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Induction of cell cycle arrest, DNA damage, and apoptosis by nimbolide in human renal cell carcinoma cells.

Abstract
Nimbolide is a tetranortriterpenoid isolated from the leaves and flowers of Azadirachta indica which has been shown to exhibit anticancer, antioxidant, anti-inflammatory, and anti-invasive properties in a variety of cancer cells. However, the anti-tumor effect on human renal cell carcinoma (RCC) cells is unknown. In this study, we found that nimbolide treatment had a cytotoxic effect on 786-O and A-498 RCC cells in a dose-dependent manner. According to flow cytometric analysis, nimbolide treatment resulted in G2/M arrest in 786-O and A-498 cells accompanied with an increase in the phosphorylation status of p53, cdc2, cdc25c, and decreased expressions of cyclin A, cyclin B, cdc2, and cdc25c. Nimbolide also caused DNA damage in a dose-dependent manner as determined by comet assay and measurement of γ-H2AX. In addition, apoptotic cells were observed in an Annexin V-FITC/propidium iodide double-stained assay. The activities of caspase-3, -9, and poly ADP-ribose polymerase (PARP) were increased, and the expression of pro-caspase-8 was decreased in nimbolide-treated 786-O and A-498 cells. Western blot analysis revealed that the levels of intrinsic-related apoptotic proteins Bax and extrinsic-related proteins (DR5, CHOP) were significantly increased in nimbolide-treated 786-O and A-498 cells. In addition, the expressions of Bcl-2 and Mcl-1 were decreased in 786-O and A-498 cells after nimbolide treatment. We conclude that nimbolide can inhibit the growth of human RCC cells by inducing G2/M phase arrest by modulating cell cycle-related proteins and cell apoptosis by regulating intrinsic and extrinsic caspase signaling pathways. Nimbolide may be a promising therapeutic strategy for the treatment of RCC.
AuthorsYi-Hsien Hsieh, Chien-Hsing Lee, Hsiao-Yun Chen, Shu-Ching Hsieh, Chia-Liang Lin, Jen-Pi Tsai
JournalTumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine (Tumour Biol) Vol. 36 Issue 10 Pg. 7539-47 (Sep 2015) ISSN: 1423-0380 [Electronic] Netherlands
PMID25916210 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Apoptosis Regulatory Proteins
  • Cell Cycle Proteins
  • Limonins
  • nimbolide
Topics
  • Apoptosis (drug effects)
  • Apoptosis Regulatory Proteins (metabolism)
  • Carcinoma, Renal Cell (drug therapy, metabolism)
  • Cell Cycle Checkpoints (drug effects)
  • Cell Cycle Proteins (metabolism)
  • Cell Line, Tumor
  • DNA Damage (drug effects)
  • G2 Phase Cell Cycle Checkpoints (drug effects)
  • Humans
  • Kidney Neoplasms (drug therapy, metabolism)
  • Limonins (pharmacology)
  • Signal Transduction (drug effects)

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