Allosteric modulation of sigma receptors by BH3 mimetics ABT-737, ABT-263 (Navitoclax) and ABT-199 (Venetoclax)

Lever, John R.; Fergason-Cantrell, Emily A.

doi:10.1016/j.phrs.2019.01.040

Cited by 14 publications

(13 citation statements)

References 75 publications

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“…A highly selective Bcl-2 antagonist, venetoclax, which can competitively abolish the specific binding of pro-apoptotic proteins BIM and Bcl-2 interaction has been developed. This new BH3 mimetics overcomes the shortcomings of low specificity of the previous Bcl-2 antagonists such as ABT-737 and navitoclax [15]. Recently, the U.S. FDA approved ABT-199 combined with demethylating agents (decitabine or azacitidine) or low-dose cytarabine to treat newly diagnosed AML patients who cannot tolerate induction chemotherapy or elderly AML patients older than 75 years old [7][8][9]16].…”

Section: Ivyspringmentioning

confidence: 99%

Metformin exerts a synergistic effect with venetoclax by downregulating Mcl-1 protein in acute myeloid leukemia

Zhou¹,

Zeng²,

Cheng³

et al. 2021

J. Cancer

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Background: Recently, one of the specific BH3-mimetics, Venetoclax has been approved by FDA providing new options for newly diagnosed AML patient especially who are unfitted to receive conventional chemotherapy. Though the clinical success of venetoclax has been achieved in clinical outcomes such as complete remission (CR) and overall survival. Acquired resistance to ABT-199 which is induced by the regulation of apoptosis pathway is still an important clinical problem. To this end, the attempt to combine drugs which can reverse the compensatory regulation is urgent. Methods: In three AML cell lines (KG-1, Kasumi-1 and THP-1), the anti-AML effects of the combination of and metformin or the two drugs used alone were compared. CCK8 was used to evaluate the cell viability, and flow cytometry was used to estimate the rate of apoptosis, Western blot method was performed to detect apoptosis-related protein levels. In mice experiments, female BALB/c-nu nude mice were subcutaneously injected with THP-1 cells for subcutaneous tumor formation, and the combined effect of ABT-199 and metformin was tested. The evaluation indicators were tumor size, tumor weight, and Ki67 staining. Mouse body weight and HE staining were detected to evaluate liver damage and adverse drug reactions. Results: Both in vitro and in vivo experiments showed that compared with metformin or ABT-199 alone, the combined use of the two drugs exerts a synergistic effect on promoting apoptosis, thereby producing a strong anti-leukemia effect. Furthermore, after a short incubation time, ABT-199 swiftly increased the expression level of the anti-apoptotic protein Mcl-1, while the combined use of metformin and ABT-199 significantly reduced the level of Mcl-1. Notably, Metformin significantly downregulates the level of Mcl-1 protein by inhibiting its protein production. To less extent, metformin can also downregulate the expression of another anti-apoptotic protein, BCL-xl. Conclusion:Metformin downregulates the expression of anti-apoptotic proteins Mcl-1 and Bcl-xl by inhibiting protein production, and shows a synergistic anti-tumor effect with ABT-199 in acute myeloid leukemia.

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Section: Ivyspringmentioning

confidence: 99%

Metformin exerts a synergistic effect with venetoclax by downregulating Mcl-1 protein in acute myeloid leukemia

Zhou¹,

Zeng²,

Cheng³

et al. 2021

J. Cancer

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“…Notably, BCL‐2 proteins generally present a hydrophobic groove which binds BH3 domain to be pro‐apoptotic [11,12] . Great efforts were invested to develop suitable small molecules and peptides to target this groove by mimicking BH3 domain [1,13–18] . Small molecule candidate ABT‐263 could reduce tumor burden in most patients with CLL and is currently in clinical trials [19,20] .…”

Section: Methodsmentioning

confidence: 99%

“…[11,12] Great efforts were invested to develop suitable small molecules and peptides to target this groove by mimicking BH3 domain. [1,[13][14][15][16][17][18] Small molecule candidate ABT-263 could reduce tumor burden in most patients with CLL and is currently in clinical trials. [19,20] ABT199 (venetoclax) was approved by the US Food and Drug Administration (FDA) in 2016 as a single agent treatment for CLL patients with 17p chromosomal deletion, a biomarker for TP53 loss and poor prognosis.…”

mentioning

confidence: 99%

Selective Covalent Targeting of Anti‐apoptotic BFL‐1 by a Sulfonium‐Tethered Peptide

et al. 2020

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Anti-apoptotic B cell lymphoma 2 (BCL-2) family proteins are proven targets for human cancers. Targeting the BH3-binding pockets of these anti-apoptotic proteins could reactivate apoptosis in BCL-2-depedent cancers. BFL-1 is a BCL-2 family protein overexpressed in various chemoresistant cancers. A unique cysteine at the binding interface of the BH3 and BFL-1 was previously proven to be an intriguing targeting site to irreversibly inhibit BFL-1 functions with stabilized cyclic peptide bearing a covalent warhead. Recently, we developed a sulfonium-tethered peptide cyclization strategy to construct peptide ligands that could selectively and efficiently react with the cysteine(s) of target proteins near the interacting interface. Using this method, we constructed a BFL-1 peptide inhibitor, B4-MC, that could selectively conjugate with BFL-1 both in vitro and in cell. B4-MC showed good cellular uptake, colocalized with BFL-1 on mitochondria, and showed obvious growth inhibition of BFL-1 over-expressed cancer cell lines.

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“…Of interest in this context is that novel small molecule inhibitors of pro-survival proteins involved with the B-cell lymphoma family (Bcl-2) have produced promising results in hematologic cancers [44]. Their mechanism of action is to cause apoptosis by binding to the pro-survival proteins and mimicking the prodeath Bcl-2 homology 3 (BH3) proteins [44]. These agents are sometimes called BH3 mimetics [44].…”

Section: Neuropathy With Hematological Cancermentioning

confidence: 99%

Sigma Antagonists for Treatment of Neuropathic Pain Syndromes in Cancer Patients: A Narrative Review

Pergolizzi

LeQuang

2022

J. Can. Res. Updates

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Almost 40% of cancer patients have neuropathic pain or mixed pain with a neuropathic component, which can be intense, debilitating, and challenging to treat. New studies on sigma receptors show these enigmatic ligand-binding protein chaperones may be helpful drug targets for new pharmacologic options to reduce many types of neuropathies, including chemotherapy-induced peripheral neuropathy (CIPN) and other cancer-related neuropathic pain syndromes. Our objective was to review the literature, including preclinical findings, in support of sigma-1 receptor (S1R) antagonists in reducing neuropathic pain and sigma-2 receptor (S2R) agonists for neuroprotection. The mechanisms behind these effects are not yet fully elucidated. The role of S1R antagonists in treating CIPN appears promising. In some cases, combination therapy of an opioid—which is a true analgesic—with a S1R antagonist, which is an anti-hyperalgesic and anti-allodynic agent, has been proposed. Of interest, but not well studied is whether or not S1R antagonists might be effective in treating CIPN in patients with pre-existing peripheral diabetic neuropathy. While neuropathic syndromes may occur with hematologic cancers, the role of S1R agonists may be effective. Sigma receptors are being actively studied now for a variety of conditions ranging from Alzheimer’s disease to Parkinson’s disease as well as neuropathic pain.

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Allosteric modulation of sigma receptors by BH3 mimetics ABT-737, ABT-263 (Navitoclax) and ABT-199 (Venetoclax)

Cited by 14 publications

References 75 publications

Metformin exerts a synergistic effect with venetoclax by downregulating Mcl-1 protein in acute myeloid leukemia

Metformin exerts a synergistic effect with venetoclax by downregulating Mcl-1 protein in acute myeloid leukemia

Selective Covalent Targeting of Anti‐apoptotic BFL‐1 by a Sulfonium‐Tethered Peptide

Sigma Antagonists for Treatment of Neuropathic Pain Syndromes in Cancer Patients: A Narrative Review

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