Effect of incadronate on proliferation of mesenchymal tumor cells with or without activated Ras mutation.
The present investigation examined the effect of bisphosphonates on six mesenchymal tumor cell lines and the mechanisms of inhibition of tumor cell proliferation. HT-1080, a fibrosarcoma cell line that exhibits increased Ras activity due to a mutation of the Ras gene, demonstrated significantly reduced tumor cell proliferation upon treatment with incadronate. The other cell lines, however, which lack mutation of the Ras gene, showed no influence upon treatment with incadronate. Autoradiography demonstrated no difference in the uptake of 3H-labelled incadronate between susceptible and unaffected cells. The anti-proliferation of HT-1080 was reversed by the addition of geranylgeranyl pyrophosphate. Etidronate exhibited no influence on all tested cell lines. On the basis of these data, we hypothesized that incadronate inhibits the mevalonate pathway and blocks oncogenic Ras signaling. In an effort to confirm this hypothesis, the influence of incadronate on an oncogenic Ras transfected BALB/3T3 cell line (Bhas 42) and a parental BALB/3T3 cell line were compared. The parental BALB/3T3 cells showed slight inhibition upon treatment with incadronate, however, the proliferation of Bhas 42 cells was significantly reduced. These results suggest that incadronate suppresses oncogenic Ras-activated mesenchymal tumors through the inhibition of Ras signaling pathways.
Div. of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
H
H
Kawashima
A
A
Ogose
T
T
Hotta
T
T
Ito
N
N
Endo
H
H
Kawashima
K
K
Tamura
K
K
Nakano
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001345:Autoradiography; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D004164:Diphosphonates / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000187:drug effects / Q000378:metabolism; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D008637:Mesenchymoma / Q000188:drug therapy* / Q000235:genetics; D008798:Mevalonic Acid / Q000378:metabolism; D009154:Mutation; D016133:Polymerase Chain Reaction
D050071:Bone Density Conservation Agents; D004164:Diphosphonates; C071542:cimadronate; D051231:Farnesyltranstransferase; D008798:Mevalonic Acid