Abstract
Selective inhibition of repopulation of surviving tumor cells between courses of chemotherapy might improve the outcome of treatment. A potential target for inhibiting repopulation is the mammalian target of rapamycin pathway; PTEN-negative tumor cells are particularly sensitive to inhibition of this pathway. Here we study the rapamycin analogue CCI-779, alone or with chemotherapy, as an inhibitor of proliferation of the human prostate cancer cell lines PC-3 and DU145. The PTEN and phospho-Akt/PKB status and the effect of CCI-779 on phosphorylation of ribosomal protein S6 were evaluated by immunostaining and/or Western blotting. Expression of phospho-Akt/PKB in PTEN mutant PC-3 cells and xenografts was higher than in PTEN wild-type DU145 cells. Phosphorylation of S6 was inhibited by CCI-779 in both cell lines. Cultured cells were treated weekly with mitoxantrone or docetaxel for two cycles, and CCI-779 or vehicle was given between courses. Growth and clonogenic survival of both cell lines were inhibited in a dose-dependent manner by CCI-779, but there were minimal effects when CCI-779 was given between courses of chemotherapy. CCI-779 inhibited the growth of xenografts derived from both cell lines with greater effects against PC-3 than DU145 tumors. CCI-779 caused mild myelosuppression. The activity of mitoxantrone or docetaxel was limited, but CCI-779 given between courses of chemotherapy increased growth delay of PC-3 xenografts. Our results suggest that repopulation of PTEN-negative cancer cells between courses of chemotherapy might be inhibited by CCI-779.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
-
Cell Growth Processes / drug effects
-
Cell Line, Tumor
-
Cell Proliferation / drug effects
-
Docetaxel
-
Drug Synergism
-
Humans
-
Male
-
Mice
-
Mice, Inbred BALB C
-
Mice, Nude
-
Mitoxantrone / administration & dosage
-
PTEN Phosphohydrolase
-
Phosphoric Monoester Hydrolases / deficiency
-
Phosphoric Monoester Hydrolases / metabolism
-
Phosphorylation
-
Prostatic Neoplasms / drug therapy*
-
Prostatic Neoplasms / enzymology
-
Prostatic Neoplasms / metabolism
-
Prostatic Neoplasms / pathology
-
Protein Kinase Inhibitors / administration & dosage
-
Protein Kinase Inhibitors / pharmacology*
-
Protein Kinase Inhibitors / toxicity
-
Protein Kinases / metabolism*
-
Protein Serine-Threonine Kinases / metabolism
-
Proto-Oncogene Proteins / metabolism
-
Proto-Oncogene Proteins c-akt
-
Ribosomal Protein S6 / metabolism
-
Sirolimus / administration & dosage
-
Sirolimus / analogs & derivatives*
-
Sirolimus / pharmacology*
-
Sirolimus / toxicity
-
TOR Serine-Threonine Kinases
-
Taxoids / administration & dosage
-
Tumor Suppressor Proteins / deficiency
-
Tumor Suppressor Proteins / metabolism
-
Xenograft Model Antitumor Assays
Substances
-
Protein Kinase Inhibitors
-
Proto-Oncogene Proteins
-
Ribosomal Protein S6
-
Taxoids
-
Tumor Suppressor Proteins
-
Docetaxel
-
temsirolimus
-
Mitoxantrone
-
Protein Kinases
-
MTOR protein, human
-
mTOR protein, mouse
-
AKT1 protein, human
-
Protein Serine-Threonine Kinases
-
Proto-Oncogene Proteins c-akt
-
TOR Serine-Threonine Kinases
-
Phosphoric Monoester Hydrolases
-
PTEN Phosphohydrolase
-
PTEN protein, human
-
Sirolimus