Study Of AG1478 As A New Therapeutic Agent In Cervical Cancer

Cervical cancer is one of the most common gynecologic malignancies of the reproductive tract, its incidence rate is as quite as breast cancer has been, threating to the health of women as an important"killer". Radiotherapy and chemotherapy currently is major means in treatment of of cervical cancer, playing an irreplaceable role. However, in advanced cervical cancer patients is not sensitive to radiotherapy and chemotherapy, which is one of important reasons failured to radiotherapy and chemotherapy. Explore new chemopeutic agents and agents promoting cancer cells to radiotherapy has been a hot topic in radiotherapy and chemotherapy of cervical cancer.Tyrophostin (AG1478) is a selective small molecule inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. In recent years it has been found that AG1478 causes (i) an inhibition of tumor cell proliferation; (ii) an induction of apoptosis; (iii) an interference with signal transduction pathways; and (iv) an inhibition of enzyme(s) relavant to tumor development; (v) an inhibition of cell cycle in the G1 phase resulting in the reduction of tumor cell growth and reproduction. Thus, AG1478 is expected to become a new anti-tumor drug.In this study, I found that (1) AG1478 at high doses (>10μM) significantly caused an inhibition of human cervical cancer Siha cell growth in a dose-dependent manner, which may be due to apoptosis induction and a G1 arrest of cell cycle progression; (2) AG1478 suppressed cell invasion and migration in a dose-dependent and time-dependent manner, which was associated with up-regulation of Kiss-1, a tumor metastasis suppressor. Kocking-down the Kiss-1 gene significantly reduced AG1478-anti-invasion ability. (3) Although AG1478 at low doses (<10μM) did not significantly inhibited Siha cell growth, it significantly increased the radiosensitivity, about a 3-5 fold increase, which was associated with an elvated expression of Egr-1, a early radiation-response gene. Kocking-down the Egr-1 gene significantly reduced AG1478-mediated radiosenstization. These studies indicated, for first time, AG1478 is a new promsing chemotherapeutic agent in inhibing cervical cancer cell growth and invasion by inducing apoptosis, blocking cell cycle progress and increasing Kiss-1 expression, and also works a new radiosenstiztor in radiotherapy of cervical cancer by up-regulating Egr-1 expression. The present findings will provide a research direction and experimental foundation for a potential application of AG1478 as a new clinical cancer therapy agent in controlling the growth and metastasis of cervical cancer and as a new radiosensitizer in radiotherapy in near future.