In:
Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 8, No. 12_Supplement ( 2009-12-10), p. C103-C103
Abstract:
KP1339 is a promising ruthenium based anti-cancer compound. Aim of this study was to test the in vitro and in vivo activity of KP1339 against human liver cancer. As a first step, the cytotoxic potential of KP1339 against a panel of hepatoma cell lines was determined by MTT assay. After 72 h treatment, the mean IC50 value was 124.4 µM with HCC1.2, and HCC3 being most sensitive (IC50 values of 62.9 µM and 67.5 µM, respectively). Notably, the IC50 values did not correlate with intracellular KP1339 levels determined by inductively-coupled plasma mass spectrometry (ICP-MS) measurements. All tested cell lines revealed similar Ru contents (∼5 ng Ru/105 cells) after 1 h drug exposure. To evaluate the mechanisms underlying KP1339 activity, apoptosis induction as well as impact on cell cycle distribution and proliferation of Hep3B cells was evaluated. KP1339 treatment led to typical morphological signs of programmed cell death like cell shrinkage, chromatin condensation and formation of apoptotic bodies. Apoptotic cell death induced by KP1339 was further characterized by PARP cleavage. An increase of cells with mitochondrial membrane depolarization (measured by JC-1 staining and FACS analysis) suggested that at least part of the observed apoptotic cell death is induced via the mitochondrial pathway. Furthermore, KP1339 treatment was found to significantly reduced DNA synthesis rate measured by 3H-thymidine incorporation. With regard to cell cycle distribution, 24 h treatment led to increase of cells in G2/M phase (detected by PI-staining followed by FACS analyses). This was accompanied by strong phosphorylation of the stress kinase P38 and the extracellular signal-regulated kinase (ERK), suggesting that P38 might be involved in delayed apoptosis entry. Currently the activity of KP1339 against several hepatoma cells is evaluated in xenograft experiments using female SCID mice (30 mg/kg i.v.; once a week for two weeks) as compared to the standard therapy Sorafenib (25mg/kg p.o.; five times a week for two weeks). Preliminary results indicate that KP1339 is well tolerated. In the Hep3B model, KP1339 led to a 2.4-fold increase in life span (mean survival of 80 days as compared to 33 days) and thus was superior to Sorafenib monotherapy (1.9-fold survival increase; 60 days as compared to the control). Taken together, KP1339 is a very promising anticancer drug with significant activity against human hepatoma cell lines in vitro and in vivo. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C103.
Type of Medium:
Online Resource
ISSN:
1535-7163
,
1538-8514
DOI:
10.1158/1535-7163.TARG-09-C103
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2009
detail.hit.zdb_id:
2062135-8
SSG:
12
Permalink