Non-homologous End Joining Inhibitor SCR-7 to Exacerbate Low-dose Doxorubicin Cytotoxicity in HeLa Cells

Kumar, Ajay; Bhatkar, Devyani; Jahagirdar, Devashree; Sharma, Nilesh Kumar

doi:10.15430/jcp.2017.22.1.47

Cited by 17 publications

(18 citation statements)

References 28 publications

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“…Results showed that in case of MCF-7 conditioned media, there is an increase in HeLa cell apoptotic death with respect to untreated control. Similarly, TNBC tissue non-cellular factors demonstrated more apoptotic death in HeLa cells, which is comparable to the results of doxorubicin treatment as the positive control (Kumar et al, 2017) which showed the presence of PI stained HeLa. The cell cycle analysis represented in Figure 3D and 3E depicts that the percentage of HeLa cells in G0/G1 phase significantly decreased from 66% to 41% and at the same time S phase distribution of HeLa cells increased from 11% to 25%.…”

Section: Flow Cytometry Analysis Of Hela Proliferation and Deathsupporting

confidence: 72%

Induction of Apoptotic Death and Cell Cycle Arrest in HeLa Cells by Extracellular Factors of Breast Cancer Cells

Jahagirdar

Gore

Patel

et al. 2018

Asian Pac J Cancer Prev

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Background: There are evidences on the role of extracellular factors in cellular communication between cancer cells and non-cancerous cells to support tumor progression and a phenomenon of cancer cachexia. However, evidences are scarce to show the effects of extracellular factors from one carcinoma microenvironment upon growth and survival of another carcinoma. Methodology: To address the above issue, we have selected excised breast carcinoma tissue samples and in vitro grown MCF-7 sources of extracellular factors and tested their effects to evaluate growth and proliferation inhibitory potential against a cervical carcinoma cell line HeLa. Results: Data from the in vitro experiments like Trypan blue dye exclusion, MTT assay, cell cycle assay and annexin V/PI staining lead us to suggest that the extracellular factors collected from the culture medium of in vitro grown MCF-7 and excised breast carcinoma tissue play an apoptosis inducing and cell cycle arrest role in HeLa. In these in vitro experiments, we detected the presence of up to 40-50% apoptotic cell death in HeLa cells and increase in G2-M cell cycle phase from 11%-25% due to treatment with extracellular factors from human breast carcinoma cells. Discussion and Conclusion: These observations are novel and suggest that extracellular factors from breast carcinoma play an apoptosis inducing and growth inhibitory role upon on HeLa cells. This study can also support the concept of cancer cachexia and a possible hypothesis for rare chance of synchronous two or more primary tumor in a single patient.

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Section: Flow Cytometry Analysis Of Hela Proliferation and Deathsupporting

confidence: 72%

Induction of Apoptotic Death and Cell Cycle Arrest in HeLa Cells by Extracellular Factors of Breast Cancer Cells

Jahagirdar

Gore

Patel

et al. 2018

Asian Pac J Cancer Prev

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“…Breast cancer cells were incubated for 72 h at 37 °C. The rest of the procedure was adopted as per the routine protocol [ 39 , 40 ]. The absorbance was recorded using an ELISA reader (Thermo Fisher Scientific, Waltham, WA, USA).…”

Section: Methodsmentioning

confidence: 99%

Free Fatty Acids from Cow Urine DMSO Fraction Induce Cell Death in Breast Cancer Cells without Affecting Normal GMSCs

et al. 2023

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Objective: The objective of this study was to explore the biological relevance of free fatty acids derived from cow urine DMSO fraction (CUDF) by employing in vitro and in silico approaches. Background: Metabolic heterogeneity at the intra- and intercellular levels contributes to the metabolic plasticity of cancer cells during drug-induced response. Free fatty acid (FFA) availability at intra- and intercellular levels is related to tumor heterogeneity at interpatient and xeno-heterogeneity levels. Methods: We collected fresh urine from healthy cows and subjected it to fractionation in DMSO using drying, vortexing, and centrifugation. Finally, the sterile filtrate of cow urine DMSO fraction (CUDF) was evaluated for antiproliferative and proapoptotic effects in MCF-7 and ZR-75-1 breast cancer cells using routine cell-based assays. Intracellular metabolites were studied with the help of a novel in-house vertical tube gel electrophoresis (VTGE) method to reveal the nature of CUDF components in MCF-7 cells. Identified intracellular FFAs were studied for their molecular interactions with targeted receptor histone deacetylase (HDAC) using molecular docking and molecular dynamics (MD) simulations. Results: CUDF showed a significant reduction in cell viability and cell death in MCF-7 and ZR-75-1 breast cancer cells. Interestingly, FFAs tetracosanedioic acid, 13Z-docosenoic acid (erucic acid), nervonic acid, 3-hydroxy-tetradecanoic acid, and 3-hydroxcapric acid were found inside the treated MCF-7 cancer cells. These FFAs, including tetracosanedioic acid, indicated a specific affinity to HDAC at their inhibitory sites, similar to trichostatin A, a known inhibitor. Conclusions: This study reports on FFAs derived from CUDF as potential antiproliferative and pro-cell death agents against breast cancer cells. MD simulations hinted at tetracosanedioic acid and other FFAs as inhibitors of HDAC that could explain the observed effects of FFAs in cancer cells.

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“…Previously, we have reported that combinatorial treatment of SCR7 and radiation led to the accumulation of unrepaired DSBs, activation of apoptosis, and a ≥ 2-fold reduction in the effective IR dose in cancer cell lines and mouse tumour models [24,25,52]. Studies from other research groups have also revealed the combinatorial potential of SCR7 with radiation and chemotherapeutic agents [9,26,29]. Nucleus is stained in red using propidium iodide, while green signal represents 53BP1 foci (FITC).…”

Section: Scr116 and Scr132 Can Induce Synergistic Effects When Combin...mentioning

confidence: 99%

Identification and characterization of mercaptopyrimidine‐based small molecules as inhibitors of nonhomologous DNA end joining

et al. 2022

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Mercaptopyrimidine derivatives are heterocyclic compounds with potent biological activities including antiproliferative, antibacterial, and anti‐inflammatory properties. The present study describes the synthesis and characterization of several mercaptopyrimidine derivatives through condensation of 5,6‐diamino‐2‐mercaptopyrimidin‐4‐ol with various heterocyclic and aromatic aldehydes. Previous studies have shown that SCR7, synthesized from 5,6‐diamino‐2‐mercaptopyrimidin‐4‐ol, induced cytotoxicity by targeting cancer cells by primarily inhibiting DNA Ligase IV involved in nonhomologous end joining, one of the major DNA double‐strand break repair pathways. Inhibition of DNA repair pathways is considered as an important strategy for cancer therapy. Due to limitations of SCR7 in terms of IC50 in cancer cells, here we have designed, synthesized, and characterized potent derivatives of SCR7 using 5,6‐diamino‐2‐mercaptopyrimidin‐4‐ol as the starting material. Several synthesized imine compounds exhibited significant improvement in inhibition of end joining and cytotoxicity up to 27‐fold lower concentrations than SCR7. Among these, two compounds, SCR116 and SCR132, showed increased cancer cell death in a Ligase IV‐dependent manner. Treatment with the compounds also led to reduction in V(D)J recombination efficiency, cell cycle arrest at G2/M phase, accumulation of double‐strand breaks inside cells, and improved anti‐cancer potential when combined with γ‐radiation and radiomimetic drugs. Thus, we describe novel inhibitors of NHEJ with higher efficacy and potential, which can be developed as cancer therapeutics.

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Non-homologous End Joining Inhibitor SCR-7 to Exacerbate Low-dose Doxorubicin Cytotoxicity in HeLa Cells

Cited by 17 publications

References 28 publications

Induction of Apoptotic Death and Cell Cycle Arrest in HeLa Cells by Extracellular Factors of Breast Cancer Cells

Induction of Apoptotic Death and Cell Cycle Arrest in HeLa Cells by Extracellular Factors of Breast Cancer Cells

Free Fatty Acids from Cow Urine DMSO Fraction Induce Cell Death in Breast Cancer Cells without Affecting Normal GMSCs

Identification and characterization of mercaptopyrimidine‐based small molecules as inhibitors of nonhomologous DNA end joining

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