AZD6244 and doxorubicin induce growth suppression and apoptosis in mouse models of hepatocellular carcinoma.
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.
Huynh
Hung
H
Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, National Cancer Centre, Singapore, Singapore 169610. cmrhth@nccs.com.sg
Chow
Pierce K H
PK
Soo
Khee-Chee
KC
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001562:Benzimidazoles / Q000494:pharmacology*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D050719:Crk-Associated Substrate Protein / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D005455:Fluorescent Antibody Technique; D006801:Humans; D020287:In Situ Nick-End Labeling; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D015996:Survival Rate; D014183:Transplantation, Heterologous
C517975:AZD 6244; D000903:Antibiotics, Antineoplastic; C493841:BCAR1 protein, human; D001562:Benzimidazoles; D050719:Crk-Associated Substrate Protein; D016213:Cyclins; D004317:Doxorubicin