Please use this identifier to cite or link to this item: https://doi.org/10.1158/1535-7163.MCT-07-0162
Title: AZD6244 and doxorubicin induce growth suppression and apoptosis in mouse models of hepatocellular carcinoma
Authors: Huynh, H 
Chow, P.K.H 
Soo, K.-C
Keywords: azd 6244
cell cycle protein
cell cycle protein 2
cyclin B1
cyclin D1
cyclin dependent kinase 2
cyclin dependent kinase 4
doxorubicin
mitogen activated protein kinase inhibitor
Myc protein
unclassified drug
animal experiment
animal model
animal tissue
apoptosis
article
cancer cell culture
cancer combination chemotherapy
cancer growth
cancer inhibition
cell cycle
cell proliferation
clinical study
combination chemotherapy
concentration response
controlled study
down regulation
drug potentiation
gene inactivation
liver cell carcinoma
male
mouse
nonhuman
oncogene c myc
priority journal
tumor xenograft
Animals
Antibiotics, Antineoplastic
Apoptosis
Benzimidazoles
Blotting, Western
Carcinoma, Hepatocellular
Cell Cycle
Cell Line, Tumor
Cell Proliferation
Crk-Associated Substrate Protein
Cyclins
Doxorubicin
Drug Therapy, Combination
Fluorescent Antibody Technique
Humans
In Situ Nick-End Labeling
Liver Neoplasms
Male
Mice
Mice, SCID
Survival Rate
Transplantation, Heterologous
Issue Date: 2007
Citation: Huynh, H, Chow, P.K.H, Soo, K.-C (2007). AZD6244 and doxorubicin induce growth suppression and apoptosis in mouse models of hepatocellular carcinoma. Molecular Cancer Therapeutics 6 (9) : 2468-2476. ScholarBank@NUS Repository. https://doi.org/10.1158/1535-7163.MCT-07-0162
Rights: Attribution 4.0 International
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. Copyright © 2007 American Association for Cancer Research.
Source Title: Molecular Cancer Therapeutics
URI: https://scholarbank.nus.edu.sg/handle/10635/177992
ISSN: 15357163
DOI: 10.1158/1535-7163.MCT-07-0162
Rights: Attribution 4.0 International
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