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 6μM compound 5 for 24h 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 (9μM, 48h), because the cells are less sensitive and independent to androgen than LNCaP cells. Furthermore, 6μM 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.
Bioorganic & medicinal chemistry letters. 2016 Jan 21 [Epub ahead of print]
Hyewon Suh, Ko-Woon Choi, Jongbok Lee, Chongsuk Ryou, Hakjune Rhee, Chul-Hoon Lee
Department of Pharmacy, College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Gyeonggido 15588, Republic of Korea. , Department of Pharmacy, College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Gyeonggido 15588, Republic of Korea. , Department of Bionanotechnology, Hanyang University, Gyeonggido 15588, Republic of Korea. , Department of Pharmacy, College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Gyeonggido 15588, Republic of Korea. , Department of Bionanotechnology, Hanyang University, Gyeonggido 15588, Republic of Korea; Department of Chemistry and Applied Chemistry, Hanyang University, Gyeonggido 15588, Republic of Korea. Department of Pharmacy, College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Gyeonggido 15588, Republic of Korea.