Enhanced Efficacy of Pluronic Copolymer Micelle Encapsulated SCR7 against Cancer Cell Proliferation

John, Franklin; George, Jinu; Vartak, Supriya V.; Srivastava, Mrinal; Hassan, P. A.; Aswal, Vinod K.; Karki, Subhas S.; Raghavan, Sathees C.

doi:10.1002/mabi.201400480

Cited by 31 publications

(34 citation statements)

References 68 publications

(107 reference statements)

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“…Since NHEJ inhibitors can block residual DSB repair following irradiation, this is considered as an ideal strategy to improve the efficacy of radiotherapy and, in some instances, chemotherapy. Previously, we showed that SCR7 could improve radio and chemosensitivity in mice tumor models and cancer cell lines . Interestingly, we noted that treatment with SCR7‐cyclized or SCR7‐pyrazine along with radiation resulted in elevated levels of DSBs, which was higher than either of the agents alone.…”

Section: Discussionmentioning

confidence: 88%

Autocyclized and oxidized forms of SCR7 induce cancer cell death by inhibiting nonhomologous DNA end joining in a Ligase IV dependent manner

et al. 2018

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Nonhomologous DNA end joining (NHEJ) is the major DNA double-strand break (DSB) repair pathway in mammals. Previously, we have described a small molecule inhibitor, SCR7, which can inhibit NHEJ in a Ligase IV-dependent manner. Administration of SCR7 within the cells resulted in the accumulation of DNA breaks, cell death, and inhibition of tumor growth in mice. In the present study, we report that parental SCR7, which is unstable, can be autocyclized into a stable form. Both parental SCR7 and cyclized SCR7 possess the same molecular weight (334.09) and molecular formula (C H N OS), whereas its oxidized form, SCR7-pyrazine, possesses a different molecular formula (C H N OS), molecular weight (332.07), and structure. While cyclized form of SCR7 showed robust inhibition of NHEJ in vitro, both forms exhibited efficient cytotoxicity. Cyclized and oxidized forms of SCR7 inhibited DNA end joining catalyzed by Ligase IV, whereas their impact was minimal on Ligase III, Ligase I, and T4 DNA Ligase-mediated joining. Importantly, both forms inhibited V(D)J recombination, although the effect was more pronounced for SCR7-cyclized. Both forms blocked NHEJ in a Ligase IV-dependent manner leading to the accumulation of DSBs within the cells. Although cytotoxicity due to SCR7-cyclized was Ligase IV specific, the pyrazine form exhibited nonspecific cytotoxicity at higher concentrations in Ligase IV-null cells. Finally, we demonstrate that both forms can potentiate the effect of radiation. Thus, we report that cyclized and oxidized forms of SCR7 can inhibit NHEJ in a Ligase IV-dependent manner, although SCR7-pyrazine is less specific to Ligase IV inside the cell.

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Section: Discussionmentioning

confidence: 88%

Autocyclized and oxidized forms of SCR7 induce cancer cell death by inhibiting nonhomologous DNA end joining in a Ligase IV dependent manner

et al. 2018

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“…Cell cycle analysis was carried out as described previously 38, 39 . Initially, effect of 5g (0, 10, 20 and 30 µM) on Nalm6, REH, K562, Molt4, MCF7 and EAC cells were tested at 24 h time point.…”

Section: Methodsmentioning

confidence: 99%

“…Detection of γ-H2AX foci in Nalm6 and HeLa cells post 5g treatment was performed as described previously 39, 40 . In brief, cells (50,000/ml) were seeded on coverslips and treated with 5g (10 and 30 µM for 24 h), followed by harvesting and fixing of the cells using 4% paraformaldehyde for 10′ at room temperature.…”

Section: Methodsmentioning

confidence: 99%

A Benzothiazole Derivative (5g) Induces DNA Damage And Potent G2/M Arrest In Cancer Cells

Hegde

Vartak

Kavitha

et al. 2017

Sci Rep

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Chemically synthesized small molecules play important role in anticancer therapy. Several chemical compounds have been reported to damage the DNA, either directly or indirectly slowing down the cancer cell progression by causing a cell cycle arrest. Direct or indirect reactive oxygen species formation causes DNA damage leading to cell cycle arrest and subsequent cell death. Therefore, identification of chemically synthesized compounds with anticancer potential is important. Here we investigate the effect of benzothiazole derivative (5g) for its ability to inhibit cell proliferation in different cancer models. Interestingly, 5g interfered with cell proliferation in both, cell lines and tumor cells leading to significant G2/M arrest. 5g treatment resulted in elevated levels of ROS and subsequently, DNA double-strand breaks (DSBs) explaining observed G2/M arrest. Consistently, we observed deregulation of many cell cycle associated proteins such as CDK1, BCL2 and their phosphorylated form, CyclinB1, CDC25c etc. Besides, 5g treatment led to decreased levels of mitochondrial membrane potential and activation of apoptosis. Interestingly, 5g administration inhibited tumor growth in mice without significant side effects. Thus, our study identifies 5g as a potent biochemical inhibitor to induce G2/M phase arrest of the cell cycle, and demonstrates its anticancer properties both ex vivo and in vivo.

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“…In conjugation with DSB-inducing agents, SCR7 has tremendous therapeutic value in cancer cells and with respect to genome editing in normal cells [143,[145][146][147]. It was recently reported that SCR7 in an encapsulated form possesses five times more activity than the un-encapsulated drug [148,149].…”

Section: Repair Processesmentioning

confidence: 99%

Snaps and mends: DNA breaks and chromosomal translocations

Javadekar

Raghavan

2015

The FEBS Journal

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Integrity in entirety is the preferred state of any organism. The temporal and spatial integrity of the genome ensures continued survival of a cell. DNA breakage is the first step towards creation of chromosomal translocations. In this review, we highlight the factors contributing towards the breakage of chromosomal DNA. It has been well‐established that the structure and sequence of DNA play a critical role in selective fragility of the genome. Several non‐B‐DNA structures such as Z‐DNA, cruciform DNA, G‐quadruplexes, R loops and triplexes have been implicated in generation of genomic fragility leading to translocations. Similarly, specific sequences targeted by proteins such as Recombination Activating Genes and Activation Induced Cytidine Deaminase are involved in translocations. Processes that ensure the integrity of the genome through repair may lead to persistence of breakage and eventually translocations if their actions are anomalous. An insufficient supply of nucleotides and chromatin architecture may also play a critical role. This review focuses on a range of events with the potential to threaten the genomic integrity of a cell, leading to cancer.

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Enhanced Efficacy of Pluronic Copolymer Micelle Encapsulated SCR7 against Cancer Cell Proliferation

Cited by 31 publications

References 68 publications

Autocyclized and oxidized forms of SCR7 induce cancer cell death by inhibiting nonhomologous DNA end joining in a Ligase IV dependent manner

Autocyclized and oxidized forms of SCR7 induce cancer cell death by inhibiting nonhomologous DNA end joining in a Ligase IV dependent manner

A Benzothiazole Derivative (5g) Induces DNA Damage And Potent G2/M Arrest In Cancer Cells

Snaps and mends: DNA breaks and chromosomal translocations

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