The histone deacetylase inhibitor valproic acid potently augments gemtuzumab ozogamicin-induced apoptosis in acute myeloid leukemic cells

Cate, Bram ten; Samplonius, Douwe F.; Bijma, Theo; Leij, de Louis; Helfrich, Wijnand; Bremer, Edwin

doi:10.1038/sj.leu.2404477

Cited by 46 publications

(22 citation statements)

References 19 publications

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“…Our findings are in line with similar preclinical studies, in which both HDAC inhibitors and DNMT I inhibitors have been shown to sensitize AML cells to CD33-directed therapy with GO. [37][38][39] More importantly, both HDAC inhibitors (especially when used in combination with other agents) and DNMT I inhibitors have shown encouraging results and safety in patients with AML. [40][41][42][43] Thus, our observation of a chemosensitizing effect of epigenetic-modifying drugs on AMG 330-induced cytotoxicity may be directly translatable to the clinic.…”

Section: Discussionmentioning

confidence: 99%

Cellular determinants for preclinical activity of a novel CD33/CD3 bispecific T-cell engager (BiTE) antibody, AMG 330, against human AML

Laszlo

Gudgeon

Harrington

et al. 2014

Blood

154

133

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Key Points• AMG 330 cytotoxicity against AML cells is proportional to the level of CD33 expression but is not affected by ABC transporter activity.• AMG 330 cytotoxicity is amenable to modulation and augmentation by clinically available drugs such as histone deacetylase or DNA methyltransferase I inhibitors.CD33 is a valid target for acute myeloid leukemia (AML) but has proven challenging for antibody-drug conjugates. Herein, we investigated the cellular determinants for the activity of the novel CD33/CD3-directed bispecific T-cell engager antibody, AMG 330. In the presence of T cells, AMG 330 was highly active against human AML cell lines and primary AML cells in a dose-and effector to target cell ratio-dependent manner. Using cell lines engineered to express wild-type CD33 at increased levels, we found a quantitative relationship between AMG 330 cytotoxicity and CD33 expression; in contrast, AMG 330 cytotoxicity was neither affected by common CD33 single nucleotide polymorphisms nor expression of the adenosine triphosphate-binding cassette (ABC) transporter proteins, P-glycoprotein or breast cancer resistance protein. Unlike bivalent CD33 antibodies, AMG 330 did not reduce surface CD33 expression. The epigenetic modifier drugs, panobinostat and azacitidine, increased CD33 expression in some cell lines and augmented AMG 330-induced cytotoxicity. These findings demonstrate that AMG 330 has potent CD33-dependent cytolytic activity in vitro, which can be further enhanced with other clinically available therapeutics. As it neither modulates CD33 expression nor is affected by ABC transporter activity, AMG 330 is highly promising for clinical exploration as it may overcome some limitations of previous CD33-targeted agents. (Blood. 2014;123(4):554-561) IntroductionAcute myeloid leukemia (AML) has served as a paradigm for the therapeutic use of monoclonal antibodies because of well-defined cell-surface antigens and easy tumor accessibility. The most investigated target so far is CD33, a myeloid differentiation antigen found on AML blasts in most patients and, perhaps, leukemic stem cells in some.1,2 Recent randomized phase 3 trials have demonstrated that the CD33 antibody-drug conjugate, gemtuzumab ozogamicin (GO), improves survival for some patients with newly diagnosed AML when added to conventional chemotherapy, with benefit primarily seen for those with favorable-risk disease and, to a smaller extent, intermediate-risk disease. [3][4][5] Although this experience indicates that CD33 is a valid target for this disease, 1,2 it is a challenging one for toxin-loaded antibodies due to its relatively low abundance, slow internalization, and drug transporter activity in AML cells. In fact, GO given alone or in combination with other chemotherapeutics is ineffective in many patients and, as a consequence, is currently no longer commercially available in many countries. 1,2Bispecific T-cell engager (BiTE) antibodies are a novel subclass of therapeutic single-chain antibodies. [6][7][8] What distinguishes BiTE antibodies ...

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Section: Discussionmentioning

confidence: 99%

Cellular determinants for preclinical activity of a novel CD33/CD3 bispecific T-cell engager (BiTE) antibody, AMG 330, against human AML

Laszlo

Gudgeon

Harrington

et al. 2014

Blood

154

133

View full text Add to dashboard Cite

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“…A combination index (CI) calculated based on the Chou-Talalay method was used to evaluate the synergism between ZGDHu-1 and fludarabine (2,(17)(18)(19). The following formula was used: CI = (sum of single agent treatment/specific apoptosis of combined treatment).…”

Section: Evaluation Of the Combination Indexmentioning

confidence: 99%

ZGDHu-1 and fludarabine have a synergistic effect on apoptosis of chronic lymphocytic leukemia cells

et al. 2015

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Abstract. Previously, it was demonstrated that the novel proteasome inhibitor N,N'-di-(m-methylphenyi)-3,6-dimethyl-1,4-dihydro-1,2,4,5-tetrazine-1,4-dicarboamide (ZGDHu-1) possesses activity against chronic lymphocytic leukemia (CLL). In the present study, we attempted to assess whether this drug has a synergistic effect with fludarabine on the apoptosis of CLL cells. Annexin V/PI staining, mitochondrial membrane potential (ΔΨm) and reactive oxygen species (ROS) levels were examined by flow cytometry in short-term cell culture of blood cells from untreated newly diagnosed patients ex vivo. Expression of active caspase-3 and the Bcl-2/Bax ratio for determination of apoptosis were also investigated by flow cytometry and western blot analysis. Our results revealed that the ZGDHu-1 may induce the apoptosis of CLL cells through the mitochondrial pathway and its pro-apoptotic effect is CLL-specific, not affecting normal lymphocytes. Most importantly, a combination of ZGDHu-1 and a non-cytotoxic dose of fludarabine had a synergistic apoptotic effect. To some extent, caspase-3 activation may be involved in the mechanism of the ZGDHu-1 synergistic cytotoxic effect with fludarabine, as well as the cleavage of PARP, consequently leading to apoptosis. Notably, the rate of apoptosis caused by ZGDHu-1 alone or in combination with fludarabine was independent of prognostic markers of CLL disease such as ZAP-70 and CD38 expression or clinical Rai classification stage. In conclusion, ZGDHu-1 exhibited a significant synergistic effect with fludarabine to induce the apoptosis of CLL cells, which implies a possible clinical application.

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“…G-CSF enhanced the effect of GO, and induced AML cells to enter G 2 /M and hypodiploid phase [65]. Valproic acid, a histone deacetylase inhibitor, can also strengthen the effect of GO [66]. However, the synergistic effect of GO with these agents has not been well elucidated in clinical studies.…”

Section: Drug Resistancementioning

confidence: 99%

Efficacy and resistance of gemtuzumab ozogamicin for acute myeloid leukemia

Takeshita

2013

Int J Hematol

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Seventy to 80 % of patients with acute myeloid leukemia (AML) achieve complete remission following intensive chemotherapy, but more than 50 % of patients in remission subsequently relapse, which is often associated with clinical drug resistance. Therapy based on monoclonal antibodies (mAbs) has been developed to increase the selectivity of cytotoxic agents by conjugating them with a mAb. Gemtuzumab ozogamicin (GO) is a conjugate of a cytotoxic agent, a calicheamicin derivative, linked to a recombinant humanized mAb directed against the CD33 antigen, which is expressed on leukemia cells from more than 90 % of patients with AML. This conjugated mAb was introduced following promising results from phase I and II studies. However, the initial phase III study did not confirm the efficacy of GO in combination with conventional chemotherapies. Several subsequent phase III studies have shown the efficacy of GO in favorable and intermediate risk AML. Several resistance mechanisms against GO have been reported. Multidrug resistant (MDR) P-glycoprotein (P-gp), a trans-membrane glycoprotein that pumps out many anti-leukemic agents from cells, also affects GO. For this reasons, GO has been used in combination with MDR modifiers, such as cyclosporine, and in cases without P-gp. Several investigators have reported successful results of the use of GO in acute promyelocytic leukemia (APL). GO has also been described as effective in cases relapsed after treatment with all-trans retinoic acid (ATRA), arsenic acid and conventional chemotherapeutic agents. The efficacy of GO will be studied mainly in a favorable risk of AML, such as core binding factor leukemia and APL. In addition, suitable combinations with other chemotherapies and administration schedules should be discussed.

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The histone deacetylase inhibitor valproic acid potently augments gemtuzumab ozogamicin-induced apoptosis in acute myeloid leukemic cells

Cited by 46 publications

References 19 publications

Cellular determinants for preclinical activity of a novel CD33/CD3 bispecific T-cell engager (BiTE) antibody, AMG 330, against human AML

Cellular determinants for preclinical activity of a novel CD33/CD3 bispecific T-cell engager (BiTE) antibody, AMG 330, against human AML

ZGDHu-1 and fludarabine have a synergistic effect on apoptosis of chronic lymphocytic leukemia cells

Efficacy and resistance of gemtuzumab ozogamicin for acute myeloid leukemia

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