Dataset Information

One-pot three-component synthesis of novel spirooxindoles with potential cytotoxic activity against triple-negative breast cancer MDA-MB-231 cells.

ABSTRACT: Triple-negative breast cancer (TNBC) is a highly aggressive malignancy with limited treatment options due to its heterogeneity and the lack of well-defined molecular targets. In our endeavour towards the development of novel anti-TNBC agents, herein we report a one-pot three-component synthesis of novel spirooxindoles 6a-p, and evaluation of their potential anti-proliferative activity towards TNBC MDA-MB-231 cells. Spirooxindoles 6a, 6e and 6i emerged as the most potent analogues with IC₅₀ = 6.70, 6.40 and 6.70 µM, respectively. Compounds 6a and 6e induced apoptosis in MDA-MB-231 cells, as evidenced by the up-regulation of the Bax and down-regulation of the Bcl-2, besides boosting caspase-3 levels. Additionally, 6e displayed significant increase in the percent of annexin V-FITC positive apoptotic cells from 1.34 to 44%. Furthermore, spirooxindoles 6e and 6i displayed good inhibitory activity against EGFR (IC₅₀ = 120 and 150 nM, respectively). Collectively, these data demonstrated that 6e might be a potential lead compound for the development of effective anti-TNBC agents.

SUBMITTER: Eldehna WM

PROVIDER: S-EPMC6009943 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

One-pot three-component synthesis of novel spirooxindoles with potential cytotoxic activity against triple-negative breast cancer MDA-MB-231 cells.

Eldehna Wagdy M WM El-Naggar Dina H DH Hamed Ahmed R AR Ibrahim Hany S HS Ghabbour Hazem A HA Abdel-Aziz Hatem A HA

Journal of enzyme inhibition and medicinal chemistry 20181201 1

Triple-negative breast cancer (TNBC) is a highly aggressive malignancy with limited treatment options due to its heterogeneity and the lack of well-defined molecular targets. In our endeavour towards the development of novel anti-TNBC agents, herein we report a one-pot three-component synthesis of novel spirooxindoles 6a-p, and evaluation of their potential anti-proliferative activity towards TNBC MDA-MB-231 cells. Spirooxindoles 6a, 6e and 6i emerged as the most potent analogues with IC<sub>50< ...[more]

PMID: 29281924

Similar Datasets

Project description:IntroductionTriple-negative breast cancer (TNBC) represents a significant global health crisis due to its resistance to conventional therapies and lack of specific molecular targets. This study explored the potential of Eriocephalus racemosus (E. racemosus) as an alternative treatment for TNBC. The cytotoxic properties and high-resolution respirometry mitochondrial activities of E. racemosus against the MDA-MB 231 TNBC cell line were evaluated.MethodsHexane solvent and bioactive fraction extractions of E. racemosus were performed, while mass spectrometry-based metabolite profiling was used to identify the phytochemical constituents of the extracts. The extracts were further tested against MDA-MB 231 TNBC cells to determine their cytotoxicity. The mode of cell death was determined using flow cytometry. The activities of caspases 3, 8, and 9 were assessed using a multiplex activity assay kit. Glycolytic activity and High-resolution respirometry measurements of mitochondrial function in the MDA-MB 231 cell line were conducted using the Seahorse XFp and Oroboros O2K.ResultsMetabolite profiling of E. racemosus plant crude extracts identified the presence of coumarins, flavonoids, sesquiterpenoids, triterpenoids, and unknown compounds. The extracts demonstrated promising cytotoxic activities, with a half maximal inhibitory concentration (IC50) of 12.84 µg/mL for the crude hexane extract and 15.49 µg/mL for the bioactive fraction. Further, the crude hexane and bioactive fraction extracts induced apoptosis in the MDA-MB-231 TNBC cells, like the reference drug cisplatin (17.44%, 17.26% and 20.25%, respectively) compared to untreated cells. Caspase 3 activities confirmed the induction of apoptosis in both cisplatin and the plant crude extracts, while caspase 8 and 9 activities confirmed the activation of both the intrinsic and extrinsic apoptosis pathways. Increased levels of glycolytic activity were observed in the hexane crude extract. High-resolution respiratory measurements showed elevated mitochondrial activities in all mitochondrial states except for complex-IV activity.ConclusionThese findings support further exploration of E. racemosus as a potential therapeutic agent for TNBC, offering a promising avenue for the development of targeted treatments with minimal adverse effects.

Project description:Vasculogenic mimicry (VM) with the pattern of endothelial independent tubular structure formation lined by aggressive tumor cells mimics regular tumor blood vessels to ensure robust blood supply and correlates with the proliferation, invasion, metastasis, and poor prognosis of malignant tumors, which was demonstrated to be a major obstacle for resistance to antiangiogenesis therapy. Therefore, it is urgent to discover methods to abrogate the VM formation of tumors, which possesses important practical significance for improving tumor therapy. Brucine is a traditional medicinal herb extracted from seeds of Strychnos nux-vomica L. (Loganiaceae) exhibiting antitumor activity in a variety of cancer models. In the present study, the effect of brucine on vasculogenic mimicry and the related mechanism are to be investigated. We demonstrated that, in a triple-negative breast cancer cell line MDA-MB-231, brucine induced a dose-dependent inhibitory effect on cell proliferation along with apoptosis induction at higher concentrations. The further study showed that brucine inhibited cell migration and invasion with a dose-dependent manner. Our results for the first time indicated that brucine could disrupt F-actin cytoskeleton and microtubule structure, thereby impairing hallmarks of aggressive tumors, like migration, invasion, and holding a possibility of suppressing vasculogenic mimicry. Hence, the inhibitory effect of brucine on vasculogenic mimicry was further verified. The results illustrated that brucine significantly suppressed vasculogenic mimicry tube formation with a dose-dependent effect indicated by the change of the number of tubules, intersections, and mean length of tubules. The in-depth molecular mechanism of vasculogenic mimicry suppression induced by brucine was finally suggested. It was demonstrated that brucine inhibited vasculogenic mimicry which might be through the downregulation of erythropoietin-producing hepatocellular carcinoma-A2 and matrix metalloproteinase-2 and metalloproteinase-9.

Project description:Natural killer cells (NK cells) are essential in cancer immunosurveillance in the body as they can recognize cancer cells that lacking MHC class 1 on their surface. Regulatory cytokines, including interleukin (IL)-18, IL-12, IL-10, IL-8, interferon-γ (IFN-γ), and secretory granules like perforin and granzyme are involved in NK cell-mediated cytotoxicity. Stimulating NK cells cytotoxicity towards cancer cells is an ideal strategy to combat cancer naturally. Medicinal plants have been reported to enhance immunity, with Pereskia bleo (P. bleo) particularly noteworthy due to its abundant bioactive compounds and ability to activate immune cells. This study aimed to evaluate the potential of methanol extract of P. bleo leaves (MEPB) for enhancing NK cell cytotoxicity against triple-negative human breast cancer cells (MDA-MB-231). The optimal concentration of MEPB to activate NK cells was determined using healthy blood samples, assessing the expression of IL-12, IL-18, IL-10, IL-8, IFN-γ, perforin, and granzyme B via an enzyme-linked immunosorbent assay (ELISA). NK cell purity from healthy donors and breast cancer patients was determined using specific antibodies, and the number of NK cells was assessed using flow cytometry and a hemocytometer. A co-culture experiment, ELISA, and apoptosis assay were used to evaluate NK-mediated cytotoxicity pathways. ELISA data indicated that MEPB at 7.5 µg/ml significantly increased the expression of IFN-γ, IL-12, IL-18, perforin, and granzyme B while decreasing IL-8 and IL-10 expression after 20 hrs of incubation. The average NK cell purity was 87.09 ± 0.043%. Breast cancer patients exhibited lower NK cell counts than healthy donors. Co-culture experiments demonstrated that NK cells induced apoptosis in MDA-MB-231 breast cancer cells in the presence of MEPB by increasing perforin, granzyme B, and IFN-γ expression in both healthy donors and breast cancer patients-experimental groups. P. bleo enhances NK cell activation, promoting the apoptosis of triple-negative human breast cancer cells (MDA-MB-231), suggesting the potential use of MEPB leaves as an anti-cancer immunostimulant.

Dataset Information

One-pot three-component synthesis of novel spirooxindoles with potential cytotoxic activity against triple-negative breast cancer MDA-MB-231 cells.

Publications

One-pot three-component synthesis of novel spirooxindoles with potential cytotoxic activity against triple-negative breast cancer MDA-MB-231 cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets