Reverse Screening Bioinformatics Approach to Identify Potential Anti Breast Cancer Targets Using Thymoquinone from Neutraceuticals Black Cumin Oil

2019 ◽  
Vol 19 (5) ◽  
pp. 599-609 ◽  
Author(s):  
Sumathi Sundaravadivelu ◽  
Sonia K. Raj ◽  
Banupriya S. Kumar ◽  
Poornima Arumugamand ◽  
Padma P. Ragunathan
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cell Cycle ◽  
Cell Death ◽  
In Silico ◽  
Chemotherapeutic Agents ◽  
Normal Cells ◽  
Black Cumin ◽  
In Silico Docking ◽  
Wide Range

Background: Functional foods, neutraceuticals and natural antioxidants have established their potential roles in the protection of human health and diseases. Thymoquinone (TQ), the main bioactive component of Nigella sativa seeds (black cumin seeds), a plant derived neutraceutical was used by ancient Egyptians because of their ability to cure a variety of health conditions and used as a dietary food supplement. Owing to its multi targeting nature, TQ interferes with a wide range of tumorigenic processes and counteracts carcinogenesis, malignant growth, invasion, migration, and angiogenesis. Additionally, TQ can specifically sensitize tumor cells towards conventional cancer treatments (e.g., radiotherapy, chemotherapy, and immunotherapy) and simultaneously minimize therapy-associated toxic effects in normal cells besides being cost effective and safe. TQ was found to play a protective role when given along with chemotherapeutic agents to normal cells. Methods: In the present study, reverse in silico docking approach was used to search for potential molecular targets for cancer therapy. Various metastatic and apoptotic targets were docked with the target ligand. TQ was also tested for its anticancer activities for its ability to cause cell death, arrest cell cycle and ability to inhibit PARP gene expression. Results: In silico docking studies showed that TQ effectively docked metastatic targets MMPs and other apoptotic and cell proliferation targets EGFR. They were able to bring about cell death mediated by apoptosis, cell cycle arrest in the late apoptotic stage and induce DNA damage too. TQ effectively down regulated PARP gene expression which can lead to enhanced cancer cell death. Conclusion: Thymoquinone a neutraceutical can be employed as a new therapeutic agent to target triple negative breast cancer which is otherwise difficult to treat as there are no receptors on them. Can be employed along with standard chemotherapeutic drugs to treat breast cancer as a combinatorial therapy.

The IGF1-R Inhibitor AEW541 Is a Potent Anti-Myeloma Agent That Overcomes Drugs Resistance, and Has Synergistic Activity with Other New Drugs.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2599-2599
Author(s):  
Patricia Maiso ◽  
Enrique M. Ocio ◽  
Mercedes Garayoa ◽  
Mark A. Pearson ◽  
Atanasio Pandiella ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Cell Death ◽  
Expression Profiles ◽  
Chemotherapeutic Agents ◽  
Mitochondrial Outer Membrane ◽  
Late Time ◽  
Synergistic Activity ◽  
Dependent Manner ◽  
Myeloma Cells

Abstract Multiple myeloma (MM) represents an incurable disease for which development of new therapies is required. Here we report the effect on myeloma cells of AEW541, a new small molecule, belonging to the pyrrolo[2,3-d] pyrimidine class, identified as inhibitor of the IGF-1R in vitro kinase activity. AEW541 showed a potent antimyeloma activity (IC50 <4.5 μM) on MM cell lines both sensitive (MM1S, U266, OPM2, RPMI8226) and resistant (MM1R and U266LR7) to conventional chemotherapeutic agents. In fresh cells from five MM patients a marked antitumor activity was confirmed. AEW541 showed a synergistic effect with dexamethasone and lenalidomide, while it was additive with melphalan and bortezomib. Moreover the triple combination of AEW541, bortezomib and dexamethasone showed even higher anti-MM activity. Gene expression profiles of MM1S cells identified a total of 967 genes to be significantly deregulated (transcriptional changes in gene expression of 2-fold or greater) by treatment with AEW541. The classification of these genes according to functional categories indicated that 3.5% were involved in apoptosis/responses to stress and 13% in the control of cell cycle/proliferation. By Western analyses, we observed that AEW541 affected genes involved in cell cycle and cell death pathways. AEW541 blocked cell cycle progression, and this was accompanied by p27, up-regulation and pRb, CCND1, CCNA and CCNE downregulation. AEW541 induced cell death through an increase in the mitochondrial outer membrane permeability and provoked DNA fragmentation. AEW541 induced apoptosis and at late time points, also activated caspases 8,9 and 3. The pan-caspase inhibitor Z-VAD-FMK only slightly decreased the sensitivity to AEW541. In addition, AEW541 stimulated a caspase-independent pathway, through the release of AIF and Endonuclease G from the mitochondria. It is therefore conceivable that both caspase dependent and independent pathways are activated by AEW541 in MM cells, although the effect of AEW541 on cell cycle arrest is an earlier and more potent event. Finally, AEW541 was able to overcome the protective effect that confers IL-6, IGF-1 and BMSCs to myeloma cells in a dose dependent manner. All these data indicate that AEW541 could be a useful drug for the treatment of MM patients, particularly in combination with other novel agents such as bortezomib or lenalidomide together with dexamethasone.

scholarly journals Palbociclib Induces Senescence in Melanoma and Breast Cancer Cells and Leads to Additive Growth Arrest in Combination With Irradiation

2021 ◽  
Vol 11 ◽  
Author(s):  
Tina Jost ◽  
Lucie Heinzerling ◽  
Rainer Fietkau ◽  
Markus Hecht ◽  
Luitpold V. Distel
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Death ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Growth Arrest ◽  
Melanoma Cells ◽  
Cellular Growth ◽  
Cycle Arrest ◽  
Wide Range

IntroductionSeveral kinase inhibitors (KI) bear the potential to act as radiosensitizers. Little is known of the radiosensitizing effects of a wide range of other KI like palbociclib, which is approved in ER+/HER2- metastatic breast cancer.MethodIn our study, we used healthy donor fibroblasts and breast cancer and skin cancer cells to investigate the influence of a concomitant KI + radiation therapy. Cell death and cell cycle distribution were studied by flow cytometry after Annexin-V/7-AAD and Hoechst staining. Cellular growth arrest was studied in colony-forming assays. Furthermore, we used C12-FDG staining (senescence) and mRNA expression analysis (qPCR) to clarify cellular mechanisms.ResultsThe CDK4/6 inhibitor palbociclib induced a cell cycle arrest in the G0/G1 phase. Cellular toxicity (cell death) was only slightly increased by palbociclib and not enhanced by additional radiotherapy. As the main outcome of the colony formation assays, we found that cellular growth arrest was induced by palbociclib and improved by radiotherapy in an additive manner. Noticeably, palbociclib treatment clearly induced senescence not only in breast cancer and partly in melanoma cells, but also in healthy fibroblasts. According to these findings, the downregulation of senescence-related FOXM1 might be an involved mechanism of the senescence-induction potential of palbociclib.ConclusionThe effect on cellular growth arrest of palbociclib and radiotherapy is additive. Palbociclib induces permanent G0/G1 cell cycle arrest by inducing senescence in fibroblasts, breast cancer, and melanoma cells. Direct cell death induction is only a minor secondary mechanism of action. Concomitant KI and radiotherapy is a strategy worth studying in clinical trials.

Structure Guided Molecular Docking Assisted Alignment Dependent 3DQSAR Study on Steroidal Aromatase Inhibitors (SAIs) as Anti-breast Cancer Agents

2019 ◽  
Vol 16 (7) ◽  
pp. 808-817 ◽  
Author(s):  
Laxmi Banjare ◽  
Sant Kumar Verma ◽  
Akhlesh Kumar Jain ◽  
Suresh Thareja
Keyword(s):  
Breast Cancer ◽  
Molecular Docking ◽  
Aromatase Inhibitors ◽  
Direct Synthesis ◽  
3D Qsar ◽  
Chemotherapeutic Agents ◽  
Modeling Tools ◽  
Data Set ◽  
Wide Range ◽  
Steroidal Aromatase Inhibitors

Background: In spite of the availability of various treatment approaches including surgery, radiotherapy, and hormonal therapy, the steroidal aromatase inhibitors (SAIs) play a significant role as chemotherapeutic agents for the treatment of estrogen-dependent breast cancer with the benefit of reduced risk of recurrence. However, due to greater toxicity and side effects associated with currently available anti-breast cancer agents, there is emergent requirement to develop target-specific AIs with safer anti-breast cancer profile. Methods: It is challenging task to design target-specific and less toxic SAIs, though the molecular modeling tools viz. molecular docking simulations and QSAR have been continuing for more than two decades for the fast and efficient designing of novel, selective, potent and safe molecules against various biological targets to fight the number of dreaded diseases/disorders. In order to design novel and selective SAIs, structure guided molecular docking assisted alignment dependent 3D-QSAR studies was performed on a data set comprises of 22 molecules bearing steroidal scaffold with wide range of aromatase inhibitory activity. Results: 3D-QSAR model developed using molecular weighted (MW) extent alignment approach showed good statistical quality and predictive ability when compared to model developed using moments of inertia (MI) alignment approach. Conclusion: The explored binding interactions and generated pharmacophoric features (steric and electrostatic) of steroidal molecules could be exploited for further design, direct synthesis and development of new potential safer SAIs, that can be effective to reduce the mortality and morbidity associated with breast cancer.

scholarly journals Differential Mechanisms of Cell Death Induced by HDAC Inhibitor SAHA and MDM2 Inhibitor RG7388 in MCF-7 Cells

Cells ◽  
2018 ◽  
Vol 8 (1) ◽  
pp. 8 ◽  
Author(s):  
Umamaheswari Natarajan ◽  
Thiagarajan Venkatesan ◽  
Vijayaraghavan Radhakrishnan ◽  
Shila Samuel ◽  
Appu Rathinavelu
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Death ◽  
Cancer Cells ◽  
Hdac Inhibitor ◽  
The Other ◽  
Combination Treatments ◽  
Cycle Arrest ◽  
Anti Cancer ◽  
Mcf 7

Gene expression is often altered by epigenetic modifications that can significantly influence the growth ability and progression of cancers. SAHA (Suberoylanilide hydroxamic acid, also known as Vorinostat), a well-known Histone deacetylase (HDAC) inhibitor, can stop cancer growth and metastatic processes through epigenetic alterations. On the other hand, Letrozole is an aromatase inhibitor that can elicit strong anti-cancer effects on breast cancer through direct and indirect mechanisms. A newly developed inhibitor, RG7388 specific for an oncogene-derived protein called MDM2, is in clinical trials for the treatment of various cancers. In this paper, we performed assays to measure the effects of cell cycle arrest resulting from individual drug treatments or combination treatments with SAHA + letrozole and SAHA + RG7388, using the MCF-7 breast cancer cells. When SAHA was used individually, or in combination treatments with RG7388, a significant increase in the cytotoxic effect was obtained. Induction of cell cycle arrest by SAHA in cancer cells was evidenced by elevated p21 protein levels. In addition, SAHA treatment in MCF-7 cells showed significant up-regulation in phospho-RIP3 and MLKL levels. Our results confirmed that cell death caused by SAHA treatment was primarily through the induction of necroptosis. On the other hand, the RG7388 treatment was able to induce apoptosis by elevating BAX levels. It appears that, during combination treatments, with SAHA and RG7388, two parallel pathways might be induced simultaneously, that could lead to increased cancer cell death. SAHA appears to induce cell necroptosis in a p21-dependent manner, and RG7388 seems to induce apoptosis in a p21-independent manner, outlining differential mechanisms of cell death induction. However, further studies are needed to fully understand the intracellular mechanisms that are triggered by these two anti-cancer agents.

scholarly journals Docosahexaenoic acid alters cell death, cancer and cell‐cycle signaling networks in breast cancer cell lines

2012 ◽  
Vol 26 (S1) ◽  
Author(s):  
Catherine J Field ◽  
Julia B Ewaschuk ◽  
Randy Nelson ◽  
Marnie Newell ◽  
Rene Jacobs
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Death ◽  
Docosahexaenoic Acid ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Signaling Networks ◽  
Breast Cancer Cell Lines ◽  
Cell Cycle Signaling

scholarly journals SYNTHESIS AND CHARACTERIZATION OF CYCLOHEXANE-1,3-DIONE DERIVATIVES AND THEIR IN SILICO AND IN VITRO STUDIES ON ANTIMICROBIAL AND BREAST CANCER ACTIVITY

2019 ◽  
pp. 311-320 ◽  
Author(s):  
RAJA CHINNAMANAYAKAR ◽  
EZHILARASI MR ◽  
PRABHA B ◽  
KULANDHAIVEL M
Keyword(s):  
Breast Cancer ◽  
Antimicrobial Activity ◽  
Anticancer Activity ◽  
Mtt Assay ◽  
In Silico ◽  
Biologically Active ◽  
Diffusion Method ◽  
Breast Adenocarcinoma ◽  
In Silico Docking

Objective: The objective of this study was to evaluate in silico and in vitro anticancer activity for synthesized cyclohexane-1,3-dione derivatives. Methods: The new series of cyclohexane-1,3-dione derivatives were synthesized based on the Michael addition reaction. Further, the structures of the synthesized compounds were confirmed by Fourier-transform infrared spectroscopy, 1H nuclear magnetic resonance (NMR), and 13C NMR spectral data. Then, the in silico molecular docking studies were carried out using AutoDock tool version 1.5.6 and AutoDock version 4.2.5.1 docking program. The antimicrobial activity was carried out using the agar disk diffusion method, and the in vitro anticancer activity was performed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for the synthesized compound. Results: In silico docking study, compound 5c showed good binding score and binding interactions with selected bacterial proteins and breast cancer protein. Further, compound (5a-5h) was tested for their antimicrobial activity and compound 5c was only tested for anticancer activity (human breast adenocarcinoma 3,4-methylenedioxyamphetamine-MB-231 cell line). Compound 5c was found to be the most active one of all the tested compounds. In the MTT assay compound, 5c showed the LC50 value of 10.31±0.003 μg/ml. In antimicrobial activity, the minimum inhibitory concentration of compound 5c is 2.5 mg/ml. Conclusion: An efficient synthesis of biologically active cyclohexane-1, 3-dione derivatives has been developed.

scholarly journals Changes in DNA Damage Repair Gene Expression and Cell Cycle Gene Expression Do Not Explain Radioresistance in Tamoxifen-Resistant Breast Cancer

2020 ◽  
Vol 28 (1) ◽  
pp. 33-40 ◽  
Author(s):  
Annemarie E. M. Post ◽  
Johan Bussink ◽  
Fred C. G. J. Sweep ◽  
Paul N. Span
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cell Cycle ◽  
Dna Damage ◽  
Dna Damage Repair ◽  
Cross Resistance ◽  
Damage Repair ◽  
Breast Cancer Cohort ◽  
Tamoxifen Resistant ◽  
Repair Genes

Tamoxifen-induced radioresistance, reported in vitro, might pose a problem for patients who receive neoadjuvant tamoxifen treatment and subsequently receive radiotherapy after surgery. Previous studies suggested that DNA damage repair or cell cycle genes are involved, and could therefore be targeted to preclude the occurrence of cross-resistance. We aimed to characterize the observed cross-resistance by investigating gene expression of DNA damage repair genes and cell cycle genes in estrogen receptor-positive MCF-7 breast cancer cells that were cultured to tamoxifen resistance. RNA sequencing was performed, and expression of genes characteristic for several DNA damage repair pathways was investigated, as well as expression of genes involved in different phases of the cell cycle. The association of differentially expressed genes with outcome after radiotherapy was assessed in silico in a large breast cancer cohort. None of the DNA damage repair pathways showed differential gene expression in tamoxifen-resistant cells compared to wild-type cells. Two DNA damage repair genes were more than two times upregulated (NEIL1 and EME2), and three DNA damage repair genes were more than two times downregulated (PCNA, BRIP1, and BARD1). However, these were not associated with outcome after radiotherapy in the TCGA breast cancer cohort. Genes involved in G1, G1/S, G2, and G2/M phases were lower expressed in tamoxifen-resistant cells compared to wild-type cells. Individual genes that were more than two times upregulated (MAPK13) or downregulated (E2F2, CKS2, GINS2, PCNA, MCM5, and EIF5A2) were not associated with response to radiotherapy in the patient cohort investigated. We assessed the expression of DNA damage repair genes and cell cycle genes in tamoxifen-resistant breast cancer cells. Though several genes in both pathways were differentially expressed, these could not explain the cross-resistance for irradiation in these cells, since no association to response to radiotherapy in the TCGA breast cancer cohort was found.

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