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

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• 作者：Hyewon Suh^a ; ^&dagger ; ; Ko-woon Choi^a ; ^&dagger ; ; Jongbok Lee^b ; Chongsuk Ryou^a ; Hakjune Rhee^b ; ^c ; ^{hrhee@hanyang.ac.kr" class="auth_mail" title="E-mail the corresponding author} ; Chul-Hoon Lee^a ; ^{chhlee@hanyang.ac.kr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Pyrrolo[2 ; 3-d]pyrimidine ; Prostate cancer ; Apoptosis ; Autophagy ; p21Cip1 ; Androgen
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 February 2016
• 年：2016
• 卷：26
• 期：4
• 页码：1130-1135
• 全文大小：1018 K

文摘

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.