Unveiling anticancer potential of glibenclamide: Its synergistic cytotoxicity with doxorubicin on cancer cells

Nithyananthan, Subramaniyam; Arumugam, Suyavaran; Ezthupurakkal, Preedia Babu; Subastri, Ariraman; Biswas, Indrani; Muthuvel, Suresh Kumar; Balakrishnan, Arun; Alshammari, Ghedeir M.; Thirunavukkarasu, Chinnasamy

doi:10.1016/j.jpba.2018.03.025

Cited by 14 publications

(4 citation statements)

References 26 publications

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“…After long-term (24 h) incubation Glib had similar toxicity in both genotypes. Previous studies have demonstrated that ex vivo longterm exposure to KATP channel inhibitors is coupled to apoptosis and atrophic signaling in muscle fibers (Tricarico et al, 2010;Mele et al, 2014a;Mele et al, 2014b;Cetrone et al, 2014), although this may be due to non-KATP channeldependent actions of the drug (de Sant'Anna et al, 2015;Subramaniyam et al, 2018). We have recently shown that Glib treatment can effectively reverse many of the cardiovascular complications of CS (Ma et al, 2019;McClenaghan et al, 2020).…”

Section: The Cellular and Pharmacological Consequence In Cantù Syndromentioning

confidence: 99%

Pathophysiological Consequences of KATP Channel Overactivity and Pharmacological Response to Glibenclamide in Skeletal Muscle of a Murine Model of Cantù Syndrome

et al. 2020

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Cantù syndrome (CS) arises from mutations in ABCC9 and KCNJ8 genes that lead to gain of function (GOF) of ATP-sensitive potassium (KATP) channels containing SUR2A and Kir6.1 subunits, respectively, of KATP channels. Pathological consequences of CS have been reported for cardiac and smooth muscle cells but consequences in skeletal muscle are unknown. Children with CS show muscle hypotonia and adult manifest fatigability. We analyzed muscle properties of Kir6.1[V65M] CS mice, by measurements of forelimb strength and ultrasonography of hind-limb muscles, as well as assessing KATP channel properties in native Flexor digitorum brevis (FDB) and Soleus (SOL) fibers by the patch-clamp technique in parallel with histopathological, immunohistochemical and Polymerase Chain Reaction (PCR) analysis. Forelimb strength was lower in Kir6.1wt/VM mice than in WT mice. Also, a significant enhancement of echodensity was observed in hind-limb muscles of Kir6.1wt/VM mice relative to WT, suggesting the presence of fibrous tissue. There was a higher KATP channel current amplitude in Kir6.1wt/VM FDB fibers relative to WT and a reduced response to glibenclamide. The IC50 of glibenclamide to block KATP channels in FDB fibers was 1.3 ± 0.2 × 10−7 M in WT and 1.2 ± 0.1 × 10−6 M in Kir6.1wt/VM mice, respectively; and it was 1.2 ± 0.4 × 10−7 M in SOL WT fibers but not measurable in Kir6.1wt/VM fibers. The sensitivity of the KATP channel to MgATP was not modified in Kir6.1wt/VM fibers. Histopathological/immunohistochemical analysis of SOL revealed degeneration plus regressive-necrotic lesions with regeneration, and up-regulation of Atrogin-1, MuRF1, and BNIP3 mRNA/proteins in Kir6.1wt/VM mice. Kir6.1wt/VM mutation in skeletal muscle leads to changes of the KATP channel response to glibenclamide in FDB and SOL fibers, and it is associated with histopathological and gene expression changes in slow-twitch muscle, suggesting marked atrophy and autophagy.

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Section: The Cellular and Pharmacological Consequence In Cantù Syndromentioning

confidence: 99%

Pathophysiological Consequences of KATP Channel Overactivity and Pharmacological Response to Glibenclamide in Skeletal Muscle of a Murine Model of Cantù Syndrome

et al. 2020

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“…Additionally, the enlargement of the spheres of gli–LPS–ATP-treated cells could suggest that tumor self-renewal by activating multipotent CRC cells in the presence of inflammatory stimuli [ 57 ]. Although multiple studies have reported the antiproliferative and proapoptotic effects of gli in cancer cells in vitro [ 17 , 58 , 59 ], epidemiological evidence has associated the use of gli with an increased mortality rate in various malignancies, including pancreatic and lung cancer [ 60 , 61 , 62 ]. The findings of this study confirm that caution should be exercised regarding the use of gli in CRC patients with high NLRP3 because it could promote invasion and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Implications of NLRP3 Suppression Using Glibenclamide and miR-223 against Colorectal Cancer

Hamza,

Garanina,

Shkair

et al. 2024

Pharmaceuticals

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The NLR family pyrin domain containing 3 (NLRP3) promotes the growth of colorectal cancer (CRC). However, the therapeutic effect of NLRP3 inhibition on CRC cell progression is controversial. This study comparatively investigated the therapeutic effect of a pharmacological NLRP3 inhibitor, glibenclamide (gli), and the post-translational suppression of NLRP3 by miR-223 on CRC cell progression in HCT-116 and HCT-15 cells. LPS and ATP were used to activate Gli-treated and LSB-hsa-miR-223-3p (WTmiR-223)-expressing HCT-116 cells. NLRP3.AB.pCCL.sin.cPPT.U6.miR-223-Decoy.hPGK.GFP.WPRE plasmid (DmiR-223) was the negative control for miR-223 expression. NLRP3, gasdermin D, and BAX expressions were analyzed using western blotting. Real-time PCR detected the RNA expression of autophagy-related genes ATG5, BECN1, and miR-223 in non-transfected cells. ELISA analyzed IL-1β and IL-18 in the medium. MTS-1, annexin V, wound-healing, and sphere-invasion assays were used to assess cell viability and progression. A multiplex cytokine assay detected proinflammatory cytokine secretion. LPS–ATP-activated NLRP3 produced gasdermin D cleavage, released IL-1b and IL-18, and activated cell migration and sphere invasion. In contrast, reduced cell growth, miR-223 expression, IFN-γ, CXCL10, and LIF secretion were found in cells after inflammasome activation. Both gli and WTmiR-223 induced autophagy genes ATG5 and BECN1 and reduced the NLRP3 activation and its downstream proteins. However, while gli had a limited effect on the production of IFN-γ, CXCL10, and LIF, WTmiR-223 increased the release of those cytokines. In addition, gli did not suppress cell growth, while WTmiR-223 promoted apoptosis. Notably, neither gli nor WTmiR-223 effectively prevented sphere invasion. These data suggest that, while WTmiR-223 could have a better anticancer effect in CRC compared to gli, the sole usage of miR-223-mediated NLRP3 suppression may not be sufficient to prevent CRC metastasis.

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“…Moreover, glyburide, also known as glibenclamide, was able to prevent NLRP3 activation and IL-1β production induced by microbial ligands and DAMPs [116]. Of note, accumulating evidence has proven the anticancer property of glibenclamide [117,118,119]. In addition, MCC950 was a specific small-molecule inhibitor of NLRP3 and AIM2 inflammasomes, which might represent a promising therapeutic approach for inflammasome-associated cancers [120].…”

Section: The Role Of Inflammasomes In Cancermentioning

confidence: 99%

The Multifaceted Roles of Pyroptotic Cell Death Pathways in Cancer

Wang

Jiang

Zhang

et al. 2019

Cancers

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Cancer is a category of diseases involving abnormal cell growth with the potential to invade other parts of the body. Chemotherapy is the most widely used first-line treatment for multiple forms of cancer. Chemotherapeutic agents act via targeting the cellular apoptotic pathway. However, cancer cells usually acquire chemoresistance, leading to poor outcomes in cancer patients. For that reason, it is imperative to discover other cell death pathways for improved cancer intervention. Pyroptosis is a new form of programmed cell death that commonly occurs upon pathogen invasion. Pyroptosis is marked by cell swelling and plasma membrane rupture, which results in the release of cytosolic contents into the extracellular space. Currently, pyroptosis is proposed to be an alternative mode of cell death in cancer treatment. Accumulating evidence shows that the key components of pyroptotic cell death pathways, including inflammasomes, gasdermins and pro-inflammatory cytokines, are involved in the initiation and progression of cancer. Interfering with pyroptotic cell death pathways may represent a promising therapeutic option for cancer management. In this review, we describe the current knowledge regarding the biological significance of pyroptotic cell death pathways in cancer pathogenesis and also discuss their potential therapeutic utility.

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Unveiling anticancer potential of glibenclamide: Its synergistic cytotoxicity with doxorubicin on cancer cells

Cited by 14 publications

References 26 publications

Pathophysiological Consequences of KATP Channel Overactivity and Pharmacological Response to Glibenclamide in Skeletal Muscle of a Murine Model of Cantù Syndrome

Pathophysiological Consequences of KATP Channel Overactivity and Pharmacological Response to Glibenclamide in Skeletal Muscle of a Murine Model of Cantù Syndrome

Implications of NLRP3 Suppression Using Glibenclamide and miR-223 against Colorectal Cancer

The Multifaceted Roles of Pyroptotic Cell Death Pathways in Cancer

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