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Antisecretory Factor-Mediated Inhibition of Cell Volume Dynamics Produces Antitumor Activity in Glioblastoma.

ABSTRACT: Interstitial fluid pressure (IFP) presents a barrier to drug uptake in solid tumors, including the aggressive primary brain tumor glioblastoma (GBM). It remains unclear how fluid dynamics impacts tumor progression and can be targeted therapeutically. To address this issue, a novel telemetry-based approach was developed to measure changes in IFP during progression of GBM xenografts. Antisecretory factor (AF) is an endogenous protein that displays antisecretory effects in animals and patients. Here, endogenous induction of AF protein or exogenous administration of AF peptide reduced IFP and increased drug uptake in GBM xenografts. AF inhibited cell volume regulation of GBM cells, an effect that was phenocopied in vitro by the sodium-potassium-chloride cotransporter 1 (SLC12A2/NKCC1) inhibitor bumetanide. As a result, AF induced apoptosis and increased survival in GBM models. In vitro, the ability of AF to reduce GBM cell proliferation was phenocopied by bumetanide and NKCC1 knockdown. Next, AF's ability to sensitize GBM cells to the alkylating agent temozolomide, standard of care in GBM patients, was evaluated. Importantly, combination of AF induction and temozolomide treatment blocked regrowth in GBM xenografts. Thus, AF-mediated inhibition of cell volume regulation represents a novel strategy to increase drug uptake and improve outcome in GBM. Mol Cancer Res; 16(5); 777-90. ©2018 AACR.

SUBMITTER: Ilkhanizadeh S

PROVIDER: S-EPMC5932284 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Antisecretory Factor-Mediated Inhibition of Cell Volume Dynamics Produces Antitumor Activity in Glioblastoma.

Ilkhanizadeh Shirin S Sabelström Hanna H Miroshnikova Yekaterina A YA Frantz Aaron A Zhu Wen W Idilli Aurora A Lakins Jon N JN Schmidt Christin C Quigley David A DA Fenster Trenten T Yuan Edith E Trzeciak Jacqueline R JR Saxena Supna S Lindberg Olle R OR Mouw Janna K JK Burdick Jason A JA Magnitsky Sergey S Berger Mitchel S MS Phillips Joanna J JJ Arosio Daniele D Sun Dandan D Weaver Valerie M VM Weiss William A WA Persson Anders I AI

Molecular cancer research : MCR 20180205 5

Interstitial fluid pressure (IFP) presents a barrier to drug uptake in solid tumors, including the aggressive primary brain tumor glioblastoma (GBM). It remains unclear how fluid dynamics impacts tumor progression and can be targeted therapeutically. To address this issue, a novel telemetry-based approach was developed to measure changes in IFP during progression of GBM xenografts. Antisecretory factor (AF) is an endogenous protein that displays antisecretory effects in animals and patients. Her ...[more]

PMID: 29431617

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Project description:BackgroundTo optimize the antitumor activity of oncrasin-1, a small molecule identified through synthetic lethality screening on isogenic K-Ras mutant tumor cells, we developed several analogues and determined their antitumor activities. Here we investigated in vitro and in vivo antitumor activity of NSC-743380 (1-[(3-chlorophenyl) methyl]-1H-indole-3-methanol, oncrasin-72), one of most potent analogues of oncrasin-1.Methodology and principal findingsIn vitro antitumor activity was determined in NCI-60 cancer cell line panel using cell viability assay. In vivo antitumor activity was determined in parallel with NSC-741909 (oncrasin-60) in xenograft tumors established in nude mice from A498, a human renal cancer cell line. Changes in gene expression levels and signaling pathway activities upon treatment with NSC-743380 were analyzed in breast and renal cancer cells by Western blot analysis. Apoptosis was demonstrated by Western blot analysis and flow cytometric analysis. NSC-743380 is highly active against a subset of cancer cell lines derived from human lung, colon, ovary, kidney, and breast cancers. The 50% growth-inhibitory concentration (GI(50)) for eight of the most sensitive cell lines was ≤ 10 nM. In vivo study showed that NSC-743380 has a better safety profile and greater antitumor activity than NSC-741909. Treatment with NSC-743380 caused complete regression of A498 xenograft tumors in nude mice at the tested doses ranging from 67 mg/kg to 150 mg/kg. Mechanistic characterization revealed that NSC-743380 suppressed the phosphorylation of C-terminal domain of RNA polymerase II, induced JNK activation, inhibited JAK2/STAT3 phosphorylation and suppressed cyclin D1 expression in sensitive human cancer cells. Blocking JNK activation or overexpression of constitutively active STAT3 partially blocked NSC-743380-induced antitumor activity.ConclusionsNSC-743380 induces antitumor activity through modulation of functions in multiple cancer related pathways and could be a potential anticancer agent for some solid tumors.

Dataset Information

Antisecretory Factor-Mediated Inhibition of Cell Volume Dynamics Produces Antitumor Activity in Glioblastoma.

Publications

Antisecretory Factor-Mediated Inhibition of Cell Volume Dynamics Produces Antitumor Activity in Glioblastoma.

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