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
- 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
- Author
- 이철훈
- Keywords
- Pyrrolo[2,3-d]pyrimidine; Prostate cancer; Apoptosis; Autophagy; p21(Cip1); Androgen
- Issue Date
- 2016-02
- Publisher
- PERGAMON-ELSEVIER SCIENCE LTD
- Citation
- BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, v. 26, No. 4, Page. 1130-1135
- 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), LNCaPC4-2 (androgen-independent and -sensitive; androgen-refractory), and DU145 (androgen-independent and -insensitive) cells. The treatment of LNCaP cells with 6 mu M 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 LNCaPC4-2 cells was possible by intensive cell treatment with compound 5 (9 mu M, 48 h), because the cells are less sensitive and independent to androgen than LNCaP cells. Furthermore, 6 mu M 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. (C) 2016 Elsevier Ltd. All rights reserved.
- URI
- https://www.sciencedirect.com/science/article/pii/S0960894X16300579http://hdl.handle.net/20.500.11754/49647
- ISSN
- 0960-894X; 1464-3405
- DOI
- 10.1016/j.bmcl.2016.01.057
- Appears in Collections:
- COLLEGE OF PHARMACY[E](약학대학) > PHARMACY(약학과) > Articles
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