TAT-RasGAP317-326Enhances Radiosensitivity of Human Carcinoma Cell Lines In Vitro and In Vivo through Promotion of Delayed Mitotic Cell Death.
The synthetic peptide TAT-RasGAP317-326has been shown to potentiate the efficacy of anti-cancer drugs. In this study, we explored the action of TAT-RasGAP317-326when combined with radiation by investigating its radiosensitizing activity in vitro and in vivo. To investigate the modulation of intrinsic radiosensitivity induced by TAT-RasGAP317-326, clonogenic assays were performed using four human cancer cell lines, HCT116 p53+/+(ATCC: CCL-247), HCT116 p53-/-, PANC-1 (ATCC: CRL-1469) and HeLa (ATCC: CCL-2), as well as one nontumor cell line, HaCaT (CLS: 300493). Next, to investigate tumor growth delay after irradiation, HCT116 cell lines were selected and xenografted onto nude mice that were then treated with TAT-RasGAP317-326alone or in combination with radiation or cisplatin. Afterwards, cell cycle and death modulation were investigated by quantification of micronuclei and apoptosis-related protein array. TAT-RasGAP317-326radiosensitized all four human carcinoma cell lines tested but displayed no effect on normal cells. It also displayed no effect when administered as monotherapy. This radiosensitizing effect was confirmed in vivo in both p53-positive and p53-negative HCT116 xenografts. TAT-RasGAP317-326combined with radiation enhanced the number of cells in S phase and subsequently delayed cell death, but had almost no effect on major apoptosis-related proteins. TAT-RasGAP317-326is a radiosensitizing agent that acts on carcinoma cells and its radiosensitizing effect might be mediated, at least in part, by the enhancement of mitotic cell death.
Department of a   Radiation Oncology, Lausanne University Hospital, Lausanne, Switzerland.|c   Laboratoire de Radio-Oncologie, CHUV, Lausanne, Switzerland.|e   Department of Radiation Oncology, Hôpital Neuchâtelois, La Chaux-de-Fonds, Switzerland.
Pelagia
P
Tsoutsou
d   Department of Physiology, University of Lausanne, Lausanne, Switzerland.
Alessandro
A
Annibaldi
Department of a   Radiation Oncology, Lausanne University Hospital, Lausanne, Switzerland.|b   Department of Nuclear Medicine, Lausanne University Hospital, Lausanne, Switzerland.|c   Laboratoire de Radio-Oncologie, CHUV, Lausanne, Switzerland.
David
D
Viertl
c   Laboratoire de Radio-Oncologie, CHUV, Lausanne, Switzerland.
Jonathan
J
Ollivier
b   Department of Nuclear Medicine, Lausanne University Hospital, Lausanne, Switzerland.
Franz
F
Buchegger
c   Laboratoire de Radio-Oncologie, CHUV, Lausanne, Switzerland.
Marie-Catherine
MC
Vozenin
Department of a   Radiation Oncology, Lausanne University Hospital, Lausanne, Switzerland.
Jean
J
Bourhis
d   Department of Physiology, University of Lausanne, Lausanne, Switzerland.
Christian
C
Widmann
Department of a   Radiation Oncology, Lausanne University Hospital, Lausanne, Switzerland.
Oscar
O
Matzinger
D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D020690:GTPase-Activating Proteins / Q000008:administration & dosage*; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis / Q000187:drug effects / Q000528:radiation effects*; D009374:Neoplasms, Experimental / Q000473:pathology* / Q000532:radiotherapy*; D010446:Peptide Fragments / Q000008:administration & dosage*; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage; D011879:Radiotherapy Dosage; D016896:Treatment Outcome
D020690:GTPase-Activating Proteins; D010446:Peptide Fragments; D011838:Radiation-Sensitizing Agents; C525242:TAT-RasGAP(317-326)