Regulation of tumor signaling pathways by AZD3409 in vitro.
BACKGROUND
The antineoplastic activity of AZD3409 was evaluated in relation to paclitaxel in human breast (MDA-MB-231, BT-474) and ovarian (A2780, A2780cp) cancer cell lines. Biomarkers of apoptosis, protein prenylation, survival, angiogenesis and cellular growth were determined.


METHODS
Cytotoxicity was evaluated by MTS assay, and apoptosis was evaluated by TUNEL. Biomarkers were measured by Western blots and ELISA.


RESULTS
The IC50 concentrations of AZD3409 in MDA-MB-231, BT-474, A2780 and A2780cp were 19.16, 5.69, 3.19, and 8.86 microM, respectively. The corresponding apoptogenic EC50 concentrations were 6.81, 4.15, 1.54 and 4.59 microM.


CONCLUSIONS
Famesylation of HDJ-2 was inhibited in all cell lines. Secretion of VEGF, bFGF and MMP-1 were inhibited in the breast lines but augmented in the ovarian lines. AZD3409 increased Akt activation in breast lines and decreased it in ovarian lines, without effect on MEK or ERK activation. AZD3409 cytotoxicity is mediated in part by inhibition of farnesylation.
Streeper
Robert
R
Cancer Therapy and Research Center, Institute for Drug Development, San Antonio, TX 78245 USA.
Campos
David
D
Carrizales
Gilbert
G
Stephens
Trevor C
TC
Izbicka
Elzbieta
E
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D020287:In Situ Nick-End Labeling; D015398:Signal Transduction / Q000187:drug effects*
D000970:Antineoplastic Agents