A ruthenium-containing organometallic compound reduces tumor growth through induction of the endoplasmic reticulum stress gene CHOP.
Cisplatin-derived anticancer therapy has been used for three decades despite its side effects. Other types of organometallic complexes, namely, some ruthenium-derived compounds (RDC), which would display cytotoxicity through different modes of action, might represent alternative therapeutic agents. We have studied both in vitro and in vivo the biological properties of RDC11, one of the most active compounds of a new class of RDCs that contain a covalent bond between the ruthenium atom and a carbon. We showed that RDC11 inhibited the growth of various tumors implanted in mice more efficiently than cisplatin. Importantly, in striking contrast with cisplatin, RDC11 did not cause severe side effects on the liver, kidneys, or the neuronal sensory system. We analyzed the mode of action of RDC11 and showed that RDC11 interacted poorly with DNA and induced only limited DNA damages compared with cisplatin, suggesting alternative transduction pathways. Indeed, we found that target genes of the endoplasmic reticulum stress pathway, such as Bip, XBP1, PDI, and CHOP, were activated in RDC11-treated cells. Induction of the transcription factor CHOP, a crucial mediator of endoplasmic reticulum stress apoptosis, was also confirmed in tumors treated with RDC11. Activation of CHOP led to the expression of several of its target genes, including proapoptotic genes. In addition, the silencing of CHOP by RNA interference significantly reduced the cytotoxicity of RDC11. Altogether, our results led us to conclude that RDC11 acts by an atypical pathway involving CHOP and endoplasmic reticulum stress, and thus might provide an interesting alternative for anticancer therapy.
Meng
Xiangjun
X
UMRS692 INSERM, Signalisations Moléculaires et Neurodégénérescence, Université de Strasbourg, France.
Leyva
Mili L
ML
Jenny
Marjorie
M
Gross
Isabelle
I
Benosman
Samir
S
Fricker
Bastien
B
Harlepp
Sébastien
S
Hébraud
Pascal
P
Boos
Anne
A
Wlosik
Pauline
P
Bischoff
Pierre
P
Sirlin
Claude
C
Pfeffer
Michel
M
Loeffler
Jean-Philippe
JP
Gaiddon
Christian
C
D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology; D002455:Cell Division / Q000187:drug effects*; D002945:Cisplatin / Q000627:therapeutic use / Q000633:toxicity; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000235:genetics*; D005434:Flow Cytometry; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D008156:Luciferases / Q000235:genetics; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009942:Organometallic Compounds / Q000627:therapeutic use*; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012428:Ruthenium / Q000627:therapeutic use*; D051742:Transcription Factor CHOP / Q000235:genetics*
C497250:Ddit3 protein, mouse; D009942:Organometallic Compounds; D051742:Transcription Factor CHOP; D012313:RNA; D012428:Ruthenium; D008156:Luciferases; D002945:Cisplatin