Iodinin (1,6-dihydroxyphenazine 5,10-dioxide) from Streptosporangium sp. induces apoptosis selectively in myeloid leukemia cell lines and patient cells.
Despite recent improvement in therapy, acute myeloid leukemia (AML) is still associated with high lethality. In the presented study, we analyzed the bioactive compound iodinin (1,6-dihydroxyphenazine 5,10-dioxide) from a marine actinomycetes bacterium for the ability to induce cell death in a range of cell types. Iodinin showed selective toxicity to AML and acute promyelocytic (APL) leukemia cells, with EC50 values for cell death up to  40 times lower for leukemia cells when compared with normal cells. Iodinin also successfully induced cell death in patient-derived leukemia cells or cell lines with  features associated with poor prognostic such as FLT3 internal tandem duplications or mutated/deficient p53. The cell death had typical apoptotic morphology, and activation of apoptotic signaling proteins like caspase-3. Molecular modeling suggested that iodinin could intercalate between bases in the DNA in a way similar to the anti-cancer drug daunorubicin (DNR), causing DNA-strand breaks. Iodinin induced apoptosis in several therapy-resistant AML-patient blasts, but to a low degree in peripheral blood leukocytes, and in contrast to DNR, not in rat cardiomyoblasts. The low activity towards normal cell types that are usually affected by anti-leukemia therapy suggests that iodinin and related compounds represent promising structures in the development of anti-cancer therapy.
Department of Biomedicine, University of Bergen, Jonas Lies vei 91, N-5009 Bergen, Norway. lene.myhren@biomed.uib.no
Lene E
LE
Myhren
Gyrid
G
Nygaard
Gro
G
Gausdal
Håvard
H
Sletta
Knut
K
Teigen
Kristin F
KF
Degnes
Kolbjørn
K
Zahlsen
Anders
A
Brunsvik
Øystein
Ø
Bruserud
Stein Ove
SO
Døskeland
Frode
F
Selheim
Lars
L
Herfindal
D039903:Actinobacteria / Q000737:chemistry / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D003630:Daunorubicin / Q000737:chemistry; D005260:Female; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology; D006801:Humans; D007951:Leukemia, Myeloid; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D015394:Molecular Structure; D010619:Phenazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D055815:Young Adult
D000970:Antineoplastic Agents; D010619:Phenazines; C008134:iodinin; D003630:Daunorubicin