A novel arsenical has antitumor activity toward As2O3-resistant and MRP1/ABCC1-overexpressing cell lines.
Inorganic arsenic trioxide (As(2)O(3)) is a highly effective treatment for acute promyelocytic leukemia (APL). However, other cancers do not respond well to this form of arsenic at clinically achievable doses. We tested a novel arsenical, S-dimethylarsino-glutathione (darinaparsin) for efficacy in various malignancies in vitro. Darinaparsin is significantly more potent than As(2)O(3) at mediating apoptosis in various malignant cell lines and is highly active against APL cells derived for As(2)O(3) resistance. We provide evidence that darinaparsin triggers apoptosis by inducing signaling pathways that do not completely overlap with As(2)O(3). We show that darinaparsin induces apoptosis and oxidative stress to a greater extent than As(2)O(3), although like As(2)O(3), darinaparsin-induced toxicity is c-Jun NH(2)-terminal kinase-dependent. However, darinaparsin does not induce promyelocytic leukemia/retinoic acid receptor alpha (PML/RAR alpha) degradation or rearrange PML nuclear bodies in APL cells, nor is its toxicity increased by glutathione depletion. Darinaparsin treatment results in higher intracellular arsenic accumulation when compared to As(2)O(3) treatment. This may be explained by our finding that As(2)O(3), but not darinaparsin, is efficiently exported by ABCC1, suggesting increased therapeutic efficacy of darinaparsin in ABCC1-overexpressing tumors. Our studies indicate that darinaparsin efficiently kills tumor cells with increased antioxidant capacity and drug exporters and suggest that darinaparsin may have a broader therapeutic spectrum than As(2)O(3).
Diaz
Z
Z
Department of Oncology, Segal Cancer Comprehensive Center, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montréal, Quebec, Canada.
Mann
K K
KK
Marcoux
S
S
Kourelis
M
M
Colombo
M
M
Komarnitsky
P B
PB
Miller
W H
WH
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005978:Glutathione / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000502:physiology; D051379:Mice; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000032:analysis / Q000502:physiology*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010087:Oxides / Q000494:pharmacology*
D000873:Anthracenes; D000970:Antineoplastic Agents; D000077237:Arsenic Trioxide; D001152:Arsenicals; D005978:Glutathione; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015514:Oncogene Proteins, Fusion; D010087:Oxides; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C432165:pyrazolanthrone; C515055:darinaparsin; C421109:multidrug resistance-associated protein 1