Inhibitors that target protein kinases for the treatment of ovarian carcinoma.
OBJECTIVE
Ovarian cancer is the leading cause of death from gynecologic malignancies in the United States. In an attempt to develop drugs that suppress ovarian cancer cells, we examined the effect of selective inhibitors of protein tyrosine kinases-tyrphostins, which are likely to play a role in ovarian cancer cells.


METHODS
We examined the cellular and biochemical effects of tyrphostins AG1478, PP2, AGL2592, and AG490 from four different families on the ovarian carcinoma cell line OV1063.


RESULTS
We found that the AG1478, PP2, AGL2592, and AG490 tyrphostins suppressed cell proliferation and altered cell cycle distribution of the OV1063 cells in a dose- and time-dependent manner. Immunoblotting analysis indicated that AG1478 effectively inhibited epidermal growth factor receptor autophosphorylation, that AG490 decreased the level of Jak2 and phosphorylated Stat3, and that PP2 decreased the level of pp60Src protein. AGL2592 decreased the level of constitutive activated epidermal growth factor receptor and pStat3, but its molecular targets have not been identified completely.


CONCLUSIONS
The growth-arresting properties of these tyrphostins identify them as possible candidates for signal transduction therapy.
Arbel
Revital
R
Laboratory of Experimental Surgery, Hadassah University Hospital, Jerusalem, Israel.
Rojansky
Nathan
N
Klein
Benjamin Y
BY
Levitzki
Rubina
R
Hartzstark
Zipora
Z
Laufer
Neri
N
Ben-Bassat
Hannah
H
D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002396:Catechols / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D009570:Nitriles / Q000627:therapeutic use; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines / Q000627:therapeutic use; D011799:Quinazolines; D013997:Time Factors; D014407:Tumor Cells, Cultured; D020032:Tyrphostins / Q000008:administration & dosage / Q000627:therapeutic use*
C412373:AG 1879; C466796:AGL 2592; D000970:Antineoplastic Agents; D002396:Catechols; D004791:Enzyme Inhibitors; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C101044:RTKI cpd