ABT-737 accelerates butyrate-induced death of HL-60 cells. Involvement of mitochondrial apoptosis pathway

Stefanikova, A.; Kliková, Katarína; Hatok, Jozef; Račay, Peter

doi:10.4149/gpb_2013053

Cited by 5 publications

(4 citation statements)

References 51 publications

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“…Likewise, BT is a substrate for energy production, a regulator of energy metabolism 40 , a histone deacetylase inhibitor 41 , a modulator of immune function 42 , and a modulator of local gut physiology 43 . BT has positive effects in biological models of several important human diseases, including diabetes 43 , 44 , neurodegenerative disorders 18 , 45 , leukemia 46 , lymphoma 47 , and colorectal 48 , 49 , breast 50 , 51 , and pancreatic 52 cancers.…”

Section: Introductionmentioning

confidence: 99%

Butyrate enhances mitochondrial function during oxidative stress in cell lines from boys with autism

et al. 2018

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Butyrate (BT) is a ubiquitous short-chain fatty acid (SCFA) principally derived from the enteric microbiome. BT positively modulates mitochondrial function, including enhancing oxidative phosphorylation and beta-oxidation and has been proposed as a neuroprotectant. BT and other SCFAs have also been associated with autism spectrum disorders (ASD), a condition associated with mitochondrial dysfunction. We have developed a lymphoblastoid cell line (LCL) model of ASD, with a subset of LCLs demonstrating mitochondrial dysfunction (AD-A) and another subset of LCLs demonstrating normal mitochondrial function (AD-N). Given the positive modulation of BT on mitochondrial function, we hypothesized that BT would have a preferential positive effect on AD-A LCLs. To this end, we measured mitochondrial function in ASD and age-matched control (CNT) LCLs, all derived from boys, following 24 and 48 h exposure to BT (0, 0.1, 0.5, and 1 mM) both with and without an in vitro increase in reactive oxygen species (ROS). We also examined the expression of key genes involved in cellular and mitochondrial response to stress. In CNT LCLs, respiratory parameters linked to adenosine triphosphate (ATP) production were attenuated by 1 mM BT. In contrast, BT significantly increased respiratory parameters linked to ATP production in AD-A LCLs but not in AD-N LCLs. In the context of ROS exposure, BT increased respiratory parameters linked to ATP production for all groups. BT was found to modulate individual LCL mitochondrial respiration to a common set-point, with this set-point slightly higher for the AD-A LCLs as compared to the other groups. The highest concentration of BT (1 mM) increased the expression of genes involved in mitochondrial fission (PINK1, DRP1, FIS1) and physiological stress (UCP2, mTOR, HIF1α, PGC1α) as well as genes thought to be linked to cognition and behavior (CREB1, CamKinase II). These data show that the enteric microbiome-derived SCFA BT modulates mitochondrial activity, with this modulation dependent on concentration, microenvironment redox state, and the underlying mitochondrial function of the cell. In general, these data suggest that BT can enhance mitochondrial function in the context of physiological stress and/or mitochondrial dysfunction, and may be an important metabolite that can help rescue energy metabolism during disease states. Thus, insight into this metabolic modulator may have wide applications for both health and disease since BT has been implicated in a wide variety of conditions including ASD. However, future clinical studies in humans are needed to help define the practical implications of these physiological findings.

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Section: Introductionmentioning

confidence: 99%

Butyrate enhances mitochondrial function during oxidative stress in cell lines from boys with autism

et al. 2018

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“…Both intrinsic and extrinsic pathways can cause cell apoptosis. The intrinsic pathway is also called the mitochondrial pathway, which is initiated by p53 [78]. Tumor protein p53, a tumor suppressor, controls G1 and G2 checkpoints activating or inhibiting genes involved in the cell cycle, apoptosis and DNA repair [78].…”

Section: Mitochondrial Apoptotic Pathway Altered By Butyratementioning

confidence: 99%

“…The intrinsic pathway is also called the mitochondrial pathway, which is initiated by p53 [78]. Tumor protein p53, a tumor suppressor, controls G1 and G2 checkpoints activating or inhibiting genes involved in the cell cycle, apoptosis and DNA repair [78]. In response to environmental stimuli such as UV and toxins, p53 is increased to promote DNA repair or cause cell death if DNA damage is too severe to repair.…”

Section: Mitochondrial Apoptotic Pathway Altered By Butyratementioning

confidence: 99%

Effects of Intestinal Microbial–Elaborated Butyrate on Oncogenic Signaling Pathways

2019

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The intestinal microbiota is well known to have multiple benefits on human health, including cancer prevention and treatment. The effects are partially mediated by microbiota-produced short chain fatty acids (SCFAs) such as butyrate, propionate and acetate. The anti-cancer effect of butyrate has been demonstrated in cancer cell cultures and animal models of cancer. Butyrate, as a signaling molecule, has effects on multiple signaling pathways. The most studied effect is its inhibition on histone deacetylase (HDAC), which leads to alterations of several important oncogenic signaling pathways such as JAK2/STAT3, VEGF. Butyrate can interfere with both mitochondrial apoptotic and extrinsic apoptotic pathways. In addition, butyrate also reduces gut inflammation by promoting T-regulatory cell differentiation with decreased activities of the NF-κB and STAT3 pathways. Through PKC and Wnt pathways, butyrate increases cancer cell differentiation. Furthermore, butyrate regulates oncogenic signaling molecules through microRNAs and methylation. Therefore, butyrate has the potential to be incorporated into cancer prevention and treatment regimens. In this review we summarize recent progress in butyrate research and discuss the future development of butyrate as an anti-cancer agent with emphasis on its effects on oncogenic signaling pathways. The low bioavailability of butyrate is a problem, which precludes clinical application. The disadvantage of butyrate for medicinal applications may be overcome by several approaches including nano-delivery, analogue development and combination use with other anti-cancer agents or phytochemicals.

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“…It seems that the extent of Bcl-2 bound to BIM, rather than total Bcl-2 expression levels, may determine cellular sensitivity to ABT-737 (Deng et al 2007). In hand with this, ABT-737 has been shown to interact with certain anticancer agents capable of up-regulating BIM (Kuroda et al 2006;Zhang et al 2008b;Stefaniková et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Cyclin-dependent kinase 2 inhibitor SU9516 increases sensitivity of colorectal carcinoma cells Caco-2 but not HT29 to BH3 mimetic ABT-737

Stefanikova

Klacanova²,

Pilchová³

et al. 2017

gpb

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Colorectal carcinoma (CRC) that represents one of the major causes for cancer-related death in humans is often associated with over-expression of anti-apoptotic proteins of Bcl-2 family. The aim of presented study was to determine the effect of ABT-737 inhibitor of anti-apoptotic proteins Bcl-2, Bcl-XL and Bcl-w as well as cyclin-dependent kinase 2 (CDK2) inhibitor SU9516 alone and in combination with ABT-737 on survival of colorectal cell lines HT29 and Caco-2. We have shown that both Caco-2 and HT29 cells that are relatively resistant to ABT-737 are also partially sensitive to SU9516, which increased sensitivity of Caco-2 but not HT29 cells to ABT-737. Increased sensitivity of Caco-2 cells to ABT-737 after addition of SU9516 correlated well with SU9516-induced decrease of Mcl-1 expression while we have not observed downregulation of Mcl-1 after the treatment of HT29 cells with SU9516. Instead of this, we have shown that treatment of HT29 cells with SU9516 is associated with decreased expression of tumour suppressor protein p53. Our findings provide a rationale for clinical use of Bcl-2 family inhibitors in combination with CDK2 inhibitors for treatment of Mcl-1-dependent colorectal tumours associated with expression of Bcl-2, Bcl-XL and Bcl-w proteins. In addition, we have shown potential of CDK2 inhibitors for treatment of tumours expressing R273H mutant p53.

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ABT-737 accelerates butyrate-induced death of HL-60 cells. Involvement of mitochondrial apoptosis pathway

Cited by 5 publications

References 51 publications

Butyrate enhances mitochondrial function during oxidative stress in cell lines from boys with autism

Butyrate enhances mitochondrial function during oxidative stress in cell lines from boys with autism

Effects of Intestinal Microbial–Elaborated Butyrate on Oncogenic Signaling Pathways

Cyclin-dependent kinase 2 inhibitor SU9516 increases sensitivity of colorectal carcinoma cells Caco-2 but not HT29 to BH3 mimetic ABT-737

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