RRC ID 38797
Author Kondo S, Yin D, Morimura T, Kubo H, Nakatsu S, Takeuchi J.
Title Combination therapy with cisplatin and nifedipine induces apoptosis in cisplatin-sensitive and cisplatin-resistant human glioblastoma cells.
Journal Br. J. Cancer
Abstract We attempted to determine whether calcium channel blockers (CCBs) enhance the anti-tumour activity of cis-diamminedichloroplatinum (cisplatin) against both cisplatin-sensitive human glioblastoma U87 MG cells and cisplatin-resistant U87-MG-CR cells, the latter of which we developed for resistance to cisplatin. Nifedipine, a dihydropyridine class CCB, significantly enhanced the anti-tumour effect of cisplatin on these two cell types in vitro and in vivo. Our findings also indicated that, in the absence of normal extracellular Ca2+ nifedipine was capable of enhancing the cytotoxicity of cisplatin. In addition, this anti-tumour activity was partially inhibited by actinomycin D and cycloheximide, suggesting that it is possibly dependent upon new RNA and protein synthesis. Interestingly, ultrastructural analysis, DNA fragmentation assay and cell cycle analysis demonstrated that synergism between cisplatin and nifedipine results in apoptosis (programmed cell death) at a relatively low concentration of cisplatin, which when tested alone did not induce apoptosis. Furthermore, we demonstrated that nuclei from these cells lack a Ca(2+)-dependent endonuclease that degrade chromatin in the linker region between nucleosomes. In conclusion, our studies suggest that the non-cytotoxic agent nifedipine is able to synergistically enhance the anti-tumour effects of cisplatin on U87-MG and U87-MG-CR cells lacking a Ca(2+)-dependent endonuclease and subsequently to induce apoptosis via interaction of nifedipine with an as yet uncharacterised functional site other than a calcium channel on target cells.
Volume 71(2)
Pages 282-9
Published 1995-2
DOI 10.1038/bjc.1995.57
PMID 7841041
PMC PMC2033593
MeSH Animals Antineoplastic Combined Chemotherapy Protocols / therapeutic use* Apoptosis / drug effects* Calcium / physiology Calcium Channels / drug effects Calcium Channels / physiology Cell Nucleus / drug effects Cell Nucleus / enzymology Cisplatin / administration & dosage Cisplatin / pharmacology* Cycloheximide / pharmacology DNA Damage DNA, Neoplasm / drug effects Dactinomycin / pharmacology Drug Resistance Drug Synergism Endonucleases / deficiency Female Glioblastoma / drug therapy Glioblastoma / pathology* Humans Mice Mice, Inbred BALB C Neoplasm Proteins / physiology Neoplasm Transplantation Nifedipine / administration & dosage Nifedipine / pharmacology* Nucleosomes / drug effects Tumor Cells, Cultured / drug effects
IF 5.416
Times Cited 35
Human and Animal Cells