TY - JOUR
T1 - ZD6474 enhances paclitaxel antiproliferative and apoptotic effects in breast carcinoma cells
AU - Sarkar, Siddik
AU - Mazumdar, Abhijit
AU - Dash, Rupesh
AU - Sarkar, Devanand
AU - Fisher, Paul B.
AU - Mandal, Mahitosh
N1 - Copyright:
Copyright 2011 Elsevier B.V., All rights reserved.
PY - 2011/2
Y1 - 2011/2
N2 - Chemotherapy employing paclitaxel and docetaxel is widely used for treating early-stage breast cancer and metastasis, which is frequently associated with overexpression of epidermal growth factor receptor (EGFR) and resistance to apoptosis. ZD6474, a dual tyrosine kinase inhibitor of EGFR and VEGFR, inhibits cell proliferation of solid tumors, including breast. Phase III clinical trials using ZD6474 in non-small cell lung carcinoma when combined with standard chemotherapy appear promising. In order to improve the antineoplastic activity of paclitaxel, we presently investigated the effects of ZD6474 in combination with paclitaxel in EGFR and VEGFR expressing human breast cancer cell lines MCF-7 and MDA-MB-231. ZD6474 synergistically decreased cell viability when used in combination with paclitaxel. ZD6474 inhibited cyclin D1 and cyclin E expression and induced p53 expression when combined with paclitaxel. The combination of ZD6474 with paclitaxel versus either agent alone also more potently down-regulated the antiapoptotic bcl-2 protein, up-regulated pro-apoptotic signaling events involving expression of bax, activation of caspase-3 and caspase-7 proteins, and induced poly(ADP-ribose) polymerase resulting in apoptosis. ZD6474 combined with paclitaxel inhibited anchorage-independent colony formation and invasion of breast cancer cells in vitro as compared to either single agent, indicating a potential involvement of altered expression and reorganization of cytoskeletal proteins in combinatorial treated breast cancer cells. Collectively, our studies indicate that incorporating an anti-EGFR plus VEGFR strategy (ZD6474) with chemotherapy (paclitaxel), where clinical studies of dose-intensive paclitaxel therapy are currently in progress, may be more effective in treating patients with locally advanced or metastatic breast cancer than either approach alone.
AB - Chemotherapy employing paclitaxel and docetaxel is widely used for treating early-stage breast cancer and metastasis, which is frequently associated with overexpression of epidermal growth factor receptor (EGFR) and resistance to apoptosis. ZD6474, a dual tyrosine kinase inhibitor of EGFR and VEGFR, inhibits cell proliferation of solid tumors, including breast. Phase III clinical trials using ZD6474 in non-small cell lung carcinoma when combined with standard chemotherapy appear promising. In order to improve the antineoplastic activity of paclitaxel, we presently investigated the effects of ZD6474 in combination with paclitaxel in EGFR and VEGFR expressing human breast cancer cell lines MCF-7 and MDA-MB-231. ZD6474 synergistically decreased cell viability when used in combination with paclitaxel. ZD6474 inhibited cyclin D1 and cyclin E expression and induced p53 expression when combined with paclitaxel. The combination of ZD6474 with paclitaxel versus either agent alone also more potently down-regulated the antiapoptotic bcl-2 protein, up-regulated pro-apoptotic signaling events involving expression of bax, activation of caspase-3 and caspase-7 proteins, and induced poly(ADP-ribose) polymerase resulting in apoptosis. ZD6474 combined with paclitaxel inhibited anchorage-independent colony formation and invasion of breast cancer cells in vitro as compared to either single agent, indicating a potential involvement of altered expression and reorganization of cytoskeletal proteins in combinatorial treated breast cancer cells. Collectively, our studies indicate that incorporating an anti-EGFR plus VEGFR strategy (ZD6474) with chemotherapy (paclitaxel), where clinical studies of dose-intensive paclitaxel therapy are currently in progress, may be more effective in treating patients with locally advanced or metastatic breast cancer than either approach alone.
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U2 - 10.1002/jcp.22343
DO - 10.1002/jcp.22343
M3 - Article
C2 - 20665703
AN - SCOPUS:78649651308
SN - 0021-9541
VL - 226
SP - 375
EP - 384
JO - Journal of Cellular Physiology
JF - Journal of Cellular Physiology
IS - 2
ER -