1. Academic Validation
  2. The novel tryptamine derivative JNJ-26854165 induces wild-type p53- and E2F1-mediated apoptosis in acute myeloid and lymphoid leukemias

The novel tryptamine derivative JNJ-26854165 induces wild-type p53- and E2F1-mediated apoptosis in acute myeloid and lymphoid leukemias

  • Mol Cancer Ther. 2010 Sep;9(9):2545-57. doi: 10.1158/1535-7163.MCT-10-0337.
Kensuke Kojima 1 Jared K Burks Janine Arts Michael Andreeff
Affiliations

Affiliation

  • 1 Section of Molecular Hematology and Therapy, Department of Stem Cell Transplantation and Cellular Therapy, M.D. Anderson Cancer Center, The University of Texas, Houston, Texas 77030, USA.
Abstract

The development of small-molecule activators of p53 is currently focused on malignancies containing a wild-type p53 genotype, which is present in most leukemias. JNJ-26854165 is one such p53-activating agent, but its mechanism of action remains to be elucidated. Here, we report the effects of JNJ-26854165 in acute leukemias. JNJ-26854165 treatment induced p53-mediated Apoptosis in acute leukemia cells with wild-type p53, in which p53 rapidly drives transcription-independent Apoptosis followed by activation of a transcription-dependent pathway. JNJ-26854165 accelerated the proteasome-mediated degradation of p21 and antagonized the transcriptional induction of p21 by p53. Interestingly, JNJ-26854165 induced S-phase delay and upregulated E2F1 expression in p53 mutant cells, resulting in Apoptosis preferentially of S-phase cells. E2F1 knockdown blocked Apoptosis induced by JNJ-26854165 in p53 mutant cells. Apoptotic activity of JNJ-26854165 against primary acute leukemia cells was maintained in leukemia/stroma cocultures, unlike doxorubicin, which has reduced cytrotoxicity in coculture systems. JNJ-26854165 synergizes with 1-β-arabinofuranosylcytosine or doxorubicin to induce p53-mediated Apoptosis. Our data suggest that JNJ-26854165 may provide a novel therapeutic approach for the treatment of acute leukemias. The presence of p53-independent apoptotic activity in addition to p53-mediated Apoptosis induction, if operational in vivo, may prevent the selection of p53 mutant subclones during therapy.

Figures
Products