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

Abstract

Abstract2,4,6-Triiodophenol (Bobel-24, AM-24) was originally described as a nonsteroid antiinflammatory molecule. We have synthesized three derivatives of 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 IC 50 in these cell lines ranged between 14 and 50 Mmol/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 G 0 /G 1 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]

Bobel-24 and Derivatives Induce Caspase-Independent Death in Pancreatic Cancer Regardless of Apoptotic Resistance

“…S2). These results suggest a marginal or negligible participation of Bcl-2 family members in Bobel-induced cell death and are consistent with overexpression of Bcl-2 not altering cytotoxicity by Bobel-24 or derivatives in leukemic cells (6).…”

“…Cancer Res 2008; 68: (15 finding in caspase-dependent and caspase-independent pancreatic carcinoma cell death induced by Bobel-24 or its derivatives, as we have previously described in caspase-independent cell death in leukemic cells (6). Consequently, we explored whether pancreatic carcinoma cell death by Bobel-24 or Bobel-16 was mediated by cytochrome c release (common in caspase-dependent death) and/ or mitochondrial release and nuclear translocation of AIF (common in caspase-independent death).…”

“…We previously identified a series of cycloxygenase and 5-lypoxigenase inhibitors (Bobel-24 and derivatives) that are cytotoxic on leukemia cells; however, we did not observe an association between their antitumor effect and the inhibition of these enzymes (6); thus, their mechanism of action is still currently unknown. Nevertheless, we decided to evaluate their antitumor activity in human pancreatic cancer cell lines on the basis of (a) our finding that these compounds induced bcl2-independent and caspaseindependent cell death in leukemia cells (6) and (b) on the knowledge of the association between intrinsic resistance to current therapy and inhibition of apoptotic (caspase-dependent) pathways in pancreatic cancer. We reasoned that if a caspaseindependent mechanism, similar to that found in leukemia cells, was in place in pancreatic cancer cells, Bobel-24 and derivatives could induce cell death regardless of the apoptotic blockade present in pancreatic cancer.…”

“…The synthesis of Bobel-24/AM-24 (2,4,6-triiodophenol), Bobel-4 (2,6-diisopropyl-4-iodophenol), Bobel-16 (4-phenyl-2,6-diiodophenol), and Bobel-30 (3-chloro-2,4,6-triiodophenol) was previously described (6). BEL, H 2 O 2 , CsA, Tiron (ROS scavenger), and DPQ were purchased from Sigma.…”

“…To determine cytochrome c and AIF release from the mitochondria to the cytosol, floating and adherent cells (10 6 /10 mL) obtained after Bobel treatment were collected at 400 Â g for 5 min, proceeding as described (6). Western blot was done using the cytoplasmic fraction.…”