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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-4498

Fedier, A. Strategies for prevention, circumvention, and reversal of drug resistance in tumor cells. 2008, University of Zurich, Faculty of Medicine.

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Abstract

Both the intrinsic and the acquired anticancer drug resistance presents until today a major drawback in the management of cancer. The handling with drug resistance is aggravated by the facts that drug resistance is a multifactorial and multifaceted phenomenon. The development of tumor-targeted pharmacological and genetic strategies to overcome intrinsic resistance and to prevent the resistance acquisition is thus still a pressing need. We put forward the two main objectives: 1) The reversal of the pre-existing drug resistance in p53-deficient cells by either the concomitant abrogation of DNA repair functions or by the concomitant blocking of cytoprotective signaling pathways. 2) The identification of members of the novel class of histone deacetylase (HDAC) inhibitors with anticancer activity that have (or do not have) the potential to cause resistance acquisition in tumor cells.
Mutations in the p53 gene and dysregulation of p53-dependent cellular processes are often associated with cancer and resistance to radio- and chemotherapy. Many Advances have been taken to reconstitute the (wildtype) p53 tumor suppressor pathway in cancer cells. We showed that genetic abrogation of the expression of the DNA mismatch repair (MMR) gene Pms2 in cells depleted for the p53 tumor suppressor function hypersensitized these cells to the cytotoxic effect of some anticancer agents through an increase in the rate of apoptosis. Expanding on this, we also showed that genetic depletion of either ATM, BRCA1, or DNA-PK resulted in an increase in the chemosensitivity of p53-deficient cells against a variety of anticancer agents. These studies indicate that tumor-targeted functional inhibition of either one or the other of these DNA repair genes may reverse resistance in p53-mutated tumors and therefore provide a strategy for increasing chemotherapy efficacy for these tumors. Analogous as well as opposing results were reported for loss of the MMR protein MLH1 in p53-deficient cells with Cisplatin. However, neither Radicicol (HSP90 inhibitor) nor LY294002 and LY294005 (Akt inhibitors) were found to reverse Cisplatin resistance specifically in MMR-deficient tumor cells. These Akt inhibitors even further decreased the sensitivity against Cisplatin, suggesting - in addition to its acknowledged cytoprotective function - a cytodestructive function of Akt.
On the other hand, we showed the potential of the HDAC inhibitor SAHA to induce stable and MDR-independent resistance in HCT116 colon tumor cells. As these results differ from those reported with FK-228, we propose a novel mechanism of resistance acquisition by the SAHA, the nature of which is still obscure. This is under investigation, as is novel and intriguing molecular approach to reverse drug resistance: the liposomal delivery of (exogenous) cytochrome c to tumor cells.

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Additional indexing

Item Type:Habilitation
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Gynecology
DDC:610 Medicine & health
Language:English
Date:2008
Deposited On:27 Nov 2008 09:36
Last Modified:19 Jul 2014 08:22

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