Panobinostat: First Global Approval

Garnock-Jones, Karly P.

doi:10.1007/s40265-015-0388-8

Cited by 169 publications

(116 citation statements)

References 46 publications

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“…Of note, pracinostat has been granted Orphan Drug status by the FDA for the treatment of AML 48 and panobinostat has recently received FDA approval after being granted "priority review" status for the treatment of multiple myeloma. 32,33 In this study, we demonstrated that combined panobinostat and MK-1775 treatment resulted in synergistic anti-leukemic activity in AML cell lines and ex vivo primary patient samples. In addition, we provide evidence to suggest that cooperative downregulation of CHK1 and Wee1 plays an important role in the synergistic anti-leukemic activity.…”

Section: Discussionmentioning

confidence: 65%

“…Previously, we demonstrated that panobinostat, a pan-HDACI which was recently approved by the US FDA for the treatment of multiple myeloma, downregulates the CHK1 pathway in AML cells. 32,33 Also, we demonstrated that MK-1775, a potent and selective Wee1 inhibitor, synergizes with LY2603618, a CHK1 selective inhibitor, in AML cells. 34 Therefore, it is conceivable that the combination of panobinostat and MK-1775 would result in synergistic anti-leukemic activity in AML cells.…”

Section: Introductionmentioning

confidence: 75%

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

Zhang

Edwards

et al. 2015

Cancer Biology & Therapy

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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.

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Section: Discussionmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 75%

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

Zhang

Edwards

et al. 2015

Cancer Biology & Therapy

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“…Vorinostat (SAHA; Sigma Aldrich, USA), Romidepsin (FK228; Istodax; Selleck Chemicals, USA), and Belinostat (PXD101; Beleodaq; Spectrum Pharmaceuticals, Inc., USA) are approved for cutaneous or peripheral T-cell lymphoma (Grant et al., 2007, Prince and Dickinson, 2012, Thompson, 2014), while Panobinostat (LBH-589; Selleck Chemicals, USA) is approved for combination therapy of multiple myeloma (Garnock-Jones, 2015). In this study, we assessed the capacity of all four drugs to inhibit the growth of parasites that cause malaria ( P. knowlesi ), leishmaniasis ( L. amazonensis and L. donovani ) and schistosomiasis ( S. mansoni ).…”

Section: Introductionmentioning

confidence: 99%

Effect of clinically approved HDAC inhibitors on Plasmodium, Leishmania and Schistosoma parasite growth

Chua

Arnold

et al. 2017

International Journal for Parasitology: Drugs and Drug Resistan

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Malaria, schistosomiasis and leishmaniases are among the most prevalent tropical parasitic diseases and each requires new innovative treatments. Targeting essential parasite pathways, such as those that regulate gene expression and cell cycle progression, is a key strategy for discovering new drug leads. In this study, four clinically approved anti-cancer drugs (Vorinostat, Belinostat, Panobinostat and Romidepsin) that target histone/lysine deacetylase enzymes were examined for in vitro activity against Plasmodium knowlesi, Schistosoma mansoni, Leishmania amazonensis and L. donovani parasites and two for in vivo activity in a mouse malaria model. All four compounds were potent inhibitors of P. knowlesi malaria parasites (IC50 9–370 nM), with belinostat, panobinostat and vorinostat having 8–45 fold selectivity for the parasite over human neonatal foreskin fibroblast (NFF) or human embryonic kidney (HEK 293) cells, while romidepsin was not selective. Each of the HDAC inhibitor drugs caused hyperacetylation of P. knowlesi histone H4. None of the drugs was active against Leishmania amastigote or promastigote parasites (IC50 > 20 μM) or S. mansoni schistosomula (IC50 > 10 μM), however romidepsin inhibited S. mansoni adult worm parings and egg production (IC50 ∼10 μM). Modest in vivo activity was observed in P. berghei infected mice dosed orally with vorinostat or panobinostat (25 mg/kg twice daily for four days), with a significant reduction in parasitemia observed on days 4–7 and 4–10 after infection (P < 0.05), respectively.

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“…It is expected to have a better outcome by practicing multi-drug combination in the treatment of MM. Combined with proteasome inhibitors, some HDAC inhibitors, including panobinostat and vorinostat have been shown synergistic effects in growth inhibition of MM [53,54]. It is also reported that HDAC inhibitors combined with traditional chemotherapies synergistically induced apoptosis in MM cells.…”

Section: Discussionmentioning

confidence: 99%

Cladribine in combination with entinostat synergistically elicits anti-proliferative/anti-survival effects on multiple myeloma cells

et al. 2018

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Cladribine (2CdA), a synthetic purine analog interfering with DNA synthesis, is a medication used to treat hairy cell leukemia (HCL) and B-cell chronic lymphocytic leukemia. Entinostat, a selective class I histone deacetylase (HDAC) inhibitor, shows antitumor activity in various human cancers, including hematological malignancies. The therapeutic potential of cladribine and entinostat against multiple myeloma (MM) remains unclear. Here we investigate the combinatorial effects of cladribine and entinostat within the range of their clinical achievable concentrations on MM cells. While either agent alone inhibited MM cell proliferation in a dose-dependent manner, their combinations synergistically induced anti-proliferative/anti-survival effects on all MM cell lines (RPMI8226, U266, and MM1.R) tested. Further studies showed that the combinations of cladribine and entinostat as compared to either agent alone more potently induced mitotic catastrophe in the MM cells, and resulted in a marked increase of the cells at G1 phase associated with decrease of Cyclin D1 and E2F-1 expression and upregulation of p21waf−1. Apoptotic ELISA and western blot analyses revealed that the combinations of cladribine and entinostat exerted a much more profound activity to induce apoptosis and DNA damage response, evidenced by enhanced phosphorylation of histone H2A.X and the DNA repair enzymes Chk1 and Chk2. Collectively, our data demonstrate that the combinations of cladribine and entinostat exhibit potent activity to induce anti-proliferative/anti-survival effects on MM cells via induction of cell cycle G1 arrest, apoptosis, and DNA damage response. Regimens consisting of cladribine and/or entinostat may offer a new treatment option for patients with MM. Abbreviations: MM, multiple myeloma; HCL, hairy cell leukemia; HDAC, histone deacetylase; Ab, antibody; mAb, monoclonal Ab; FBS, fetal bovine serum; CI, combination index; PAGE, polyacrylamide gel electrophoresis; ELISA, enzyme-linked immunosorbent assay; PARP, poly(ADP-ribose) polymerase; MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium,inner salt

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Panobinostat: First Global Approval

Cited by 169 publications

References 46 publications

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

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

Effect of clinically approved HDAC inhibitors on Plasmodium, Leishmania and Schistosoma parasite growth

Cladribine in combination with entinostat synergistically elicits anti-proliferative/anti-survival effects on multiple myeloma cells

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