This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Huynh, H. Articles by Soo, K.-C. Search for Related Content PubMed PubMed Citation Articles by Huynh, H. Articles by Soo, K.-C.

Research Articles: Therapeutics, Targets, and Development

AZD6244 and doxorubicin induce growth suppression and apoptosis in mouse models of hepatocellular carcinoma

¹ Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, National Cancer Centre; and ² Department of Experimental Surgery, and Department of General Surgery, Singapore General Hospital, Singapore, Singapore

Requests for reprints: Hung Huynh, Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, National Cancer Centre, Singapore, Singapore 169610. Phone: 65-436-8347; Fax: 65-226-5694. E-mail: cmrhth{at}nccs.com.sg

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide, with no effective treatment for most individuals who succumb to this neoplasm. We report that treatment of primary HCC cells with the mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase 1/2 inhibitor AZD6244 (ARRY-142886) plus doxorubicin led to synergistic growth inhibition and apoptosis. In vivo administration of AZD6244, doxorubicin, or the combination of AZD6244 and doxorubicin in mice bearing 5-1318 HCC xenografts resulted in approximately 52% ± 15%, 12% ± 9%, and 76% ± 7% growth inhibition, respectively. AZD6244-inhibited tumor growth was associated with increased apoptosis, inactivation of ERK1/2, inhibition of cell proliferation, and down-regulation of cell cycle regulators, including cyclin D1, cdc-2, cyclin-dependent kinases 2 and 4, cyclin B1, and c-Myc. The AZD6244-doxorubicin combined protocol not only promoted apoptosis but also induced a synergistic effect not seen in single-agent–treated tumors, including increased expression of the p130 RB tumor suppressor gene. Our study provides a strong rationale for clinical investigation of combination therapy with the mitogen-activated protein/ERK kinase 1/2 inhibitor AZD6244 and doxorubicin in patients with HCC. [Mol Cancer Ther 2007;6(9):2468–76]

Grant support: Singapore Cancer Syndicate grant SCS-AS0032 (H. Huynh).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

³ Supplementary materials for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 3/ 7/07; revised 6/15/07; accepted 8/ 2/07.