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

Hegde, Mahesh; Vartak, Supriya V.; Kavitha, C.; Ananda, Hanumappa; Shivaramu, Prasanna D.; Gopalakrishnan, Vidya; Choudhary, Bibha; Rangappa, Kanchugarakoppal S.; Raghavan, Sathees C.

doi:10.1038/s41598-017-02489-3

Cited by 25 publications

(10 citation statements)

References 42 publications

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“…After 14 days of Disarib oral administration, two mice from each group were dissected as detailed above and the internal organs were collected. The tissues were fixed in 4% paraformaldehyde and processed according to published protocols 27 , 33 . For the current study, we have chosen kidney, liver and intestine from the control and higher dose (800, 1,200 and 2000 mg/kg body weight) treated groups for histological analyses.…”

Section: Methodsmentioning

confidence: 99%

Acute toxicity analysis of Disarib, an inhibitor of BCL2

Sharma

Varsha

Kumari

et al. 2020

Sci Rep

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Small molecule inhibitors targeting BCL2 are explored as anticancer therapeutics. Previously, we have reported identification and characterization of a novel BCL2 inhibitor, Disarib. Disarib induced cancer cell death in a BCL2 dependent manner in different cancer cell lines and mouse tumor models when it was administered intraperitoneally. In the present study, using two syngeneic mouse models, breast adenocarcinoma (EAC) and Dalton’s lymphoma (DLA), we show that oral administration of Disarib resulted in significant tumor regression in a concentration dependent manner. Importantly, tumor developed in both female and male mice were equally sensitive to Disarib. Further, we have investigated the toxicity of Disarib in normal cells. Single dose toxicity analysis of Disarib in male and female mice after oral administration revealed no significant variations compared to control group for parameters such as body weight, food and water consumption and behavioural changes which were analysed for the entire period of study. Haematological and histopathological analyses also did not show any significant difference from the control groups. Thus, our results reveal safe use of Disarib as a small molecule inhibitor and provide the foundation for investigation of other preclinical studies.

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Section: Methodsmentioning

confidence: 99%

Acute toxicity analysis of Disarib, an inhibitor of BCL2

Sharma

Varsha

Kumari

et al. 2020

Sci Rep

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“…Apoptosis serves an important role in the normal development and differentiation of multicellular organisms ( 13 , 14 ). Activation of apoptosis in cancer cells may contribute to the elimination of cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Apoptosis induced by ursodeoxycholic acid in human melanoma cells through the mitochondrial pathway

Huang

et al. 2018

Oncol Rep

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Ursodeoxycholic acid (UDCA) is a type of hydrophilic bile acid extracted from animal bile with a wide range of biological functions. The present results demonstrated that UDCA could effectively inhibit the proliferation of two human melanoma cell line (M14 and A375) with time- and concentration-dependence. Following exposure to various concentrations of UDCA, M14 cells exhibited typical morphological changes and weaker ability of colony forming. Flow cytometry analysis demonstrated that UDCA could induce a decrease of mitochondrial membrane potential and an increase in reactive oxygen species (ROS) levels in M14 cells. The cell cycle was arrested in the G2/M phase, which was confirmed by the decrease of cyclin-dependent kinase 1 and cyclinB1 at the protein level. However, when M14 cells were treated with UDCA and Z-VAD-FMK (caspase inhibitor) synchronously, the apoptosis rate of the cells was reduced significantly. In addition, it was demonstrated that UDCA induced apoptosis of human melanoma M14 cells through the ROS-triggered mitochondrial-associated pathway, which was indicated by the increased expression of cleaved-caspase-3, cleaved-caspase-9, apoptotic protease activating factor-1, cleaved-poly (ADP-ribose) polymerase 1 and the elevation of B cell lymphoma-2 (Bcl-2) associated X protein/Bcl-2 ratio associated with apoptosis. Therefore, UDCA may be a potential drug for the treatment of human melanoma.

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“…Following treatment with SCR7 (100 µM) alone or in conjunction with 0.25 Gy IR, Nalm6 cells (0.25×10 5 ) were cultured in six‐well plates for 24 h and processed for comet assay as described 55–57 . Refer to Supporting Information for details.…”

Section: Methodsmentioning

confidence: 99%

SCR7, an inhibitor of NHEJ can sensitize tumor cells to ionization radiation

Gopalakrishnan

Sharma

Ray

et al. 2021

Molecular Carcinogenesis

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Nonhomologous end joining (NHEJ), one of the major DNA double‐strand break repair pathways, plays a significant role in cancer cell proliferation and resistance to radio and chemotherapeutic agents. Previously, we had described a small molecule inhibitor, SCR7, which inhibited NHEJ in a DNA Ligase IV dependent manner. Here, we report that SCR7 potentiates the effect of γ‐radiation (IR) that induces DNA breaks as intermediates to eradicate cancer cells. Dose fractionation studies revealed that coadministration of SCR7 and IR (0.5 Gy) in mice Dalton's lymphoma (DLA) model led to a significant reduction in mice tumor cell proliferation, which was equivalent to that observed for 2 Gy dose when both solid and liquid tumor models were used. Besides, co‐treatment with SCR7 and 1 Gy of IR further improved the efficacy. Notably, there was no significant change in blood parameters, kidney and liver functions upon combinatorial treatment of SCR7 and IR. Further, the co‐treatment of SCR7 and IR resulted in a significant increase in unrepaired DSBs within cancer cells compared to either of the agent alone. Anatomy, histology, and other studies in tumor models confirmed the cumulative effects of both agents in activating apoptotic pathways to induce cytotoxicity by modulating DNA damage response and repair pathways. Thus, we report that SCR7 has the potential to reduce the side effects of radiotherapy by lowering its effective dose ex vivo and in mice tumor models, with implications in cancer therapy.

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

Cited by 25 publications

References 42 publications

Acute toxicity analysis of Disarib, an inhibitor of BCL2

Acute toxicity analysis of Disarib, an inhibitor of BCL2

Apoptosis induced by ursodeoxycholic acid in human melanoma cells through the mitochondrial pathway

SCR7, an inhibitor of NHEJ can sensitize tumor cells to ionization radiation

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