by western blot analysis. MHY-449 treatment activated extracellular signal-regulated kinase (ERK) signaling in a concentration-dependent manner. MHY-449-induced apoptosis was partially prevented by pretreatment with the ERK inhibitor PD98059 suggesting involvement of ERK in the MHY-449-induced apoptosis. Taken together, these findings suggest that MHY-449 induces apoptosis via downregulation of the Akt/FoxO1 and activation of ERK in androgen-independent, p53-null and PTEN-negative PC3 human prostate cancer cells.
authors.affiliation: College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Sun Hwa
authors.initials: SH
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Yong Jung
authors.initials: YJ
authors.lastname: Kang
authors.affiliation: College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Bokyung
authors.initials: B
authors.lastname: Sung
authors.affiliation: College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Dong Hwan
authors.initials: DH
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Hyun Sook
authors.initials: HS
authors.lastname: Lim
authors.affiliation: College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Hye Rim
authors.initials: HR
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Seong Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Jeong-Hyun
authors.initials: JH
authors.lastname: Yoon
authors.affiliation: College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Hyung Ryong
authors.initials: HR
authors.lastname: Moon
authors.affiliation: College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Hae Young
authors.initials: HY
authors.lastname: Chung
authors.affiliation: College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Nam Deuk
authors.initials: ND
authors.lastname: Kim
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001572:Benzofurans / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009287:Naphthyridines / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D001572:Benzofurans; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C579798:MHY-449; D009287:Naphthyridines; D051057:Proto-Oncogene Proteins c-akt