p21 Waf1/Cip1 can protect human colon carcinoma cells against p53-dependent and p53-independent apoptosis induced by natural chemopreventive and therapeutic agents

Abstract

The molecular basis for the sensitivity of tumor cells to chemopreventive natural food compounds and commonly used chemotherapeutic agents is not well understood, not least because studies are frequently confounded by the diversity among cell lines or rely on experimental protein overexpression. Here we investigated the e ects of nbutyrate, a cancer-preventive short-chain fatty acid produced by anaerobic bacteria in the gastrointestinal tract, on the human wild-type p53 and p21 expressing HCT116 colon carcinoma cell line and on HCT116 cells with either p53 or p21 alleles inactivated by homologous recombination. The e ects of n-butyrate were then compared with those elicited by cytotoxic drugs and the natural chemopreventive phytoalexin of wine and grapes, resveratrol. We document that physiological concentrations of n-butyrate stimulate p21 expression and induce apoptosis independently of p53, and that the absence of p21 increases apoptosis drastically. The apoptosis is mediated through the mitochondria and is accompanied by mitochondrial proliferation and membrane potential changes. Adriamycin, etoposide, cisplatinum, colcemid and resveratrol induce distinct cellular responses; however, absence of p21 favors apoptosisinduction by adriamycin, etoposide and colcemid. Thus, control of p21 expression may support chemoprevention and certain tumor therapies. Oncogene (2001) 20, 3387 ± 3398.

p21WAF1 modulates drug-induced apoptosis and cell cycle arrest in B-cell precursor acute lymphoblastic leukemia

“…A number of studies evaluating the impact of p21 WAF1 on cell death have been conducted in epithelial derived tumor cells such as MCF-7 or HCT116 cell lines. [6][7][8][9]46,47 In general, most of the tumor cell lines showed inherent resistance to the effects of certain cytotoxic stimuli. 7,46 Furthermore, enhanced apoptotic responses of p21 WAF1 -deficient HCT116 cells to DNA damage occurred after 24 h exposure.…”

“…[6][7][8][9]46,47 In general, most of the tumor cell lines showed inherent resistance to the effects of certain cytotoxic stimuli. 7,46 Furthermore, enhanced apoptotic responses of p21 WAF1 -deficient HCT116 cells to DNA damage occurred after 24 h exposure. 9,46,47 Cell death was observed within 6 h after drug exposure in both T-ALL and BCP-ALL PDXs and cell lines, demonstrating the increased cytotoxic sensitivity of leukemia cells compared to epithelial derived cell lines.…”

Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

“…As a p53 transcriptional target, p21 is classically proposed to be under the regulation of the ATM-p53 pathway where it induces G1 arrest. Modulation of p21 expression and consequent apoptosis can also occur via p53-independent pathways (Mahyar-Roemer and Roemer, 2001). In fact, p21 expression in pancreatic carcinoma is independent of p53 status (DiGiuseppe et al, 1995).…”

Resveratrol induces colon tumor cell apoptosis independently of p53 and precede by epithelial differentiation, mitochondrial proliferation and membrane potential collapse

“…However, the protective effect of p53 and p21 against resveratrol is not nearly as strong as that against doxorubicin. 10,21 Several studies have suggested that the chemopreventive activity of resveratrol is largely based on its proapoptotic effects. For instance, azomethane-induced colon carcinogenesis in rats appears to be counteracted by apoptosis of damaged cells.…”