Inhibition of ornithine decarboxylase 1 facilitates pegylated arginase treatment in lung adenocarcinoma xenograft models

Our plain-English summary of Inhibition of ornithine decarboxylase 1 facilitates pegylated arginase treatment in lung adenocarcinoma xenograft models, by S.K. Lam, K.P. U, Y.Y. Li, et al (Oncology Reports, 2018).

The study

• Authors: S.K. Lam, K.P. U, Y.Y. Li, S. Xu, P.N. Cheng, J.C. Ho
• Journal: Oncology Reports
• Published: 2018;40(4):1994-2004
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Arginine depletion has shown anticancer effects among arginine auxotrophic cancers. An anti‑proliferative effect of pegylated arginase (BCT‑100) has been shown in acute myeloid leukaemia, hepatocellular carcinoma and mesothelioma. The aim of the present study was to evaluate the effect of BCT‑100 in lung adenocarcinoma. A panel of lung adenocarcinoma cell lines and xenograft models were used to investigate the effect of BCT‑100. Protein expression, arginine level, putrescine level, spermidine level and apoptosis were analyzed by western blotting, ELISA, high performance liquid chromatography, dot blot and TUNEL assay, respectively. BCT‑100 converts arginine to ornithine. BCT‑100 reduced in vitro cell viability across different lung adenocarcinoma cell lines and suppressed tumour growth in an HCC4006 xenograft, while paradoxical growth stimulation was observed in H358, HCC827, H1650 and H1975 xenografts. Upon BCT‑100 treatment, ornithine decarboxylase 1 (ODC1) was induced in two solid tumour xenografts (H1650 and H1975). It was postulated that the accumulated ornithine could be channeled via ODC1 to produce polyamines that promoted tumour growth. The action of an ODC1 inhibitor (α‑difluoromethylornithine, DFMO) was studied in the restoration of the anticancer effects of BCT‑100 in lung adenocarcinoma. In both H1650 and H1975 xenografts, a combination of DFMO and BCT‑100 significantly suppressed tumour growth, resulting in doubled median survival compared with the control. Putrescine was decreased in almost all treatment arms in the H1650, H1975 and HCC4006 xenografts. Nonetheless spermidine was reduced only following DFMO/BCT‑100 treatment in the H1650 and H1975 xenografts. Apoptosis was enhanced in the combined treatment arm in both H1650 and H1975 xenografts. In the HCC4006 xenograft, addition of DFMO did not alter the tumour suppressive effect of BCT‑100. In conclusion, inhibition of ODC1 by DFMO was crucial in facilitating BCT‑100 treatment in lung adenocarcinoma that was partially mediated by depleting arginine and polyamines with consequent apoptosis.

In plain English

This laboratory and animal study tested BCT-100, a pegylated form of arginase (an enzyme that breaks down the amino acid arginine), against lung adenocarcinoma. It did not study asbestos exposure or people. BCT-100 reduced growth of all seven lung adenocarcinoma cell lines tested. In mice carrying human lung tumours (xenografts), BCT-100 alone made tumours grow faster in four models (H358, HCC827, H1650, H1975) and slowed growth only in HCC4006. In H1650 and H1975 tumours, BCT-100 raised levels of the enzyme ODC1. Adding DFMO, a drug that blocks ODC1, significantly suppressed tumour growth in these two models. Median survival (time until death or until mice were put down at a tumour size of 600 mm3) rose from 12 days in controls to 24 and 25 days with the combination. DFMO alone did not significantly change tumour size. In HCC4006, the combination worked about the same as BCT-100 alone. In H1650 and H1975 tumours, the combination lowered spermidine levels and increased cell death. The authors concluded that an ODC1 inhibitor such as DFMO should be combined with BCT-100 to treat lung adenocarcinoma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study of human lung adenocarcinoma cell lines plus animal experiments in mice carrying human tumour xenografts
• Who was studied: Seven human lung adenocarcinoma cell lines (H23, H358, HCC827, H1650, H1975, HCC2935, HCC4006). Female nude mice aged 4 to 6 weeks carried xenografts from five of these lines. There were 6 mice per group in the two-group BCT-100 experiments and 8 per group in the four-group combination experiments. Work was done at the University of Hong Kong.
• Exposure: Pegylated arginase (BCT-100), 20 mg/kg twice a week by injection into the abdomen. The ODC1 inhibitor DFMO was given as 2% in drinking water. Mice received each drug alone or the two combined, compared with saline (PBS) controls. No asbestos exposure was studied.
• Main results:
  • In cell lines, BCT-100 reduced cell growth in all seven lung adenocarcinoma lines, with greater effect at higher doses.
  • In mouse xenografts, BCT-100 alone promoted tumour growth in the H358, HCC827 (printed once as 'H827'), H1650 and H1975 models. It suppressed growth in the HCC4006 model.
  • BCT-100 upregulated ODC1 in H1650 and H1975 xenografts. ODC1 was unaltered in the H358 xenograft.
  • DFMO alone did not significantly change tumour size compared with control in any xenograft model.
  • Survival in the mouse experiments was measured as time to the humane endpoint or death.
  • The humane endpoint was a tumour size of 600 mm3, at which point the mice were put down.
  • In the H1650 and H1975 models, the DFMO/BCT-100 combination significantly suppressed tumour growth. Median survival rose from 12 days in the control arm to 24 days (H1650) and 25 days (H1975) in the combination arm (P less than 0.01).
  • In the HCC4006 model, the combination and BCT-100 alone had similar effects.
  • Spermidine levels in the tumours fell significantly only in the combination arm, and only in the H1650 and H1975 xenografts.
  • Apoptosis (cell death) was further increased by the combination in the H1650 xenograft. It was significantly increased by the combination in the H1975 xenograft.
• The authors' conclusion: The authors concluded that an ODC1 inhibitor such as DFMO should be used together with pegylated arginase (BCT-100) in treating lung adenocarcinoma.
• Limitations the authors state:
  • The authors noted it remains unknown whether BCT-100 induces ODC1 in cancers other than lung adenocarcinoma.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Lung Adenocarcinoma, Carcinoma, Mesothelioma, Apoptosis, Median Overall Survival.

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