Sulindac corrects defective apoptosis and suppresses azoxymethane‐induced colonic oncogenesis in p53 knockout mice

Abstract

The acute apoptotic response to genotoxic carcinogens (AARGC) might be important for controlling the subsequent colonic mutational load and progression through oncogenesis. We have found previously that AARGC is p53-dependent with a gene-dosage effect, and that decreased AARGC in p53 1/2 and p53 2/2 mice is associated with increased susceptibility to carcinogen-induced oncogenesis. We tested the ability of sulindac to reverse these defects. The effect of sulindac on azoxymethane (AOM)-induced apoptosis was measured in colonic epithelium in wild-type, p53 1/2 and p53 2/2 mice, 8 hr after a single AOM injection. Sulindac supplementation (0.5 6 0.1 mg/day) restored defective AARGC in p53 1/2 but not in p53 2/2 mice. For effect on colon tumor development, sulindac treatment was started at age 4 weeks in wild-type, p53 1/2 and p53 2/2 mice; three weekly AOM injections were commenced at 6 weeks of age to induce tumors. Sulindac reduced significantly tumor incidence and multiplicity in wild-type mice (17% and 0.3 tumors/mouse compared to 36% and 0.8 respectively without drug), in p53 1/2 mice (38% and 0.8 compared to 64% and 1.63) and in p53 2/2 mice (63% and 1.0 compared to 90% and 1.74). Although loss of p53 function impairs the apoptotic response to AOM-induced DNA damage, sulindac is capable of partly restoring this defect. As sulindac also reverses the increased risk of oncogenesis due to p53 dysfunction, its enhancement of the apoptotic response to initiating mutations might act to reduce mutational load driving oncogenesis. Sulindac is an effective chemopreventive agent in the presence of p53 dysfunction. ' 2005 Wiley-Liss, Inc.Key words: sulindac; apoptosis; carcinogen; intestinal epithelia; colorectal cancer; p53Numerous experimental, epidemiologic, and clinical studies indicate that nonsteroidal anti-inflammatory drugs (NSAID) act as chemopreventive agents for colorectal cancer. [1][2][3][4][5] Despite the clear involvement of COX-2 inhibition, 6,7 other molecular mechanisms seem also to be involved. [8][9][10] Studies demonstrate that certain NSAID possess an ability to induce apoptosis and inhibit cell proliferation. 11-13 COX-2 inhibition plays a role in these effects. 14,15 But as oncogenesis is a complex process with multiple molecular pathways and biological disorders of genomic instability, 16 it is uncertain whether the biological actions of NSAID can protect against oncogenesis across this diversity.Sulindac is representative of nonselective NSAID that have significant activity in inhibiting colon tumor formation in several settings. Sulindac inhibits azoxymethane (AOM)-induced tumor incidence and increases apoptosis in rat tumors 17,18 where the molecular pathway frequently involves K-ras defects 19-21 but not other human-relevant genes such as APC and p53. 22,23 It also protects in Min mice, 24 where APC function is defective. Additionally, induction of apoptosis by sulindac was reported in cases of familial adenomatous polyposis. 11,25,26 Ability of sulindac or other NSAID to protect in the face ...

Suppression of Colorectal Oncogenesis by Selenium-Enriched Milk Proteins: Apoptosis and K-ras Mutations

“…In this study, we hypothesized that selenium intake exerts its anticarcinogenic effect by enhancing the acute apoptotic response to carcinogen-induced DNA damage (AARGC). This is an important mechanism for removing cells harboring oncogenic DNA adducts and is a regulatory target for a variety of dietary agents and drugs (22,23,(25)(26)(27)40). We found that AARGC in the colon was significantly enhanced in animals fed MPSe1 and CasYSe4 but not in animals fed CasYSe1.…”

“…The colons were scored for macroscopically visible tumors. Tumors were dissected, embedded in paraffin, and stained by H&E for histopathologic evaluation to classify them as adenoma and adenocarcinoma (23). Endpoints were colon tumor incidence (i.e., proportion of mice affected by a tumor), tumor multiplicity, tumor size, and number of mice with adenocarcinomas (cancers).…”

“…In our previous studies, we showed that administration of azoxymethane to rodents was rapidly followed 6 to 8 hours later by an acute apoptotic response (termed AARGC) in the distal colon. Protection against CRC by some dietary agents and drugs is associated with their ability to up-regulate AARGC for controlling DNA damage (22)(23)(24)(25)(26)(27).…”

Probiotics, prebiotics and synbiotics: A role in chemoprevention for colorectal cancer?

“…2 Current treatment options for CRC include surgery, chemotherapy and radiation therapy, all of which can significantly reduce quality of life. Emerging therapeutic strategies for CRC include the nonsteroidal anti-inflammatory drug, Sulindac, 3 new chemotherapeutics including Capecitabine, 4 and antibodies such as the monoclonal epidermal growth factor receptor (EGFR) antibody, Cetuximab. 5 However, probiotics represent another emerging therapeutic option.…”

The potential of sphingomyelin as a chemopreventive agent in AOM‐induced colon cancer model: wild‐type and p53+/– mice

“…With respect to the potential of dietary SM on preventing tumour initiation, our particular interest was to examine whether SM regulated the apoptotic response to DNA damage (AARGC), which is important for eliminating DNA-damaged cells during tumour initiation [35]. Our previous studies have shown that defective AARGC is associated with increased risk for CRC in p53 +/ -and p53 -/ -mice [28,29], and that up-regulation of AARGC by a variety of dietary agents and drugs is associated with protection for CRC [29, 35, 48 -52]. In keeping with earlier studies [5,34,47], our study showed that SM intake (0.05 -0.1%) did not affect baseline apoptosis.…”