Browsing by Author "Rizvanov, Albert A."

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Doxycycline attenuates cancer cell growth by suppressing NLRP3-mediated inflammation
(Mdpi, 2021-08-24) Alsaadi, Mohammad; Tezcan, Gülçin; Garanina, Ekaterina E.; Hamza, Shaimaa; McIntyre, Alan; Rizvanov, Albert A.; Khaiboullina, Svetlana F.; TEZCAN, GÜLÇİN; Bursa Uludağ Üniversitesi/Diş Hekimliği Fakültesi/Temel Bilimler Bölümü.; 0000-0002-5956-8755; AAH-3843-2020
NLR family pyrin domain containing 3 (NLRP3) inflammasome formation is triggered by the damaged mitochondria releasing reactive oxygen species. Doxycycline was shown to regulate inflammation; however, its effect on NLRP3 in cancer remains largely unknown. Therefore, we sought to determine the effect of doxycycline on NLRP3 regulation in cancer using an in vitro model. NLRP3 was activated in a prostate cancer cell line (PC3) and a lung cancer cell line (A549) before treatment with doxycycline. Inflammasome activation was assessed by analyzing RNA expression of NLRP3, Pro-CASP-1, and Pro-IL1 beta using RT-qPCR. Additionally, NLPR3 protein expression and IL-1 beta secretion were analyzed using Western blot and ELISA, respectively. Tumor cell viability was determined using Annexin V staining and a cell proliferation assay. Cytokine secretion was analyzed using a 41Plex assay for human cytokines. Data were analyzed using one-way ANOVA model with Tukey's post hoc tests. Doxycycline treatment decreased NLRP3 formation in PC3 and A549 cells compared to untreated and LPS only treated cells (p < 0.05). Doxycycline also decreased proliferation and caused cell death through apoptosis, a response that differed to the LPS-Nigericin mediated pyroptosis. Our findings suggest that doxycycline inhibits LPS priming of NLRP3 and reduces tumor progression through early apoptosis in cancer.
Therapeutic potential of pharmacological targeting nlrp3 inflammasome complex in cancer
(Frontiers Media Sa, 2021-02-03) Garanina, Ekaterina E.; Alsaadi, Mohammad; Gilazieva, Zarema E.; Martinova, Ekaterina, V; Markelova, Maria, I; Arkhipova, Svetlana S.; Hamza, Shaimaa; McIntyre, Alan; Rizvanov, Albert A.; Khaiboullina, Svetlana F.; Tezcan, Gulcin; TEZCAN, GÜLÇİN; Bursa Uludağ Üniversitesi/Diş Hekimliği Fakültesi.; 0000-0002-5956-8755; 0000-0001-7445-2091; 0000-0002-4082-515X; 0000-0002-5012-4760; 0000-0002-4791-7292; 0000-0002-9427-5739; AAH-3843-2020; H-4486-2013; HTO-8900-2023; AAE-4652-2022; AAP-5140-2021; W-9788-2018; P-4183-2017
IntroductionDysregulation of NLRP3 inflammasome complex formation can promote chronic inflammation by increased release of IL-1 beta. However, the effect of NLRP3 complex formation on tumor progression remains controversial. Therefore, we sought to determine the effect of NLRP3 modulation on the growth of the different types of cancer cells, derived from lung, breast, and prostate cancers as well as neuroblastoma and glioblastoma in-vitro.MethodThe effect of Caspase 1 inhibitor (VX765) and combination of LPS/Nigericin on NLRP3 inflammasome activity was analyzed in A549 (lung cancer), MCF-7 (breast cancer), PC3 (prostate cancer), SH-SY5Y (neuroblastoma), and U138MG (glioblastoma) cells. Human fibroblasts were used as control cells. The effect of VX765 and LPS/Nigericin on NLRP3 expression was analyzed using western blot, while IL-1 beta and IL-18 secretion was detected by ELISA. Tumor cell viability and progression were determined using Annexin V, cell proliferation assay, LDH assay, sphere formation assay, transmission electron microscopy, and a multiplex cytokine assay. Also, angiogenesis was investigated by a tube formation assay. VEGF and MMPs secretion were detected by ELISA and a multiplex assay, respectively. Statistical analysis was done using one-way ANOVA with Tukey's analyses and Kruskal-Wallis one-way analysis of variance.ResultsLPS/Nigericin increased NRLP3 protein expression as well as IL-1 beta and IL-18 secretion in PC3 and U138MG cells compared to A549, MCF7, SH-SY5Y cells, and fibroblasts. In contrast, MIF expression was commonly found upregulated in A549, PC3, SH-SY5Y, and U138MG cells and fibroblasts after Nigericin treatment. Nigericin and a combination of LPS/Nigericin decreased the cell viability and proliferation. Also, LPS/Nigericin significantly increased tumorsphere size in PC3 and U138MG cells. In contrast, the sphere size was reduced in MCF7 and SH-SY5Y cells treated with LPS/Nigericin, while no effect was detected in A549 cells. VX765 increased secretion of CCL24 in A549, MCF7, PC3, and fibroblasts as well as CCL11 and CCL26 in SH-SY5Y cells. Also, VX765 significantly increased the production of VEGF and MMPs and stimulated angiogenesis in all tumor cell lines.DiscussionOur data suggest that NLRP3 activation using Nigericin could be a novel therapeutic approach to control the growth of tumors producing a low level of IL-1 beta and IL-18.