Role of the p53/p21 system in the response of human colon carcinoma cells to Doxorubicin

BACKGROUND: Colon adenocarcinomas are refractory to a number of widely used anticancer agents. Multifactorial mechanisms have been implicated in this intrinsically resistant phenotype, including deregulation of cell death pathways. In this regard, the p53 protein has a well established role in the control of tumor cell response to DNA damaging agents; however, the relationship between p53-driven genes and drug sensitivity remains controversial. The present study investigates the role of the p53/p21 system in the response of human colon carcinoma cells to treatment with the cytotoxic agent doxorubicin (DOX) and the possibility to modify the therapeutic index of DOX by modulation of p53 and/or p21 protein levels. METHODS: The relationship between p53 and p21 protein levels and the cytotoxic effect of DOX was investigated, by MTT assay and western blot analysis, in HCT116 (p53-positive) and HT29 (p53-negative) colon cancer cells. We then assessed the effects of DOX in two isogenic cell lines derived from HCT116 by abrogating the expression and/or function of p53 and p21 (HCT116-E6 and HCT116 p21-/-, respectively). Finally, we evaluated the effect of pre-treatment with the piperidine nitroxide Tempol (TPL), an agent that was reported to induce p21 expression irrespective of p53 status, on the cytotoxicity of DOX in the four cell lines. Comparisons of IC50 values and apoptotic cell percentages were performed by ANOVA and Bonferroni's test for independent samples. C.I. calculations were performed by the combination Index method. RESULTS: Our results indicate that, in the colon carcinoma cell lines tested, sensitivity to DOX is associated with p21 upregulation upon drug exposure, and DOX cytotoxicity is potentiated by pre-treatment with TPL, but only in those cell lines in which p21 can be upregulated. CONCLUSIONS: p21 induction may significantly contribute to the response of colon adenocarcinomas cells to DOX treatment; and small molecules that can exploit p53-independent pathways for p21 induction, such as TPL, may find a place in chemotherapeutic protocols for the clinical management of colorectal cancer, where p53 function is often lost, due to genetic or epigenetic defects or to post-transcriptional inactivating mechanisms

The igfr1 inhibitor nvp-aew541 disrupts a pro-survival and pro-angiogenic igf-stat3-hif1 pathway in human glioblastoma cells

International audienceInappropriate activation of the IGF (insulin-like growth factor) system has been implicated in the growth and progression of a number of tumor types. Recent evidence indicates a possible role for the IGF system in modulating/mediating tumor cell response to hypoxia, a common occurrence in solid tumors, and particularly in malignant gliomas, causing tumor cells either to die, or to mount a pleiotropic adaptive response that is mainly orchestrated through activation of the hypoxia-inducible transcription factor HIF1. Experimental evidence suggests possible links between IGF- and HIF1-dependent signaling pathways, as well as a role for activated STAT3 in mediating their activities. Interestingly, is among the target genes transactivated by HIF1, thereby providing the missing link in a hypothetical autocrine self-amplifying circuit

Percentage of apoptotic cells in HCT116, HT29, HCT116 E6 and HCT116 p21-/- cells before and after 1 h exposure to DOX followed by 23 h incubation in drug-free medium (white bars: untreated; light grey bars: DOX 1 μM; dark grey bars: DOX 10 μM)

<p><b>Copyright information:</b></p><p>Taken from "Role of the p53/p21 system in the response of human colon carcinoma cells to Doxorubicin"</p><p>BMC Cancer 2004;4():92-92.</p><p>Published online 15 Dec 2004</p><p>PMCID:PMC544559.</p><p>Copyright © 2004 Ravizza et al; licensee BioMed Central Ltd.</p> Mean ± s.e.m. of 3 independent experiments

Dose-response curves of HCT116 (■), HT29 (▲), HCT116E6 (▼), and HCT116 p21-/- (●) cells after 1 hour exposure to DOX followed by 72 h incubation in drug free medium (mean ± s

<p><b>Copyright information:</b></p><p>Taken from "Role of the p53/p21 system in the response of human colon carcinoma cells to Doxorubicin"</p><p>BMC Cancer 2004;4():92-92.</p><p>Published online 15 Dec 2004</p><p>PMCID:PMC544559.</p><p>Copyright © 2004 Ravizza et al; licensee BioMed Central Ltd.</p>e.m. of 4–6 experiments)

Photodynamic effects of two photosensitizers in human adonocarcinoma cells: role of p53 in tumor cell response.

Abstract n. 541