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. 2013 Aug 19;14(8):16970-85.
doi: 10.3390/ijms140816970.

Structural properties of polyphenols causing cell cycle arrest at G1 phase in HCT116 human colorectal cancer cell lines

Soon Young Shin  1 , Hyuk Yoon, Seunghyun Ahn, Dong-Wook Kim, Dong-Ho Bae, Dongsoo Koh, Young Han Lee, Yoongho Lim
Affiliations

Structural properties of polyphenols causing cell cycle arrest at G1 phase in HCT116 human colorectal cancer cell lines

Soon Young Shin et al. Int J Mol Sci. .

Abstract

Plant-derived polyphenols are being tested as chemopreventive agents; some polyphenols arrest the cell cycle at G1 phase, whereas others inhibit cell cycle proliferation at G2/M phase. Therefore, polyphenols have been proposed to inhibit cell cycle progression at different phases via distinct mechanisms. Indeed, our previous studies showed that small structural differences in polyphenols cause large differences in their biological activities; however, the details of the structural properties causing G1 cell cycle arrest remain unknown. In this study, we prepared 27 polyphenols, including eight different scaffolds, to gain insight into the structural conditions that arrest the cell cycle at G1 phase in a quantitative structure-activity relationship study. We used cell cycle profiles to determine the biophores responsible for G1 cell cycle arrest and believe that the biophores identified in this study will help design polyphenols that cause G1 cell cycle arrest.

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Figures

Figure 1
Figure 1
The DNA histogram of polyphenol 9 (MPBC) obtained using flow cytometry. Regions M1–M4 indicate the sub-G1, G1, S, and G2/M phases, respectively.
Figure 2
Figure 2
CoMFA contour map generated using the program SYBYL 7.3. The steric and electrostatic field descriptors contributed 44.7% and 55.3%, respectively. Regarding the steric field, the region favoring steric bulk contributed 19% and that disfavoring bulk contributed 81%. Similarly, a contour map for the electrostatic field was generated, and the regions favoring electropositive and negative groups contributed 14% and 86%, respectively. MPBC had the best inhibitory effect and is embedded in the contour map.
Figure 3
Figure 3
CoMSIA contour map generated using the program SYBYL 7.3. The steric, electrostatic, and H-bond acceptor field descriptors contributed 30.8%, 51.0%, and 18.2%, respectively. Regarding the steric field, the region favoring steric bulk contributed 12% and that disfavoring bulk contributed 88%; in the electrostatic field, the region favoring electropositive groups contributed 90% and that favoring electronegative groups contributed 10%. For the H-bond acceptor field, the region favoring H-bond acceptors contributed 79% and that disfavoring H-bond acceptors contributed 21%.
Figure 4
Figure 4
The structural conditions resulting in greater inhibition of cell cycle progression in G1 phase in HCT116 human colorectal cancer cells.
Figure 5
Figure 5
(A) Treatment with MPBC significantly reduced cell viability (left) and cellular proliferation (right) in a dose- and time-dependent manner; (B) Treatment with MPBC for 7 days resulted in a dose-dependent loss of the ability of individual cells to proliferate into viable colonies; (C) Western blot analysis showed that the amount of p53 protein increased within 6 h following MPBC treatment, reached a peak around 24 h, and then dropped by 48 h; (D) Treatment with MPBC resulted in the stimulation of the −2400/+1 construct, but not the −952/+70 construct.
Figure 6
Figure 6
(A) The expression of both p53 and p21 were time-dependently increased following MPBC exposure of the wild-type HCT116 cells (p53+/+), but not p53-null HCT116 cells (p53−/−); (B) MPBC-induced G1 cell cycle arrest was impaired in p53-null HCT116 cell.
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