Colorectal carcinoma is a human malignant
tumor, which is very resistant to currently available methods of treatment. Therefore, developing an effective agent with anti-
colorectal carcinoma activity is important. In the present study, 8 structurally related
flavones including
flavone, 3-OH
flavone, 5-OH
flavone, 7-OH
flavone,
quercetin,
kaempferol,
quercetin, and
morin were used to study their effects on
colorectal carcinoma cells (HT29, COLO205, COLO320-HSR). Results of MTT assay indicated that
flavone shows the most potent cytoxic effect among them on these three cell types. The cytotoxicity induced by
flavone is mediated by inducing the occurrence of apoptosis characterized by the appearance of
DNA ladders, apoptotic bodies and hypodiploid cells. Activation of
caspase 3 protein procession and
enzyme activity with inducing cleavage of
caspase 3 substrates PARP was identified in
flavone-treated cells, and an inhibitory
peptide Ac-DEVD-FMK for
caspase 3, but not Ac-
YVAD-FMK for
caspase 1, attenuates the cytotoxic effect of
flavone in COLO205 and HT29 cells. Elevation of p21 but no p53
protein was observed in
flavone-treated cells. Increasing intracellular
peroxide level was detected in
flavone-treated cells by DCHF-DA assay, and
antioxidants such as
tiron,
catalase, SOD,
PDTC, but not DPI, suppress
flavone-induced cytotoxic effect. In vivo anti-
tumor study indicates that
flavone exhibits ability to inhibit
tumor formation elicited by s.c. injection of COLO205 cells in nude mice, and apoptotic cells and an increase in p21, but not p53,
protein were observed in
tumor tissues derived from
flavone-treated group. Additionally,
flavone induced apoptosis in primary colon
carcinoma cells COLO205-X with appearance of
DNA ladders,
caspase 3 protein procession, PARP
protein cleavage, and an increase in p21 (not p53)
protein. These data provide evidence to suggest that
flavone is an effective agent to induce apoptosis in
colorectal carcinoma cells in vitro and in vivo; activation of
caspase 3, ROS production, and increasing p21
protein are involved.