title: Effects of a novel carbocyclic analog of pyrrolo[2,3-d]pyrimidine nucleoside on pleiotropic induction of cell death in prostate cancer cells with different androgen responsiveness.
abstract: Prostate cancer is the most frequently diagnosed cancer and is one of the leading causes of male cancer death in the world. Recently, in the course of our screening for a novel anticancer compound, we synthesized carbocyclic analogs of pyrrolo[2,3-d]pyrimidine nucleoside; compounds 5, and 6. In the current study, we report the effects of compound 5 on pleiotropic induction of cell death via up-regulation of AR-associated p21(Cip1) protein in prostate cancer cells with different androgen responsiveness, such as LNCaP (androgen-dependent and -sensitive), LNCaP(C4-2) (androgen-independent and -sensitive; androgen-refractory), and DU145 (androgen-independent and -insensitive) cells. The treatment of LNCaP cells with 6 μM compound 5 for 24 h stimulated the androgen receptor (AR) activity and dramatically up-regulated transcription (56-fold) of p21(Cip1), which, in turn, induces typical apoptosis in the cells. However, induction of apoptosis through up-regulation (23-fold) of AR-associated p21(Cip1) achieved in LNCaP(C4-2) cells was possible by intensive cell treatment with compound 5 (9 μM, 48 h), because the cells are less sensitive and independent to androgen than LNCaP cells. Furthermore, 6 μM compound 5-treated DU145 cells, which exhibit extremely low AR activation due to no androgen responsiveness and dependency, showed neither up-regulation of p21(Cip1) nor apoptotic induction. Instead, a different type of cell death, autophagy-like death through the LC3B-associated autophagosome formation, was obviously induced in DU145 cells. Taken together, our results suggest that pleiotropic induction of prostate cancer cell death by compound 5 is determined by how efficiently and how abundantly androgen-dependent activation of the AR occurs, whereas compound 6 shows no induction of apoptosis in LNCaP cells.
authors.affiliation: Department of Pharmacy, College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Gyeonggido 15588, Republic of Korea.
authors.forename: Hyewon
authors.initials: H
authors.lastname: Suh
authors.affiliation: Department of Pharmacy, College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Gyeonggido 15588, Republic of Korea.
authors.forename: Ko-woon
authors.initials: KW
authors.lastname: Choi
authors.affiliation: Department of Bionanotechnology, Hanyang University, Gyeonggido 15588, Republic of Korea.
authors.forename: Jongbok
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Pharmacy, College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Gyeonggido 15588, Republic of Korea.
authors.forename: Chongsuk
authors.initials: C
authors.lastname: Ryou
authors.affiliation: Department of Bionanotechnology, Hanyang University, Gyeonggido 15588, Republic of Korea; Department of Chemistry and Applied Chemistry, Hanyang University, Gyeonggido 15588, Republic of Korea. Electronic address: hrhee@hanyang.ac.kr.
authors.forename: Hakjune
authors.initials: H
authors.lastname: Rhee
authors.affiliation: Department of Pharmacy, College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Gyeonggido 15588, Republic of Korea. Electronic address: chhlee@hanyang.ac.kr.
authors.forename: Chul-Hoon
authors.initials: CH
authors.lastname: Lee
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011471:Prostatic Neoplasms; D011725:Pyridines / Q000737:chemistry*; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011758:Pyrroles / Q000737:chemistry*; D011944:Receptors, Androgen / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D011725:Pyridines; D011741:Pyrimidine Nucleosides; D011758:Pyrroles; D011944:Receptors, Androgen; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; C486292:pyrrolo(2, 3-b)pyridine
keywords: Androgen; Apoptosis; Autophagy; Prostate cancer; Pyrrolo[2,3-d]pyrimidine; p21(Cip1)