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Fulltext The natural alkaloid Jerantinine B has activity in acute myeloid leukemia cells through a mechanism involving c-Jun

Alhuthali HM, Bradshaw TD, Lim KH, Kam TS, Seedhouse CH

BMC Cancer, 2020 Jul 07;20(1):629.
PMID: 32635894 DOI: 10.1186/s12885-020-07119-2

BACKGROUND: Acute myeloid leukemia (AML) is a heterogenous hematological malignancy with poor long-term survival. New drugs which improve the outcome of AML patients are urgently required. In this work, the activity and mechanism of action of the cytotoxic indole alkaloid Jerantinine B (JB), was examined in AML cells.
METHODS: We used a combination of proliferation and apoptosis assays to assess the effect of JB on AML cell lines and patient samples, with BH3 profiling being performed to identify early effects of the drug (4 h). Phosphokinase arrays were adopted to identify potential driver proteins in the cellular response to JB, the results of which were confirmed and extended using western blotting and inhibitor assays and measuring levels of reactive oxygen species.
RESULTS: AML cell growth was significantly impaired following JB exposure in a dose-dependent manner; potent colony inhibition of primary patient cells was also observed. An apoptotic mode of death was demonstrated using Annexin V and upregulation of apoptotic biomarkers (active caspase 3 and cleaved PARP). Using BH3 profiling, JB was shown to prime cells to apoptosis at an early time point (4 h) and phospho-kinase arrays demonstrated this to be associated with a strong upregulation and activation of both total and phosphorylated c-Jun (S63). The mechanism of c-Jun activation was probed and significant induction of reactive oxygen species (ROS) was demonstrated which resulted in an increase in the DNA damage response marker γH2AX. This was further verified by the loss of JB-induced C-Jun activation and maintenance of cell viability when using the ROS scavenger N-acetyl-L-cysteine (NAC).
CONCLUSIONS: This work provides the first evidence of cytotoxicity of JB against AML cells and identifies ROS-induced c-Jun activation as the major mechanism of action.

Matched MeSH terms: DNA Damage/drug effects
Neuroimmunomodulatory properties of DPSCs in an in vitro model of Parkinson's disease

Gnanasegaran N, Govindasamy V, Mani V, Abu Kasim NH

IUBMB Life, 2017 09;69(9):689-699.
PMID: 28685937 DOI: 10.1002/iub.1655

In neurodegenerative diseases, such as Alzheimer's and Parkinson's, microglial cell activation is thought to contribute to their degeneration by producing neurotoxic compounds. While dental pulp stem cells (DPSCs) have been regarded as the next possible cell source for cell replacement therapy (CRT), their actual role when exposed in such harsh environment remains elusive. In this study, the immunomodulatory behavior of DPSCs from human subjects was investigated in a coculture system consisting of neuron and microglia which were treated with 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine, which mimics the inflammatory conditions and contribute to degeneration of dopaminergic (DA-ergic) neurons. Assessments were performed on their proliferation, extent of DNA damage, productions of reactive oxygen species (ROS) and nitric oxide (NO), as well as secretion of inflammatory mediators. Notably, DPSCs were shown to attenuate their proliferation, production of ROS, and NO significantly (P DNA damage. Despite DPSCs were exposed to such harsh environment, they were still able to express neuronal markers such as Nestin, Pax 6, and Nurr1, at least by twofold thereby indicating their applicability for CRT especially in PD conditions. To conclude, DPSCs were shown to have immunomodulatory capacities which could probably serve as secondary effects upon transplantation in a CRT regime. © 2017 IUBMB Life, 69(9):689-699, 2017.

Matched MeSH terms: DNA Damage/drug effects
Synthesis, characterization and multiple targeting with selectivity: Anticancer property of ternary metal phenanthroline-maltol complexes

Ng CH, Tan TH, Tioh NH, Seng HL, Ahmad M, Ng SW, et al.

J Inorg Biochem, 2021 07;220:111453.
PMID: 33895694 DOI: 10.1016/j.jinorgbio.2021.111453

The cobalt(II), copper(II) and zinc(II) complexes of 1,10-phenanthroline (phen) and maltol (mal) (complexes 1, 2, 3 respectively) were prepared from their respective metal(II) chlorides and were characterized by FT-IR, elemental analysis, UV spectroscopy, molar conductivity, p-nitrosodimethylaniline assay and mass spectrometry. The X-ray structure of a single crystal of the zinc(II) analogue reveals a square pyramidal structure with distinctly shorter apical chloride bond. All complexes were evaluated for their anticancer property on breast cancer cell lines MCF-7 and MDA-MB-231, and normal cell line MCF-10A, using (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and morphological studies. Complex 2 was most potent for 24, 48 and 72 h treatment of cancer cells but it was not selective towards cancer over normal cells. The mechanistic studies of the cobalt(II) complex 1 involved apoptosis assay, cell cycle analysis, dichloro-dihydro-fluorescein diacetate assay, intracellular reactive oxygen species assay and proteasome inhibition assay. Complex 1 induced low apoptosis, generated low level of ROS and did not inhibit proteasome in normal cells. The study of the DNA binding and nucleolytic properties of complexes 1-3 in the absence or presence of H2O2 or sodium ascorbate revealed that only complex 1 was not nucleolytic.

Matched MeSH terms: DNA Damage/drug effects
Fulltext Genotoxic effects of tobacco use in residents of hilly areas and foot hills of Western Ghats, Southern India

Chandirasekar R, Murugan K, Muralisankar T, Uthayakumar V, Jayakumar R, Mohan K, et al.

Sci Rep, 2019 Oct 17;9(1):14898.
PMID: 31624274 DOI: 10.1038/s41598-019-51275-w

Smoking and smokeless tobacco consumption is a significant risk factor that provokes genetic alterations. The present investigation was to evaluate the biomarkers of genotoxicity including micronucleus (MN), chromosome aberrations (CA) and DNA strand breaks among tobacco consumers and control individuals residing in hilly areas of Western Ghats, Tamilnadu, South India. This study included 268 tobacco consumers with equal number of controls. The tobacco consumers were divided into Group I (<10 years of tobacco consumption with an age range from 15 to 35 years) and group II (>10 years consumption above 35 years of age). Chromosome aberration (CA) and comet assay were performed using blood and micronucleus assay from exfoliated buccal epithelial cells obtained from tobacco consumers and controls. Elevated levels of CA were found in group II (Chromatid type: 2.39 ± 1.13 and chromosome type: 1.44 ± 1.24) exposed subjects, high micronucleus and DNA damage (TL:4.48 ± 1.24 and TM:3.40 ± 1.58) levels were significantly (p

Matched MeSH terms: DNA Damage/drug effects*
Metformin synergizes 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) combination therapy through impairing intracellular ATP production and DNA repair in breast cancer stem cells

Soo JS, Ng CH, Tan SH, Malik RA, Teh YC, Tan BS, et al.

Apoptosis, 2015 Oct;20(10):1373-87.
PMID: 26276035 DOI: 10.1007/s10495-015-1158-5

Metformin, an AMPK activator, has been reported to improve pathological response to chemotherapy in diabetic breast cancer patients. To date, its mechanism of action in cancer, especially in cancer stem cells (CSCs) have not been fully elucidated. In this study, we demonstrated that metformin, but not other AMPK activators (e.g. AICAR and A-769662), synergizes 5-fluouracil, epirubicin, and cyclophosphamide (FEC) combination chemotherapy in non-stem breast cancer cells and breast cancer stem cells. We show that this occurs through an AMPK-dependent mechanism in parental breast cancer cell lines. In contrast, the synergistic effects of metformin and FEC occurred in an AMPK-independent mechanism in breast CSCs. Further analyses revealed that metformin accelerated glucose consumption and lactate production more severely in the breast CSCs but the production of intracellular ATP was severely hampered, leading to a severe energy crisis and impairs the ability of CSCs to repair FEC-induced DNA damage. Indeed, addition of extracellular ATP completely abrogated the synergistic effects of metformin on FEC sensitivity in breast CSCs. In conclusion, our results suggest that metformin synergizes FEC sensitivity through distinct mechanism in parental breast cancer cell lines and CSCs, thus providing further evidence for the clinical relevance of metformin for the treatment of cancers.

Matched MeSH terms: DNA Damage/drug effects
Fulltext A ruthenium polypyridyl intercalator stalls DNA replication forks, radiosensitizes human cancer cells and is enhanced by Chk1 inhibition

Gill MR, Harun SN, Halder S, Boghozian RA, Ramadan K, Ahmad H, et al.

Sci Rep, 2016 08 25;6:31973.
PMID: 27558808 DOI: 10.1038/srep31973

Ruthenium(II) polypyridyl complexes can intercalate DNA with high affinity and prevent cell proliferation; however, the direct impact of ruthenium-based intercalation on cellular DNA replication remains unknown. Here we show the multi-intercalator [Ru(dppz)2(PIP)](2+) (dppz = dipyridophenazine, PIP = 2-(phenyl)imidazo[4,5-f][1,10]phenanthroline) immediately stalls replication fork progression in HeLa human cervical cancer cells. In response to this replication blockade, the DNA damage response (DDR) cell signalling network is activated, with checkpoint kinase 1 (Chk1) activation indicating prolonged replication-associated DNA damage, and cell proliferation is inhibited by G1-S cell-cycle arrest. Co-incubation with a Chk1 inhibitor achieves synergistic apoptosis in cancer cells, with a significant increase in phospho(Ser139) histone H2AX (γ-H2AX) levels and foci indicating increased conversion of stalled replication forks to double-strand breaks (DSBs). Normal human epithelial cells remain unaffected by this concurrent treatment. Furthermore, pre-treatment of HeLa cells with [Ru(dppz)2(PIP)](2+) before external beam ionising radiation results in a supra-additive decrease in cell survival accompanied by increased γ-H2AX expression, indicating the compound functions as a radiosensitizer. Together, these results indicate ruthenium-based intercalation can block replication fork progression and demonstrate how these DNA-binding agents may be combined with DDR inhibitors or ionising radiation to achieve more efficient cancer cell killing.

Matched MeSH terms: DNA Damage/drug effects
Fulltext Cellular Homeostasis and Antioxidant Response in Epithelial HT29 Cells on Titania Nanotube Arrays Surface

Smn Mydin RB, Sreekantan S, Hazan R, Farid Wajidi MF, Mat I

Oxid Med Cell Longev, 2017;2017:3708048.
PMID: 28337249 DOI: 10.1155/2017/3708048

Cell growth and proliferative activities on titania nanotube arrays (TNA) have raised alerts on genotoxicity risk. Present toxicogenomic approach focused on epithelial HT29 cells with TNA surface. Fledgling cell-TNA interaction has triggered G0/G1 cell cycle arrests and initiates DNA damage surveillance checkpoint, which possibly indicated the cellular stress stimuli. A profound gene regulation was observed to be involved in cellular growth and survival signals such as p53 and AKT expressions. Interestingly, the activation of redox regulator pathways (antioxidant defense) was observed through the cascade interactions of GADD45, MYC, CHECK1, and ATR genes. These mechanisms furnish to protect DNA during cellular division from an oxidative challenge, set in motion with XRRC5 and RAD50 genes for DNA damage and repair activities. The cell fate decision on TNA-nanoenvironment has been reported to possibly regulate proliferative activities via expression of p27 and BCL2 tumor suppressor proteins, cogent with SKP2 and BCL2 oncogenic proteins suppression. Findings suggested that epithelial HT29 cells on the surface of TNA may have a positive regulation via cell-homeostasis mechanisms: a careful circadian orchestration between cell proliferation, survival, and death. This nanomolecular knowledge could be beneficial for advanced medical applications such as in nanomedicine and nanotherapeutics.

Matched MeSH terms: DNA Damage/drug effects