A RasGAP-derived cell permeable peptide potently enhances genotoxin-induced cytotoxicity in tumor cells.
Treatment of many cancers relies on the combined action of several genotoxins, but the detrimental effect of these drugs on normal cells can cause severe side effects. One major challenge in anticancer therapy is therefore to increase the selectivity of current treatments toward cancer cells in order to spare normal cells. We have recently demonstrated that a RasGAP caspase cleavage fragment is able to sensitize HeLa cells towards cisplatin-induced apoptosis. Here, we extend this observation by showing that this fragment also enhances cell death induced by adriamycin and mitoxantrone, two other widely used genotoxins. Furthermore, we have delineated a short sequence within this fragment that still bears the genotoxin-sensitization property. The peptide encoded by this sequence, when fused to the TAT cell permeation sequence, potently sensitized a number of tumors cells, but not normal cells, towards apoptosis induced by cisplatin, adriamycin and mitoxantrone. This sensitization effect was not mediated through modulation of NFkappaB activity or activation of the JNK and p38 MAPK pathways. Our results demonstrate the feasibility in enhancing the efficacy of currently used drugs to selectively kill cancer cells using peptides derived from pro-apoptotic caspase substrate fragments.
Department of cellular biology and morphology, Lausanne University, Switzerland.
David
D
Michod
Jiang-Yan
JY
Yang
Jianhua
J
Chen
Christophe
C
Bonny
Christian
C
Widmann
D017209:Apoptosis; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D020690:GTPase-Activating Proteins / Q000737:chemistry*; D015696:Gene Products, tat / Q000737:chemistry; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008942:Mitoxantrone / Q000494:pharmacology; D009153:Mutagens / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry*; D010957:Plasmids / Q000378:metabolism; D017434:Protein Structure, Tertiary; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020703:ras GTPase-Activating Proteins / Q000378:metabolism*; D018909:src Homology Domains
D020690:GTPase-Activating Proteins; D015696:Gene Products, tat; D009153:Mutagens; D016328:NF-kappa B; D010446:Peptide Fragments; D010455:Peptides; C525242:TAT-RasGAP(317-326); D020703:ras GTPase-Activating Proteins; D004317:Doxorubicin; D008942:Mitoxantrone; D008156:Luciferases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D002945:Cisplatin