Indole‐3‐carbinol induces a G1 cell cycle arrest and inhibits prostate‐specific antigen production in human LNCaP prostate carcinoma cells

Abstract

BACKGROUNDIndole‐3‐carbinol (I3C), a naturally occurring component of Brassica vegetables, such as cabbage, broccoli, and Brussels sprouts, is a promising anticancer agent for certain reproductive tumor cells. The objective of the current study was to characterize the cell cycle effects of I3C in human prostate carcinoma cells.METHODSThe incorporation of [3H]thymidine and flow cytometry of propidium iodide–stained nuclei were used to monitor I3C‐regulated changes in prostate carcinoma cell proliferation and cell cycle progression. Western blotting was used to document expression changes in cell cycle components and prostate‐specific antigen (PSA) levels. The enzymatic activities of cyclin‐dependent kinases (CDK) were tested by in vitro protein kinase assays using the retinoblastoma protein as a substrate.RESULTSI3C suppressed the growth of LNCaP prostate carcinoma cells in a dose‐dependent manner by inducing a G1 block in cell cycle progression. I3C selectively inhibited the expression of CDK6 protein and transcripts and strongly stimulated the production of the p16 CDK inhibitor. In vitro protein kinase assays revealed the striking inhibition by I3C of immunoprecipitated CDK2 enzymatic activity and the relatively minor down‐regulation of CDK4 enzymatic activity. In LNCaP prostate carcinoma cells, I3C treatment inhibited production of PSA, whereas combinations of I3C and the androgen antagonist flutamide more effectively inhibited DNA synthesis and PSA levels compared with either agent alone.CONCLUSIONSThe results of the current study demonstrated that I3C has a potent antiproliferative effect in LNCaP and other human prostate carcinoma cells. These findings implicate this dietary indole as a potential chemotherapeutic agent for controlling the growth of human prostate carcinoma cells. Cancer 2003. © 2003 American Cancer Society.

Molecular Targets and Anticancer Potential of Indole-3-Carbinol and Its Derivatives

“…[24][25][26][27][28][29][30][31] Cover and coworkers showed that I3C induces G 1 cell cycle arrest 24 and this arrest correlates with inhibition of the expression of cyclin-dependent kinase 6 (CDK6), inhibition of the endogenous retinoblastoma (Rb) protein phosphorylation, and increases of the p21 and p27 CDK inhibitors (see Table 1). The I3C-induced cell cycle arrest in both ER-positive MCF-7 and ER-negative MDA-MB-231 human breast cancer cells, which demonstrates that this indole can suppress the growth of mammary tumor cells independently of ER signaling.…”

3,3′-Diindolylmethane Induction of p75NTR-Dependent Cell Death via the p38 Mitogen-Activated Protein Kinase Pathway in Prostate Cancer Cells

“…The dietary indoles (I3C, DIM) exert anticancer activity by inducing apoptosis (4-6), exert antimetastatic properties (4,10), inhibit angiogenesis gene products (11), and induce cell cycle arrest (7)(8)(9) in G 1 (5,9) through modulation of cyclin-cdk holoenzyme components. These indoles down-regulate cyclin D1 (4,7,12) and its associated cdk4 (7,12) and cdk6 (5,7,9,12) holoenzyme components in mid-G 1 . They also down-regulate cdk2 (9,12) at the G 1 -S checkpoint.…”

“…These indoles down-regulate cyclin D1 (4,7,12) and its associated cdk4 (7,12) and cdk6 (5,7,9,12) holoenzyme components in mid-G 1 . They also down-regulate cdk2 (9,12) at the G 1 -S checkpoint. These effects, in turn, prevent hyperphosphorylation of the retinoblastoma protein (5), thereby preventing cell cycle progression into S phase.…”

Development of β-amino-carbonyl compounds as androgen receptor antagonists

“…Arresting the cell cycle prior to S phase suggests a common mechanism of the action for AR antagonists [16,17] . A preliminary in vivo study showed that at a daily intraperitoneal dose of 10 mg/kg, isomer 6012-4 significantly inhibited the growth of subcutaneous LNCaP xenografts.…”