Abstract A81: Synergistic antitumor efficacy of the multikinase inhibitor, sorafenib and paclitaxel combination in NSCLC tumor model

Autor: Seong-Ae Yoon, Eun Kyoung Jeon, Jin-Hyoung Kang, Xiang-Hua Zhang, Jung-Young Shin
Rok vydání: 2009
Předmět:
Zdroj: Molecular Cancer Therapeutics. 8:A81-A81
ISSN: 1538-8514
1535-7163
DOI: 10.1158/1535-7163.targ-09-a81
Popis: Background: Sorafenib (BAY 43-9006) is a multi-kinase inhibitor that targets a serine-threonine kinase, B-Raf as well as several tyrosine kinases. Given the numerous molecular targets of sorafenib, several potential mechanisms of its inhibitory activity on tumor cell proliferation, angiogenesis and anti-apoptosis have been proposed. Paclitaxel exhibits unique and potent anti-cancer activity in the treatment of non-small cell lung cancer (NSCLC). Our aim of this study, is to examine the anti-proliferative, anti-angiogenesis effect and apoptosis induction when sorafenib combined with paclitaxel in NSCLC tumor model. Methods: We investigated sorafenib's effect on cell proliferation, cell cycle distribution, ERK phosphorylation in A549 NSCLC cell line using SRB assay, flow cytometry, and Western blot analysis, respectively. In vivo, A549 tumor cells were implanted in the Balb/c nu/nu mice. Five different combination schedules of sorafenib and paclitaxel were applied with their single treatment. PPS and PSS combination therapy. Tumor volume and body weight was measured at two times per week. Intratumoral molecular changes were studied on paraffin-embedded tumor tissue block from xenograft mice using immunohistochemistry and the apoptotic change was measured with TUNEL assay. Result: In vitro study, single treatment of sorafenib or paclitaxel inhibited cell proliferation in A549 cells with dose-dependent manner. Sorafenib effectively inhibited the phosphorylation of ERK and induced G0/G1 arrest of cell cycle. When these two agents were combined with different schedules, schedule-dependent cytotoxicity and cell cycle arrest were observed. In A549 xenograft model, combination of sorafenib and paclitaxel more significantly suppressed tumor growth than their single treatment. However, PSS combination caused profound body weight loss compared with other treatment schedules. In immunohistochemistry study, greater inhibition of Ki-67 as well as pAKT and pERK, and CD31 were observed in PPS combination compared with single treatment. In TUNEL assay, significant apoptosis was observed in combination treatment. Conclusion: Taken together, sorafenib, paclitaxel, and their combination effectivity inhibited tumor growth and angiogenesis via down regulation of pAKT and pERK signaling and apoptosis induction in NSCLC tumor model. The PPS and PSS combination schedule demonstrated more potent antitumor activity including anti-proliferation, anti-angiogenesis, and apoptosis compared to other combination schedules. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A81.
Databáze: OpenAIRE
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