Motexafin gadolinium disrupts zinc metabolism in human cancer cell lines.
To gain a better understanding of the mechanism of action of the metal cation-containing chemotherapeutic drug motexafin gadolinium (MGd), gene expression profiling analyses were conducted on plateau phase human lung cancer (A549) cell cultures treated with MGd. Drug treatment elicited a highly specific response that manifested in elevated levels of metallothionein isoform and zinc transporter 1 (ZnT1) transcripts. A549 cultures incubated with MGd in the presence of exogenous zinc acetate displayed synergistic increases in the levels of intracellular free zinc, metallothionein transcripts, inhibition of thioredoxin reductase activity, and cell death. Similar effects were observed in PC3 prostate cancer and Ramos B-cell lymphoma cell lines. Intracellular free zinc levels increased in response to treatment with MGd in the absence of exogenous zinc, indicating that MGd can mobilize bound intracellular zinc. These findings lead us to suggest that an important component of the anticancer activity of MGd is related to its ability to disrupt zinc metabolism and alter cellular availability of zinc. This class of compounds may provide insight into the development of novel cancer drugs targeting control of intracellular free zinc and the roles that zinc and other metal cations play in biochemical pathways relevant to cancer.
Magda
Darren
D
Pharmacyclics, Inc., Sunnyvale, California, USA.
Lecane
Philip
P
Miller
Richard A
RA
Lepp
Cheryl
C
Miles
Dale
D
Mesfin
Mimi
M
Biaglow
John E
JE
Ho
Vincent V
VV
Chawannakul
Danny
D
Nagpal
Shailender
S
Karaman
Mazen W
MW
Hacia
Joseph G
JG
D000085:Acetates / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002104:Cadmium / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008063:Thioctic Acid / Q000378:metabolism; D015032:Zinc / Q000378:metabolism*; D019345:Zinc Acetate / Q000494:pharmacology
D000085:Acetates; D000970:Antineoplastic Agents; D008665:Metalloporphyrins; D002104:Cadmium; C060927:gadolinium (+3) acetate; C437683:motexafin gadolinium; D008063:Thioctic Acid; D019345:Zinc Acetate; D015032:Zinc