Anti-tumor effect of bisphosphonate (YM529) on non-small cell lung cancer cell lines

BACKGROUND: YM529 is a newly developed nitrogen-containing bisphosphonate (BP) classified as a third-generation BP that shows a 100-fold greater potency against bone resorption than pamidronate, a second-generation BP. This agent is, therefore expected to be extremely useful clinically for the treatment of osteoporosis and hypercalcemia. Recently, YM529 as well as other third-generation BPs have also been shown to exert anti-tumor effects against various types of cancer cells both in vitro or/and in vivo. In this study, we investigate the anti-tumor effect of YM529 on non-small cell lung cancer (NSCLC). METHODS: Direct anti-tumor effect of YM529 against 8 NSCLC cell lines (adenocarcinoma: H23, H1299, NCI-H1819, NCI-H2009, H44, A549, adenosquamous cell carcinoma: NCI-H125, squamous cell carcinoma: NCI-H157) were measured by MTS assay and calculated inhibition concentration 50 % (IC(50)) values. YM529 induced apoptosis of NCI-H1819 was examined by DNA fragmentation of 2 % agarose gel electrophoresis and flowcytometric analysis (sub-G(1 )method). We examined where YM529 given effect to apoptosis of NSCLC cells in signaling pathway of the mevalonate pathway by western blotting analysis. RESULTS: We found that there was direct anti-tumor effect of YM529 on 8 NSCLC cell lines in a dose-dependent manner and their IC(50 )values were 2.1 to 7.9 μM and YM529 induced apoptosis and G(1 )arrest cell cycle with dose-dependent manner and YM529 caused down regulation of phospholyration of ERK1/2 in signaling pathways of NSCLC cell line (NCI-H1819). CONCLUSION: Our study demonstrate that YM529 showed direct anti-tumor effect on NSCLC cell lines in vitro, which supports the possibility that third-generation BPs including YM529 can be one of therapeutic options for NSCLC

Combined effects of a third-generation bisphosphonate, zoledronic acid with other anticancer agents against murine osteosarcoma

Bisphosphonates (BPs) are widely used to treat bone diseases and also appear to possess direct antitumour activity. We have previously reported that third-generation BPs such as zoledronic acid (ZOL) and minodronic acid (YM529) synergistically augment the effects of anticancer agents in various cancer cells. Recently, we have also reported the antitumour effects of YM529 on murine osteosarcoma cells. As YM529 has not been clinically available, we herein focused on the anti-osteosarcoma effects of ZOL which is clinically available. In addition to ZOL alone, we evaluated the concurrent or sequential combined effects of ZOL with other anticancer agents against murine osteosarcoma cell lines. ZOL showed almost same anti-osteosarcoma activity compared with YM529 and more sensitive growth inhibitory effects against osteosarcoma cells than normal cells. Moreover, ZOL acted synergistically in vitro when administered concurrently with paclitaxel (PAC) or gemcitabine (GEM), not only in wild-type osteosarcoma cells but also in P-glycoprotein (P-gp)-overexpressing osteosarcoma cells, which were much less sensitive against each anticancer agent. Furthermore, 24 h of ZOL pretreatment significantly augmented the sensitivity of doxorubicin (DOX), PAC or GEM against osteosarcoma cells. These findings suggest that combined administration of ZOL with other anticancer agents may improve the osteosarcoma treatment

Why evolution matters for species conservation: perspectives from three case studies of plant metapopulations

We advocate the advantage of an evolutionary approach to conservation biology that considers evolutionary history at various levels of biological organization. We review work on three separate plant taxa, spanning from one to multiple decades, illustrating extremes in metapopulation functioning. We show how the rare endemics Centaurea corymbosa (Clape Massif, France) and Brassica insularis in Corsica (France) may be caught in an evolutionary trap: disruption of metapopulation functioning due to lack of colonization of new sites may have counterselected traits such as dispersal ability or self-compatibility, making these species particularly vulnerable to any disturbance. The third case study concerns the evolution of life history strategies in the highly diverse genus Leucadendron of the South African fynbos. There, fire disturbance and the recolonization phase after fires are so integral to the functioning of populations that recruitment of new individuals is conditioned by fire. We show how past adaptation to different fire regimes and climatic constraints make species with different life history syndromes more or less vulnerable to global changes. These different case studies suggest that management strategies should promote evolutionary potential and evolutionary processes to better protect extant biodiversity and biodiversification

Patterns or mechanisms? Bergmann’s and Rapoport’s rule in moths along an elevational gradient

Bergmann’s rule predicts increasing body sizes at higher elevations. The elevational Rapoport’s rule predicts an increase of elevational range size with higher elevations. Both rules have often been related to effects of temperature. Larger bodies allow more efficient heat preservation at lower temperature, explaining Bergmann’s rule. Higher temperature variability may select for adaptations that allow increased range sizes, explaining Rapoport’s rule. The generality of both rules has been challenged and evidence towards explanatory mechanisms has been equivocal. We investigated temperature and its variability as explanations for Bergmann’s and Rapoport’s rule in moths along an elevation gradient in Switzerland. In particular, we tested for relationships between elevation, temperature and body size across almost 300 species of Macrolepidoptera along a gradient from 600 to 2400 m a.s.l. The gradient was resampled throughout the vegetation season, which allowed assessing temperature effects independently from elevation. We controlled analyses for covariate traits of moths and their phylogeny. We found a positive relationship between body size and elevation, but no link with temperature. Furthermore, there was no positive link between average elevation and elevational range, but there was between temperature variability and elevational range. We conclude that mechanisms other than temperature can lead to increasing body sizes with elevation (supporting Bergmann’s pattern, but not the mechanism). Contrary to that, data support the mechanism for Rapoport’s rule: high temperature variability is associated with large ranges. However, because temperature variability is not necessarily increasing with elevation, it may not always lead to the geographic pattern predicted

Patterns or mechanisms? Bergmann's and Rapoport's rule in moths along an elevational gradient

Bergmann's rule predicts increasing body sizes at higher elevations. The elevational Rapoport's rule predicts an increase of elevational range size with higher elevations. Both rules have often been related to effects of temperature. Larger bodies allow more efficient heat preservation at lower temperature, explaining Bergmann's rule. Higher temperature variability may select for adaptations that allow increased range sizes, explaining Rapoport's rule. The generality of both rules has been challenged and evidence towards explanatory mechanisms has been equivocal. We investigated temperature and its variability as explanations for Bergmann's and Rapoport's rule in moths along an elevation gradient in Switzerland. In particular, we tested for relationships between elevation, temperature and body size across almost 300 species of Macrolepidoptera along a gradient from 600 to 2400 m a.s.l. The gradient was resampled throughout the vegetation season, which allowed assessing temperature effects independently from elevation. We controlled analyses for covariate traits of moths and their phylogeny. We found a positive relationship between body size and elevation, but no link with temperature. Furthermore, there was no positive link between average elevation and elevational range, but there was between temperature variability and elevational range. We conclude that mechanisms other than temperature can lead to increasing body sizes with elevation (supporting Bergmann's pattern, but not the mechanism). Contrary to that, data support the mechanism for Rapoport's rule: high temperature variability is associated with large ranges. However, because temperature variability is not necessarily increasing with elevation, it may not always lead to the geographic pattern predicted