Discordant in vitro and in vivo chemopotentiating effects of the PARP inhibitor veliparib in temozolomide-sensitive versus -resistant glioblastoma multiforme xenografts.
OBJECTIVE
Effective sensitizing strategies potentially can extend the benefit of temozolomide (TMZ) therapy in patients with glioblastoma (GBM). We previously demonstrated that robust TMZ-sensitizing effects of the [poly (ADP-ribose) polymerase] (PARP) inhibitor veliparib (ABT-888) are restricted to TMZ-sensitive GBM xenografts. The focus of this study is to provide an understanding for the differential sensitization in paired TMZ-sensitive and -resistant GBM models.


METHODS
The impact of veliparib on TMZ-induced cytotoxicity and DNA damage was evaluated in vitro and in vivo in models of acquired TMZ resistance (GBM12TMZ-mgmt(High), GBM12TMZ-mgmt(Low), and U251TMZ), inherent TMZ resistance (T98G), and TMZ-sensitive (U251 and GBM12). In vivo drug efficacy, pharmacokinetics, and pharmacodynamics were analyzed using clinically relevant dosing regimens.


RESULTS
Veliparib enhanced TMZ cytotoxicity and DNA-damage signaling in all GBM models in vitro with more pronounced effects in TMZ-resistant lines at 3 to 10 μmol/L veliparib. In vivo, combined TMZ/veliparib, compared with TMZ alone, significantly delayed tumor growth and enhanced DNA-damage signaling and γH2AX levels in the sensitive GBM12 xenograft line but not in the resistant GBM12TMZ lines. The pharmacokinetic profile of veliparib was similar for GBM12 and GBM12TMZ tumors with Cmax (∼1.5 μmol/L) in tissue significantly lower than concentrations associated with optimal in vitro sensitizing effects for resistant tumors. In contrast, robust suppression of PARP-1 expression by shRNA significantly increased TMZ sensitivity of U251TMZ in vitro and in vivo.


CONCLUSIONS
In vitro cytotoxicity assays do not adequately model the therapeutic index of PARP inhibitors, as concentrations of veliparib and TMZ required to sensitize TMZ-resistant cancer cells in vivo cannot be achieved using a tolerable dosing regimen.
Authors' Affiliations: Departments of Radiation Oncology, and.
Shiv K
SK
Gupta
Authors' Affiliations: Departments of Radiation Oncology, and.
Ann C
AC
Mladek
Authors' Affiliations: Departments of Radiation Oncology, and.
Brett L
BL
Carlson
Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester Minnesota.
Felix
F
Boakye-Agyeman
Authors' Affiliations: Departments of Radiation Oncology, and.
Katrina K
KK
Bakken
Authors' Affiliations: Departments of Radiation Oncology, and.
Sani H
SH
Kizilbash
Authors' Affiliations: Departments of Radiation Oncology, and.
Mark A
MA
Schroeder
Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester Minnesota.
Joel
J
Reid
Authors' Affiliations: Departments of Radiation Oncology, and sarkaria.jann@mayo.edu.
Jann N
JN
Sarkaria
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004249:DNA Damage; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D008819:Mice, Nude; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
D018906:Antineoplastic Agents, Alkylating; D001562:Benzimidazoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; D003606:Dacarbazine; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D000077204:Temozolomide