Y box binding protein 1 (YB-1) is a multifunctional protein associated with tumor progression and the emergence of treatment resistance (TR). Here, we report an azopodophyllotoxin small molecule, ...SU056, that potently inhibits tumor growth and progression via YB-1 inhibition. This YB-1 inhibitor inhibits cell proliferation, resistance to apoptosis in ovarian cancer (OC) cells, and arrests in the G1 phase. Inhibitor treatment leads to enrichment of proteins associated with apoptosis and RNA degradation pathways while downregulating spliceosome pathway. In vivo, SU056 independently restrains OC progression and exerts a synergistic effect with paclitaxel to further reduce disease progression with no observable liver toxicity. Moreover, in vitro mechanistic studies showed delayed disease progression via inhibition of drug efflux and multidrug resistance 1, and significantly lower neurotoxicity as compared with etoposide. These data suggest that YB-1 inhibition may be an effective strategy to reduce OC progression, antagonize TR, and decrease patient mortality.
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•Azopodophyllotoxin small molecule, SU056, inhibits YB-1•YB-1 inhibition decreases OC cell proliferation and resistance to apoptosis•YB-1 inhibition sensitizes OC cells for paclitaxel treatment
Tailor et al. reported azopodophyllotoxin derivative SU056 as a Y box binding protein 1 (YB-1) inhibitor. YB-1 inhibitor co-treatment sensitizes ovarian cancer cells for paclitaxel treatment.
Angiogenesis is an effective target in cancer control. The antiangiogenic efficacy and associated mechanisms of acacetin, a plant flavone, are poorly known. In the present study, acacetin inhibited ...growth and survival (up to 92%; P < 0.001), and capillary-like tube formation on Matrigel (up to 98%; P < 0.001) by human umbilical vein endothelial cells (HUVEC) in regular condition, as well as VEGF-induced and tumor cells conditioned medium-stimulated growth conditions. It caused retraction and disintegration of preformed capillary networks (up to 91%; P < 0.001). HUVEC migration and invasion were suppressed by 68% to 100% (P < 0.001). Acacetin inhibited Stat-1 (Tyr701) and Stat-3 (Tyr705) phosphorylation, and downregulated proangiogenic factors including VEGF, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), matrix metalloproteinase-2 (MMP-2), and basic fibroblast growth factor (bFGF) in HUVEC. It also suppressed nuclear localization of pStat-3 (Tyr705). Acacetin strongly inhibited capillary sprouting and networking from rat aortic rings and fertilized chicken egg chorioallantoic membrane (CAM; ∼71%; P < 0.001). Furthermore, it suppressed angiogenesis in Matrigel plugs implanted in Swiss albino mice. Acacetin also inhibited tyrosine phosphorylation of Stat-1 and -3, and expression of VEGF in cancer cells. Overall, acacetin inhibits Stat signaling and suppresses angiogenesis in vitro, ex vivo, and in vivo, and therefore, it could be a potential agent to inhibit tumor angiogenesis and growth.
Triple negative breast cancer is an aggressive, heterogeneous disease with high recurrence and metastasis rates even with modern chemotherapy regimens and thus is in need of new therapeutics. Here, ...three novel synthetic analogues of chalcones, plant-based molecules that have demonstrated potency against a wide variety of cancers, were investigated as potential therapeutics for triple negative breast cancer. These compounds exhibit IC50 values of ∼5 μM in triple negative breast cancer cell lines and are more potent against triple negative breast cancer cell lines than against nontumor breast cell lines according to viability experiments. Tandem mass tag-based quantitative proteomics followed by gene set enrichment analysis and validation experiments using flow cytometry, apoptosis, and Western blot assays revealed three different anticancer mechanisms for these compounds. First, the chalcone analogues induce the unfolded protein response followed by apoptosis. Second, increases in the abundances of MHC-I pathway proteins occurs, which would likely result in immune stimulation in an organism. And third, treatment with the chalcone analogues causes disruption of the cell cycle by interfering with microtubule structure and by inducing G1 phase arrest. These data demonstrate the potential of these novel chalcone derivatives as treatments for triple negative breast cancer, though further work evaluating their efficacy in vivo is needed.
Cancer remains a leading cause of death worldwide, resulting in continuous efforts to discover and develop highly efficacious anticancer drugs. High‐throughput screening of heterocyclic compound ...libraries is one of the promising approaches that provided several new lead molecules with a novel mechanism of action. On the basis of the promising anticancer potential of imidazoquinoxaline as well as the structurally similar imidazoquinoline‐derived scaffold, we prepared a set of C6‐substituted benzimidazo1,2‐aquinoxaline derivatives via two novel synthetic routes using commercially available starting materials, with good to excellent yields and evaluated their anticancer activity against the NCI‐60 cancer cell lines. The one‐dose (10 µM) anticancer screening of the synthesized compounds in the NCI‐60 cell line panel revealed that the substituents have a significant role in the activity. In particular, the indole (7f), imidazole (7g), and benzimidazole (7h) derivatives showed significant activity against the triple‐negative breast cancer cell line, MDA‐MB‐468. The lead compounds also exhibited notable IC50 values against another breast cancer cell line, MCF‐7. Furthermore, it was observed that these compounds were relatively nontoxic to normal cell lines: HEK293 (human embryonic kidney cell line) and MCF12A (nontumorigenic human breast epithelial cell line). The IC50 values against healthy cells were at least 5‐ to 11‐fold higher, offering a new class of heterocycles that can be further developed as promising therapeutics for cancer treatment.
A series of C6‐substituted benzimidazo1,2‐aquinoxaline derivatives was prepared via two novel synthetic routes using commercially available starting materials and their anticancer activities were evaluated against the NCI‐60 cancer cell panel. The indole (7f), imidazole (7g), and benzimidazole (7h) derivatives showed significant activity against the triple‐negative breast cancer cell line, MDA‐MB‐468.
Surgical resection and radiotherapy are an effective treatment in many head and neck squamous cell carcinomas (HNSCC), but in others, the development of radiotherapy resistance limits treatment ...efficacy and permits disease progression. We developed a novel multiwell radiation dosing method to increase the throughput of our investigation of the activity of a novel podophyllotoxin SU093 in acting as a radiosensitizer in the HNSCC models FaDu and SCC-25. These in vitro studies showed that combining SU093 with 5 Grays ionizing radiation acted synergistically to increase HNSCC apoptosis and decrease its proliferation via inhibition of Nuclear factor, erythroid 2 like 2 (Nrf2), a key effector of the DNA damage response induced by ionizing radiation. Combined treatment reduced in vitro migration in a simulated wounding model while also promoting cell cycle arrest at the G2/M phase. These findings validate the potential of SU093 as a synergistic radiosensitizing agent for use in combination with localized radiotherapy in treatment resistant HNSCC.
Cancer remains a leading cause of death worldwide, resulting in continuous efforts to discover and develop highly efficacious anticancer drugs. High‐throughput screening of heterocyclic compound ...libraries is one of the promising approaches that provided several new lead molecules with a novel mechanism of action. On the basis of the promising anticancer potential of imidazoquinoxaline as well as the structurally similar imidazoquinoline‐derived scaffold, we prepared a set of C6‐substituted benzimidazo1,2‐aquinoxaline derivatives via two novel synthetic routes using commercially available starting materials, with good to excellent yields and evaluated their anticancer activity against the NCI‐60 cancer cell lines. The one‐dose (10 µM) anticancer screening of the synthesized compounds in the NCI‐60 cell line panel revealed that the substituents have a significant role in the activity. In particular, the indole (7f), imidazole (7g), and benzimidazole (7h) derivatives showed significant activity against the triple‐negative breast cancer cell line, MDA‐MB‐468. The lead compounds also exhibited notable IC50 values against another breast cancer cell line, MCF‐7. Furthermore, it was observed that these compounds were relatively nontoxic to normal cell lines: HEK293 (human embryonic kidney cell line) and MCF12A (nontumorigenic human breast epithelial cell line). The IC50 values against healthy cells were at least 5‐ to 11‐fold higher, offering a new class of heterocycles that can be further developed as promising therapeutics for cancer treatment.
Guanylate-binding protein 1 (GBP1) is known as an interferon-γ-induced GTPase. Here, we used genetically modified ovarian cancer (OC) cells to study the role of GBP1. The data generated show that ...GBP1 inhibition constrains the clonogenic potential of cancer cells. In vivo studies revealed that GBP1 overexpression in tumors promotes tumor progression and reduces median survival, whereas GBP1 inhibition delayed tumor progression with longer median survival. We employed proteomics-based thermal stability assay (CETSA) on GBP1 knockdown and overexpressed OC cells to study its molecular functions. CETSA results show that GBP1 interacts with many members of the proteasome. Furthermore, GBP1 inhibition sensitizes OC cells to paclitaxel treatment via accumulated ubiquitinylated proteins where GBP1 inhibition decreases the overall proteasomal activity. In contrast, GBP1-overexpressing cells acquired paclitaxel resistance via boosted cellular proteasomal activity. Overall, these studies expand the role of GBP1 in the activation of proteasomal machinery to acquire chemoresistance.
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•GBP1 inhibition delays the ovarian cancer progression•Overexpression of GBP1 contributes to the development of paclitaxel resistance•GBP1 modulates the proteasomal activity in ovarian cancer cells
Pharmacology; Biochemistry; Molecular biology; Cancer; Proteomics
Benzyl isothiocyanate (BITC) is a highly promising phytochemical abundant in cruciferous vegetables with preclinical evidence of in vivo efficacy against breast cancer in xenograft and transgenic ...mouse models. Mammary cancer chemoprevention by BITC is associated with apoptotic cell death but the underlying mechanism is not fully understood. Herein, we demonstrate for the first time that altered mitochondrial dynamics is an early and critical event in BITC-induced apoptosis in breast cancer cells. Exposure of MCF-7 and MDA-MB-231 cells to plasma achievable doses of BITC resulted in rapid collapse of mitochondrial filamentous network. BITC treatment also inhibited polyethyleneglycol-induced mitochondrial fusion. In contrast, a normal human mammary epithelial cell line (MCF-10A) that was derived from fibrocystic breast disease, was resistant to BITC-mediated alterations in mitochondrial dynamics as well as apoptosis. Transient or sustained decrease in levels of proteins engaged in regulation of mitochondrial fission and fusion was clearly evident after BITC treatment in both cancer cell lines. A trend for a decrease in the levels of mitochondrial fission- and fusion-related proteins was also observed in vivo in tumors of BITC-treated mice compared with control. Immortalized mouse embryonic fibroblasts from Drp1 knockout mice were resistant to BITC-induced apoptosis when compared with those from wild-type mice. Upon treatment with BITC, Bak dissociated from mitofusin 2 in both MCF-7 and MDA-MB-231 cells suggesting a crucial role for interaction of Bak and mitofusins in BITC-mediated inhibition of fusion and morphological dynamics. In conclusion, the present study provides novel insights into the molecular complexity of BITC-induced cell death.
Triple negative breast cancer is an aggressive, heterogeneous disease with high recurrence and metastasis rates even with modern chemotherapy regimens and thus is in need of new therapeutics. Here, ...three novel synthetic analogues of chalcones, plant-based molecules that have demonstrated potency against a wide variety of cancers, were investigated as potential therapeutics for triple negative breast cancer. These compounds exhibit IC
50
values of ~ 5 μM in triple negative breast cancer cell lines and are more potent against triple negative breast cancer cell lines than against non-tumor breast cell lines according to viability experiments. Tandem mass tag-based quantitative proteomics followed by gene set enrichment analysis and validation experiments using flow cytometry, apoptosis, and western blot assays revealed three different anti-cancer mechanisms for these compounds. First, the chalcone analogues induce the unfolded protein response followed by apoptosis. Second, increases in the abundances of MHC-I pathway proteins occurs, which would likely result in immune stimulation in an organism. And third, treatment with the chalcone analogues causes disruption of the cell cycle by interfering with microtubule structure and by inducing G1 phase arrest. These data demonstrate the potential of these novel chalcone derivatives as treatments for triple negative breast cancer, though further work evaluating their efficacy
in vivo
is needed.
Mycobacterium-w (Mw) was shown to boost adaptive natural killer (ANK) cells and protect against COVID-19 during the first wave of the pandemic. As a follow-up of the trial, 50 healthcare workers ...(HCW) who had received Mw in September 2020 and subsequently received at least one dose of ChAdOx1 nCoV-19 vaccine (Mw + ChAdOx1 group) were monitored for symptomatic COVID-19 during a major outbreak with the delta variant of SARS-CoV-2 (April–June 2021), along with 201 HCW receiving both doses of the vaccine without Mw (ChAdOx1 group). Despite 48% having received just a single dose of the vaccine in the Mw + ChAdOx1 group, only two had mild COVID-19, compared to 36 infections in the ChAdOx1 group (HR-0.46, p = 0.009). Transcriptomic studies revealed an enhanced adaptive NK cell-dependent ADCC in the Mw + ChAdOx1 group, along with downregulation of the TLR2-MYD88 pathway and concomitant attenuation of downstream inflammatory pathways. This might have resulted in robust protection during the pandemic with the delta variant.
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