Andrographolide Sensitizes Ras-Transformed Cells to Radiation in vitro and in vivo

Journal Article · Thu Jul 15 00:00:00 EDT 2010 · International Journal of Radiation Oncology, Biology and Physics

DOI:https://doi.org/10.1016/j.ijrobp.2010.01.007· OSTI ID:21436094

Hung, Shih-Kai ^[1]; Hung, Ling-Chien ^[1]; Kuo, Cheng-Deng ^[2]

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1. Institute of Traditional Medicine, National Yang-Ming University, Taipei, Taiwan (China)
2. Department of Research and Education, Veterans General Hospital-Taipei, Taipei, Taiwan (China)

Purpose: Increasing the sensitivity of tumor cells to radiation is a major goal of radiotherapy. The present study investigated the radiosensitizing effects of andrographolide and examined the molecular mechanisms of andrographolide-mediated radiosensitization. Methods and Materials: An H-ras-transformed rat kidney epithelial (RK3E) cell line was used to measure the radiosensitizing effects of andrographolide in clonogenic assays, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide assays, and a xenograft tumor growth model. The mechanism of andrographolide-sensitized cell death was analyzed using annexin V staining, caspase 3 activity assays, and terminal transferase uridyl nick end labeling assays. The roles of nuclear factor kappa B (NF-{kappa}B) and Akt in andrographolide-mediated sensitization were examined using reporter assays, electrophoretic mobility shift assays, and Western blotting. Results: Concurrent andrographolide treatment (10 {mu}M, 3 h) sensitized Ras-transformed cells to radiation in vitro (sensitizer enhancement ratio, 1.73). Andrographolide plus radiation (one dose of 300 mg/kg peritumor andrographolide and one dose of 6 Gy radiation) resulted in significant tumor growth delay (27 {+-} 2.5 days) compared with radiation alone (22 {+-} 1.5 days; p <.05). Radiation induced apoptotic markers (e.g., caspase-3, membrane reversion, DNA fragmentation), and andrographolide treatment did not promote radiation-induced apoptosis. However, the protein level of activated Akt was significantly reduced by andrographolide. NF-{kappa}B activity was elevated in irradiated Ras-transformed cells, and andrographolide treatment significantly reduced radiation-induced NF-{kappa}B activity. Conclusion: Andrographolide sensitized Ras-transformed cells to radiation both in vitro and in vivo. Andrographolide-mediated radiosensitization was associated with downregulation of Akt and NF-{kappa}B activity. These observations indicate that andrographolide is a novel radiosensitizing agent with potential application in cancer radiotherapy.

• OSTI ID: 21436094
• Journal Information: International Journal of Radiation Oncology, Biology and Physics, Vol. 77, Issue 4; Other Information: DOI: 10.1016/j.ijrobp.2010.01.007; PII: S0360-3016(10)00030-1; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0360-3016
• Country of Publication: United States
• Language: English

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62 RADIOLOGY AND NUCLEAR MEDICINE
IN VITRO
IN VIVO
NEOPLASMS
RADIOSENSITIVITY
RADIOTHERAPY
RATS
SENSITIZERS
TETRAZOLIUM
TUMOR CELLS
ANIMAL CELLS
ANIMALS
AZOLES
CHLORIDES
CHLORINE COMPOUNDS
DISEASES
HALIDES
HALOGEN COMPOUNDS
HETEROCYCLIC COMPOUNDS
MAMMALS
MEDICINE
NUCLEAR MEDICINE
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
RADIOLOGY
REAGENTS
RODENTS
SENSITIVITY
TETRAZOLES
THERAPY
VERTEBRATES