Histone deacetylase inhibition enhances the lymphomacidal activity of the anti-CD22 monoclonal antibody HB22.7

Kong, Yaozhong; Barisone, Gustavo A.; Abuhay, Mastewal; O’Donnell, Robert T.; Buksh, Zaneb; Yousefian, Faraz; Tuscano, Joseph M.

doi:10.1016/j.leukres.2014.08.014

Cited by 4 publications

(8 citation statements)

References 47 publications

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“…No significant body weight irradiated mice and treatment initiated when tumors reached >300 mm 3 . When compared with control animals (vehicle alone), CHEK2i dramatically blocked tumor progression ( Figure 4A), which is consistent with reports in other cancer models and our own previous findings (14), AR42 also significantly inhibited progression of NHL xenografts in this model. Moreover, the combination of AR42 and CHEK2i was even more effective that either drug alone.…”

Section: Discussionsupporting

confidence: 92%

“…Colony formation assays in soft agar were performed as described previously (14). Cells were treated for 7 d with 1.6 μmol/L CHEK2i, 0.25 μmol/L AR42 or the combination of both.…”

Section: Clonogenic Survival Assaymentioning

confidence: 99%

“…After tumors reached >300 mm 3 , mice were randomly assigned to one of four treatment groups (7 animals/group): control (vehicle only), CHEK2i (1.0 mg/kg/dose), AR42 (10 mg/kg/dose), or combination of CHEK2i (1.0 mg/kg/dose) and AR42 (1.0 mg/kg/dose). Doses were based on previously published studies (14,27). Treatment consisted of intraperitoneal injections every other day for 45 d. Tumor size was measured three times per week and volume was calculated as…”

Section: Cytotoxic Effects Of Ar42 and Chek2i On Nhl Cell Linesmentioning

confidence: 99%

“…AR42, a phenylbutyrate-derived pan-HDACI, has been shown to have cytotoxic activity in several malignancies (4)(5)(6)(7)9,19,20). More recently, AR42 and other HDACIs have been reported to synergistically increase the cytotoxic activity of the α-CD22 monoclonal antibody (mAb) HB22.7 (14) and the α-CD20 mAb rituximab (11-13) on NHL cells.…”

mentioning

confidence: 99%

“…Histone deacetylases mediate chromatin remodeling by removing acetyl groups from lysine residues in the core histones, which results in a more compact, transcriptionally repressed chromatin. Histone deacetylase inhibitors ( HDACIs) have been shown to inhibit the proliferation of cancer cells in vitro and in vivo in a variety of malignancies (4)(5)(6)(7)(8)(9), including lymphoma (10)(11)(12)(13)(14). HDACIs are hypothesized to suppress cancer cell proliferation through histone hyperacetylation, resulting…”

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confidence: 99%

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Efficacy of Combined Histone Deacetylase and Checkpoint Kinase Inhibition in a Preclinical Model of Human Burkitt Lymphoma

Kong

Barisone

Sidhu

et al. 2015

Mol Med

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Checkpoint kinase inhibition has been studied as a way of enhancing the effectiveness of DNA-damaging agents. More recently, histone deacetylase inhibitors have shown efficacy in several cancers, including non-Hodgkin lymphoma. To evaluate the effectiveness of this combination for the treatment of lymphoma, we examined the combination of AR42, a histone deacetylase inhibitor, and checkpoint kinase 2 (CHEK2) inhibitor II in vitro and in vivo. The combination resulted in up to 10-fold increase in potency in five Burkitt lymphoma cell lines when compared with either drug alone. Both drugs inhibited tumor progression in xenograft models, but the combination was more effective than either agent alone, resulting in regression of established tumors. No toxicity was observed. These results suggest that the combination of histone deacetylase inhibition and checkpoint kinase inhibition represent an effective and nontoxic treatment option that should be further explored in preclinical and clinical studies. online address: http://www.molmed.org

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Section: Discussionsupporting

confidence: 92%

“…Colony formation assays in soft agar were performed as described previously (14). Cells were treated for 7 d with 1.6 μmol/L CHEK2i, 0.25 μmol/L AR42 or the combination of both.…”

Section: Clonogenic Survival Assaymentioning

confidence: 99%

Section: Cytotoxic Effects Of Ar42 and Chek2i On Nhl Cell Linesmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Efficacy of Combined Histone Deacetylase and Checkpoint Kinase Inhibition in a Preclinical Model of Human Burkitt Lymphoma

Kong

Barisone

Sidhu

et al. 2015

Mol Med

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Achiral Derivatives of Hydroxamate AR-42 Potently Inhibit Class I HDAC Enzymes and Cancer Cell Proliferation

Tng

Lim

et al. 2020

J. Med. Chem.

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AR-42 is an orally active inhibitor of histone deacetylases (HDACs) in clinical trials for multiple myeloma, leukemia, and lymphoma. It has few hydrogen bond donors and acceptors but is a chiral 2-arylbutyrate and potentially prone to racemization. We report achiral AR-42 analogues incorporating a cycloalkyl group linked via a quaternary carbon atom, with up to 40-fold increased potency against human class I HDACs (e.g., JT86, IC 50 0.7 nM, HDAC1), 25-fold increased cytotoxicity against five human cancer cell lines, and up to 70-fold less toxicity in normal human cells. JT86 was ninefold more potent than racAR-42 in promoting accumulation of acetylated histone H4 in MM96L melanoma cells. Molecular modeling and structure−activity relationships support binding to HDAC1 with tetrahydropyran acting as a hydrophobic shield from water at the enzyme surface. Such potent inhibitors of class I HDACs may show benefits in diseases (cancers, parasitic infections, inflammatory conditions) where AR-42 is active.

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Fermented Wheat Germ Protein with Histone Deacetylase Inhibitor AR42 Demonstrates Enhanced Cytotoxicity against Lymphoma Cells In Vitro and In Vivo

Meckler,

Levis,

Kong

et al. 2024

IJMS

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Current treatments for lymphoma are plagued by substantial toxicity and the inability to overcome drug resistance, leading to eventual relapse and rationalizing the development of novel, less toxic therapeutics and drug combinations. Histone deacetylase inhibitors (HDACis) are a broad class of epigenetic modulators that have been studied in multiple tumor types, including lymphoma. Currently, HDACis are FDA-approved for treating relapsed T-cell lymphomas and multiple myeloma, with ongoing trials in other lymphomas and solid tumors. As single agents, HDACis frequently elicit toxic side effects and have limited efficacy; therefore, many current treatment strategies focus on combinations to boost efficacy while attempting to minimize toxicity. Fermented wheat germ extract (FWGE) is a complementary agent that has shown efficacy in several malignancies, including lymphoma. Here, we utilize a more potent FWGE derivative, known as fermented wheat germ protein (FWGP), in combination with the HDACi AR42, to assess for enhanced activity. We report increased in vitro killing, cell cycle arrest, and in vivo efficacy for this combination compared to each agent alone with minimal toxicity, suggesting a potentially new, minimally toxic treatment modality for lymphoma.

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Histone deacetylase inhibition enhances the lymphomacidal activity of the anti-CD22 monoclonal antibody HB22.7

Cited by 4 publications

References 47 publications

Efficacy of Combined Histone Deacetylase and Checkpoint Kinase Inhibition in a Preclinical Model of Human Burkitt Lymphoma

Efficacy of Combined Histone Deacetylase and Checkpoint Kinase Inhibition in a Preclinical Model of Human Burkitt Lymphoma

Achiral Derivatives of Hydroxamate AR-42 Potently Inhibit Class I HDAC Enzymes and Cancer Cell Proliferation

Fermented Wheat Germ Protein with Histone Deacetylase Inhibitor AR42 Demonstrates Enhanced Cytotoxicity against Lymphoma Cells In Vitro and In Vivo

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