A copper chelate of thiosemicarbazone NSC 689534 induces oxidative/ER stress and inhibits tumor growth in vitro and in vivo.
In this study, a Cu(2+) chelate of the novel thiosemicarbazone NSC 689534 was evaluated for in vitro and in vivo anti-cancer activity. Results demonstrated that NSC 689534 activity (low micromolar range) was enhanced four- to fivefold by copper chelation and completely attenuated by iron. Importantly, once formed, the NSC 689534/Cu(2+) complex retained activity in the presence of additional iron or iron-containing biomolecules. NSC 689534/Cu(2+) mediated its effects primarily through the induction of ROS, with depletion of cellular glutathione and protein thiols. Pretreatment of cells with the antioxidant N-acetyl-l-cysteine impaired activity, whereas NSC 689534/Cu(2+) effectively synergized with the glutathione biosynthesis inhibitor buthionine sulfoximine. Microarray analysis of NSC 689534/Cu(2+)-treated cells highlighted activation of pathways involved in oxidative and ER stress/UPR, autophagy, and metal metabolism. Further scrutiny of the role of ER stress and autophagy indicated that NSC 689534/Cu(2+)-induced cell death was ER-stress dependent and autophagy independent. Last, NSC 689534/Cu(2+) was shown to have activity in an HL60 xenograft model. These data suggest that NSC 689534/Cu(2+) is a potent oxidative stress inducer worthy of further preclinical investigation.
Biological Testing Branch, Developmental Therapeutics Program, SAIC-Frederick, Frederick, MD 21702, USA.
Chad N
CN
Hancock
Luke H
LH
Stockwin
Bingnan
B
Han
Raymond D
RD
Divelbiss
Jung Ho
JH
Jun
Sanjay V
SV
Malhotra
Melinda G
MG
Hollingshead
Dianne L
DL
Newton
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects*; D002614:Chelating Agents / Q000378:metabolism / Q000494:pharmacology; D003300:Copper / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D009942:Organometallic Compounds / Q000494:pharmacology / Q000627:therapeutic use; D016877:Oxidants / Q000494:pharmacology / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects*; D013882:Thiosemicarbazones / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D056811:Unfolded Protein Response / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D002614:Chelating Agents; C558013:NSC 689534; D009942:Organometallic Compounds; D016877:Oxidants; D013882:Thiosemicarbazones; D003300:Copper