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Research Articles: Therapeutics

Novel triiodophenol derivatives induce caspase-independent mitochondrial cell death in leukemia cells inhibited by Myc

¹ Oncogenesis and Antitumor Drug Group, Laboratori d'Investigació Gastrointestinal ² Laboratory of Inflammation Mediators, and ³ Department of Hematology, Institut de Recerca Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, and ⁴ Grupo de Biología Molecular del Cáncer, Departamento de Biología Molecular-Unidad de Biomedicina del CSIC, Facultad de Medicina, Universidad de Cantabria, Santander, Cantabria, Spain

Requests for reprints: Javier León, Departamento de Biología Molecular, Facultad de Medicina, Universidad de Cantabria, Avenida Cardenal Herrera Oria, s/n 39011 Santander, Cantabria, Spain. Phone: 34-942-201952; Fax: 34-942-201945/934-552331. E-mail: leonj{at}unican.es

2,4,6-Triiodophenol (Bobel-24, AM-24) was originally described as a nonsteroid antiinflammatory molecule. We have synthesized three derivatives of Bobel-24 (Bobel-4, Bobel-16, and Bobel-30) and tested their activities as putative antileukemic agents. We have found that Bobel-24 and Bobel-16 were dual inhibitors of cyclooxygenase and 5-lipoxygenase, whereas Bobel-4 and Bobel-30 were selective against 5-lipoxygenase. We have tested the antiproliferative activity of these compounds on a panel of cell lines derived from myeloid and lymphoid leukemias (K562, Raji, HL-60, and Molt4). The cytotoxic IC₅₀ in these cell lines ranged between 14 and 50 µmol/L, but it was higher for nontransformed cells such as 32D, NIH3T3, or human leukocytes. All compounds showed cytotoxic activity on all tested cell lines, accompanied by DNA synthesis inhibition and arrest in the G₀/G₁ phase. Bobel-16, Bobel-4, and Bobel-24 induced a caspase-independent cell death in K562 and Raji cells, accompanied by chromatin condensation, cytochrome c release, and dissipation of mitochondrial membrane potential in a concentration-dependent manner and production of reactive oxygen species. As the proto-oncogene MYC is involved in mitochondrial biogenesis and survival of leukemia cells, we tested its effect on bobel activity. Bobel-24 induced down-regulation of MYC in K562 and, consistently, ectopic expression of MYC results in partial protection towards the cytotoxic effect of Bobel-24. In conclusion, Bobel derivatives induce a caspase- and Bcl-2-independent cell death in which mitochondrial permeabilization and MYC down-regulation are involved. Bobels may serve as prototypes for the development of new agents for the therapy of leukemia. [Mol Cancer Ther 2006;5(5):1166–75]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁵ http://www.myccancergene.org.

⁶ Matilde Parreño, Jose Pedro Vaqué, Isolda Casanova, María Virtudes Cespedes, Miguel Anguel Pavón, Javier León, Ramon Mangues, manuscript in preparation.

Received 7/19/05; revised 3/ 7/06; accepted 3/24/06.

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