Inhibition of DNA Damage Response Pathway Using Combination of DDR Pathway Inhibitors and Radiation in Treatment of Acute Lymphoblastic Leukemia Cells

Katoueezadeh, Maryam; Pilehvari, Niloofar; Fatemi, Ahmad; Hassanshahi, Gholamhossein; Torabizadeh, Seyedeh Atekeh

doi:10.2217/fon-2020-1072

Cited by 4 publications

(1 citation statement)

References 65 publications

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“…The effect of the synthesized compounds to inhibit the cancer cell’s DNA damage response (DDR) signalling pathway, a common pathway preferred by cancer cells to ensure genomic integrity, as well as cell viability [ 51 ], was analyzed by carrying out an immunoblot assay for one of the major kinases involved in the regulation of the pathway. Ataxia telangiectasia mutated and Rad-3 related (ATR) kinase, a member of the the PIKK (phosphatidylinositol-3-kinase-related kinases) family, are involved in the phosphorylation of Ser/Thr residues of its downstream substrate Chk1.…”

Section: Resultsmentioning

confidence: 99%

Benzothiazole and Chromone Derivatives as Potential ATR Kinase Inhibitors and Anticancer Agents

et al. 2022

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Despite extensive studies and the great variety of existing anticancer agents, cancer treatment remains an aggravating and challenging problem. Therefore, the development of novel anticancer drugs with a better therapeutic profile and fewer side effects to combat this persistent disease is still necessary. In this study, we report a novel series of benzothiazole and chromone derivatives that were synthesized and evaluated for their anticancer activity as an inhibitor of ATR kinase, a master regulator of the DDR pathway. The cell viability of a set of 25 compounds was performed using MTT assay in HCT116 and HeLa cell lines, involving 72 h incubation of the compounds at a final concentration of 10 µM. Cells incubated with compounds 2c, 7h and 7l were found to show viability ≤50%, and were taken forward for dose–response studies. Among the tested compounds, three of them (2c, 7h and 7l) showed higher potency, with compound 7l exhibiting the best IC50 values in both the cell lines. Compounds 2c and 7l were found to be equally cytotoxic towards both the cell lines, namely, HCT116 and HeLa, while compound 7h showed better cytotoxicity towards HeLa cell line. For these three compounds, an immunoblot assay was carried out in order to analyze the inhibition of phosphorylation of Chk1 at Ser 317 in HeLa and HCT116 cells. Compound 7h showed inhibition of pChk1 at Ser 317 in HeLa cells at a concentration of 3.995 µM. Further analysis for Chk1 and pChk1 expression was carried out in Hela cells by treatment against all the three compounds at a range of concentrations of 2, 5 and 10 µM, wherein compound 7h showed Chk1 inhibition at 2 and 5 µM, while pChk1 expression was observed for compound 7l at a concentration of 5 µM. To support the results, the binding interactions of the compounds with the ATR kinase domain was studied through molecular docking, wherein compounds 2c, 7h and 7l showed binding interactions similar to those of Torin2, a known mTOR/ATR inhibitor. Further studies on this set of molecules is in progress for their specificity towards the ATR pathway.

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Section: Resultsmentioning

confidence: 99%

Benzothiazole and Chromone Derivatives as Potential ATR Kinase Inhibitors and Anticancer Agents

et al. 2022

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Combinatorial targeting of telomerase and DNA-PK induces synergistic apoptotic effects against Pre-B acute lymphoblastic leukemia cells

Katoueezadeh,

Maleki,

Torabizadeh

et al. 2024

Mol Biol Rep

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Indole-3-carbinol (I3C) as Leukemia Therapeutic Agents: Review

Karimabad

Mohamadi

Torabizadeh

et al. 2023

MRMC

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Leukemia or blood cancer was initially discovered in 1845 and this malignancy was reported in patients who had an amplified number of blood cells, in particular, white blood cells (WBC), due to this disease. The event of leukemia was further identified as a malignant hematopoietic disorder due to both uncontrolled and unlimited proliferation in combination with lack of differentiation of the leukemic stem cells.Furethermore, 75 to 80% of the global population use herbal remedies as primary therapy, mainly because of their better efficiency and satisfaction, which elevate the human body symmetry with the minimum unwanted adverse effects. For the control of cancer, plant products, and fruits have been considered promising tools and are being consumed for centuries. Several plant extracts are also being used for the therapy and prevention of different types of known cancers. Indole-3-carbinol (I3C) is a natural material obtained from Brassica diversity of vegetables and has been reported to serve as a promising cancer preventative agent. In the present review, theauthors mainly tried to focus and emphasize I3C applications in the leukemia treatment.

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Inhibition of DNA Damage Response Pathway Using Combination of DDR Pathway Inhibitors and Radiation in Treatment of Acute Lymphoblastic Leukemia Cells

Cited by 4 publications

References 65 publications

Benzothiazole and Chromone Derivatives as Potential ATR Kinase Inhibitors and Anticancer Agents

Benzothiazole and Chromone Derivatives as Potential ATR Kinase Inhibitors and Anticancer Agents

Combinatorial targeting of telomerase and DNA-PK induces synergistic apoptotic effects against Pre-B acute lymphoblastic leukemia cells

Indole-3-carbinol (I3C) as Leukemia Therapeutic Agents: Review

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