In:
Cancer Prevention Research, American Association for Cancer Research (AACR), Vol. 5, No. 11_Supplement ( 2012-11-01), p. A48-A48
Abstract:
Objectives: The mevalonate pathway has a crucial role in maintaining cellular homeostasis by cholesterol synthesis and protein prenylation. The mevalonate pathway inhibitors, statins and bisphosphonates have long been tested as anticancer agents, but because of the tumor-selective mechanisms, effects of the drugs on lung cancer cells are not clear. P53, a central regulator of stress responses, can induce cell cycle arrest, cell death or senescence depending on the level of cellular stresses. The current study investigated the effects of simvastatin and zolendronic acid on non-small-cell lung cancer (NSCLC) cells and whether the anti-tumor effects are related to p53 mutation status. Material and Methods: We treated 3 NSCLC cells, A549 (p53 wild type), H522 (mutant) and H358 (null), with simvastatin and zolendronic acid to investigate cellular proliferation, cell cycle activity, intracellular reactive oxygen species (ROS) and expression of p53 target genes. Results: In light microscopy, simvastatin (1 uM) caused morphologic changes in all 3 NSCLC cells. The cytotoxicity assay revealed that the synergistic impact with simvastatin (1 uM) and zolendronic acid (50 uM) existed on 72 hour cell survival, which was shown only in p53-wt cells. Expression of cyclin D1, which is important regulator of G1 to S phase progression, was decreased in p53-null and mutant cells but increased in p53-wt cells. Intracellular ROS levels after 24 hour treatment with blends of simvastatin and zolendronic acid was increased more than 2-fold in p53-wt cells, not in p53-null or mutant cells. Regulation of oxidative stress by p53 was shown with the increased expression of p53 target genes, cytochrome c oxidase 2 and TP53-induced glycolysis and apoptosis regulator quantified by real-time polymerase chain reaction. Conclusions: Our data indicate that taken together, combination of simvastatin and zolendronic acid may have synergistic anti-proliferative effects in lung cancer cells which have functional p53, and those are mediated by increased cellular oxidative stress leading to apoptosis rather than cell cycle arrest. Targeting mevalonate pathway has the potential for lung cancer prevention, by inducing cellular metabolic stress responses mediated by p53. Citation Format: Hwa Young Lee, In Kyoung Kim, Hye In Lee, Hye Sun Kang, Chan Kwon Park, Jick Hwan Ha, Seung Joon Kim, Sang Haak Lee. Mevalonate pathway inhibitors as chemopreventive agents on lung cancer cell lines: p53 might be a potent regulator. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A48.
Type of Medium:
Online Resource
ISSN:
1940-6207
,
1940-6215
DOI:
10.1158/1940-6207.PREV-12-A48
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2012
detail.hit.zdb_id:
2422346-3
