Synergistic anti-leukemic interactions between panobinostat and MK-1775 in acute myeloid leukemia ex vivo

Abstract

MK-1775 is the first-in-class selective Wee1 inhibitor which has been demonstrated to synergize with CHK1 inhibitors in various malignancies. In this study, we report that the pan-histone deacetylase inhibitor (HDACI) panobinostat synergizes with MK-1775 in acute myeloid leukemia (AML), a malignancy which remains a clinical challenge and requires more effective therapies. Using both AML cell line models and primary patient samples, we demonstrated that panobinostat and MK-1775 synergistically induced proliferation arrest and cell death. We also demonstrated that panobinostat had equal anti-leukemic activities against primary AML blasts derived from patients either at initial diagnosis or at relapse. Interestingly, treatment with panobinostat alone or in combination with MK-1775 resulted in decreased Wee1 protein levels as well as downregulation of the CHK1 pathway. shRNA knockdown of CHK1 significantly sensitized AML cells to MK-1775 treatment, while knockdown of Wee1 significantly enhanced both MK-1775-and panobinostat-induced cell death. Our results demonstrate that panobinostat synergizes with MK-1775 in AML cells, at least in part through downregulation of CHK1 and/or Wee1, providing compelling evidence for the clinical development of the combination treatment in AML.

Panobinostat inhibits the proliferation of CD34+CD38−cells under stimulation of hematopoietic growth factors on AGM‐S3 cells in juvenile myelomonocytic leukemia

“…Only approximately 10% of the progenies generated from JMML CD34 + cells under stimulation with SCF+TPO in the presence of 20 nM of panobinostat on AGM‐S3 cells were apoptotic according to annexin V/PI staining and BrdU/7‐AAD staining. On the contrary, a large proportion of HL60 cells treated with panobinostat were positive for annexin V and/or PI, findings consistent with those reported by Qi et al . Furthermore, S‐phase arrest was negligible or modest in JMML CD34 + cells.…”

“…Taken together, panobinostat may be a useful antileukemic drug to target JMML stem cells at a pretransplant stage rather than at a posttransplant stage.Only approximately 10% of the progenies generated from JMML CD34 + cells under stimulation with SCF+TPO in the presence of 20 nM of panobinostat on AGM-S3 cells were apoptotic according to annexin V/PI staining and BrdU/7-AAD staining. On the contrary, a large proportion of HL60 cells treated with panobinostat were positive for annexin V and/or PI, findings consistent with those reported by Qi et al21 Furthermore, S-phase arrest was negligible or modest in JMML CD34 + cells. HL60 cells revealed a marked proliferation, whereas an increase in JMML CD34 + cells was much lower (cell numbers after 2 days of culture were 3.27-fold in HL60 cells, and 1.08-fold in JMML CD34 + cells).…”

Recent Advances of Cell-Cycle Inhibitor Therapies for Pediatric Cancer

“…In addition, AZD1775 caused activation of cell division cycle protein 2 (CDC2; also known as CDK1) in an osteosarcoma xenograft and reduced tumor growth by 50% as monotherapy, and by approximately 70% when combined with gemcitabine (50). In hematological malignancies, AZD1775 plus panobinostat demonstrated synergistic antitumor effects in preclinical models of AML (54) and when combined with CDK inhibitor (roscovitine) (53), and cytarabine (55). In the latter study, AZD1775 inhibited cytabarine-mediated S-phase arrest and prevented DNA repair.…”

Epigenome-Based Drug Repositioning in Acute Myeloid Leukemia

“…alitretinoin, panobinostat, and progesterone. Both alitretinoin, a geometric isomer of tretinoin currently used in the treatment of Acute Promyelocytic Leukemia (a subclass of AML) [34] , and panobinostat, a histone deacetylase inhibitor commonly used in multiple myeloma [35] , have been investigated for use in AML [36][37][38][39] . Lastly, while progesterone itself has not, to our knowledge, been suggested for AML treatment, a synthetic progestin, medroxyprogesterone acetate, has recently been suggested as a possible drug repositioning candidate for AML [40] .…”