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Molecular Cancer

, 11:26

First Online: 26 April 2012Received: 18 January 2012Accepted: 09 April 2012

Abstract

BackgroundPlatinum compounds such as cisplatin and carboplatin are DNA crosslinking agents widely used for cancer chemotherapy. However, the effectiveness of platinum compounds is often tempered by the acquisition of cellular drug resistance. Until now, no pharmacological approach has successfully overcome cisplatin resistance in cancer treatment. Since the Fanconi anemia FA pathway is a DNA damage response pathway required for cellular resistance to DNA interstrand crosslinking agents, identification of small molecules that inhibit the FA pathway may reveal classes of chemicals that sensitize cancer cells to cisplatin.

ResultsThrough a cell-based screening assay of over 16,000 chemicals, we identified 26 small molecules that inhibit ionizing radiation and cisplatin-induced FANCD2 foci formation, a marker of FA pathway activity, in multiple human cell lines. Most of these small molecules also compromised ionizing radiation-induced RAD51 foci formation and homologous recombination repair, indicating that they are not selective toward the regulation of FANCD2. These compounds include known inhibitors of the proteasome, cathepsin B, lysosome, CHK1, HSP90, CDK and PKC, and several uncharacterized chemicals including a novel proteasome inhibitor Chembridge compound 5929407.

Isobologram analyses demonstrated that half of the identified molecules sensitized ovarian cancer cells to cisplatin. Among them, 9 demonstrated increased efficiency toward FA pathway-proficient, cisplatin-resistant ovarian cancer cells. Six small molecules, including bortezomib proteasome inhibitor, CA-074-Me cathepsin B inhibitor and 17-AAG HSP90 inhibitor, synergized with cisplatin specifically in FA-proficient ovarian cancer cells 2008 + FANCF, but not in FA-deficient isogenic cells 2008. In addition, geldanamycin HSP90 inhibitor and two CHK1 inhibitors UCN-01 and SB218078 exhibited a significantly stronger synergism with cisplatin in FA-proficient cells when compared to FA-deficient cells, suggesting a contribution of their FA pathway inhibitory activity to cisplatin sensitization.

ConclusionOur findings suggest that, despite their lack of specificity, pharmaceutical inhibition of the FA pathway by bortezomib, CA-074-Me, CHK1 inhibitors or HSP90 inhibitors may be a promising strategy to sensitize cisplatin-resistant, FA pathway-proficient tumor cells to cisplatin. In addition, we identified four new small molecules which synergize with cisplatin. Further development of their analogs and evaluation of their combination with cisplatin may lead to the development of efficient cancer treatments.

KeywordsFanconi anemia Drug resistance Cisplatin Small molecule Homologous recombination AbbreviationsAPCAllophycocyanine

BrdU5-Bromo-2’-deoxy-Uridine

CDKCyclin-dependant kinase

CHK1Checkpoint kinase 1

DAPI4’, 6-diamidino-2-phenylindole dihydrochloride

EGFPEnhanced green fluorescent protein

FAFanconi anemia

FITCFluorescein isothiocyanate

GFPGreen fluorescent protein

HAHemagglutinin

HRHomologous recombination

HSP90Heat shock protein 90

ICLInterstrand crosslink

IRIonizing radiation

LD50Lethal dose 50%

PKCProtein kinase C.

Electronic supplementary materialThe online version of this article doi:10.1186-1476-4598-11-26 contains supplementary material, which is available to authorized users.

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Autor: Céline Jacquemont - Julian A Simon - Alan D D-Andrea - Toshiyasu Taniguchi

Fuente: https://link.springer.com/article/10.1186/1476-4598-11-26



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