ZD6474 enhances paclitaxel antiproliferative and apoptotic effects in breast carcinoma cells

Abstract

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.

Targeted therapy against EGFR and VEGFR using ZD6474 enhances the therapeutic potential of UV-B phototherapy in breast cancer cells

“…UV-B radiation in presence of ZD6474 induced DNA damage irreparable that ultimately arrested the irradiated cells at synthetic S or G 1 -S phase of cell cycle [55]. There was a decrease in expression of cyclin E in ZD6474 induced UV-B irradiated cells which is in agreement with our prior findings [56]. The alteration of both cyclin D1 and cyclin E was associated with breast cancer progression, early relapse, poor prognosis and chemo-resistance to various cytotoxic agents [57-59].…”

“…Caspase-3 and caspase-7 activity was determined by measuring the absorbance at 405 nm after cleavage of synthetic substrate acetyl-Asp-Glu-Val-Asp p-nitroanilide (Ac-DEVD-pNA) as described previously [73] with some modifications [56]. Cells were treated with ZD6474 and/or UV-B radiation for 48 h, and lysed with buffer (50 mM HEPES, pH 7.4, 5 mM CHAPS, 5 mM DTT, 1 mM PMSF, 20 μg/ml leupeptin), followed by centrifugation at 20,000 g for 15 min at 4°C.…”

Antiproliferative and proapoptotic activity of CLM3, a novel multiple tyrosine kinase inhibitor, alone and in combination with SN-38 on endothelial and cancer cells

“…Actually, the novel inhibitor CLM3 displayed significant antiproliferative and pro-apoptotic effects on endothelial and cancer cells, with a mechanism mediated by the inhibition of phosphorylation of ERK1/2 and Akt, respectively. In this, CLM3 shows a similar behaviour to other small molecules that inhibit EGFR and VEGFR-2, such as vandetanib [36,37], or VEGFR-2 such as axitinib [38,39], which have been shown to inhibit in vitro both ERK1/2 and Akt phosphorylation in endothelial and cancer cells. .…”

Antineoplastic and Apoptotic Potential of Traditional Medicines Thymoquinone and Diosgenin in Squamous Cell Carcinoma

“…For combinations of TQ and DG, interactions between the two were assessed by means of an automatically computed combination index (CI). The CI was determined at a given effect (F) for combination of cytotoxic A and cytotoxic B by the following equation:The CI provides a quantitative measure of the degree of drug interaction in terms of additive effect (CI = 1), synergism (CI<1), or antagonism (CI>1) for a given endpoint of the effect measurement [23].…”