Benzisothiazolone Derivatives Exhibit Cytotoxicity in Hodgkin’s Lymphoma Cells through NF-ҡB Inhibition and are Synergistic with Doxorubicin and Etoposide

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Author(s): Natarajan Nandakumar, Pushparathinam Gopinath, Jacob Gopas*, Kannoth M. Muraleedharan*.

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

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Background: We have investigated the NF-ҡB inhibitory role of three Benzisothiazolone (BIT) derivatives (1, 2 and 3) in Hodgkin’s Lymphoma cells (L428) which constitutively express activated NF-ҡB. All three compounds show dose dependent NF-ҡB inhibition (78.3, 70.7 and 34.6%) in a luciferase reporter gene assay and are cytotoxic at IC50 values of 3.3µg/ml, 4.35µg/ml and 13.8µg/ml respectively by XTT assay. BIT 1 and BIT 2 (but not BIT 3) suppress both NF-ҡB subunits p50 and p65 in cytoplasmic and nuclear extracts in a concentration dependent manner. Furthermore, BIT 1 shows moderate synergistic effect with the standard chemotherapy drugs etoposide, and doxorubicin, whereas BIT 2 and 3 showed moderate additive effect to antagonistic effect. Cisplatin exhibited antagonist effect for all the compounds tested under various concentrations, except in the case of 1.56µg/ml of BIT 3 with 0.156µg/ml of cisplatin. The compounds also inhibit the migration of adherent human lung adenocarcinoma cells (A549) cells in vitro. We conclude that especially BIT 1 and BIT 2 have in vitro anti-inflammatory and anti-cancer activity, with future potential therapeutic use.

Methods: Inspired by the electrophilic sulphur in Nuphar alkaloids, monomeric and dimeric Benzisothiazolones were synthesized from dithiodibenzoic acid and their NF-ҡB inhibitory role have been explored. Using luciferase reporter gene assay and XTT, its NF-ҡB inhibition and cytotoxicity were studied. Immunocytochemistry studies were performed using L428 cells. Cell migration assay was done using A549 cell line. L428 cells were used to conduct combination studies and plotted using CompuSyn software.

Results: Benzisothiazolone derivatives exhibit cytotoxicity in Hodgkin’s Lymphoma cells through NF-ҡB inhibition. Potent compound showed suppression of both NF-ҡB subunits p50 and p65 in a concentration dependent manner, both in cytoplasmic and nuclear extracts. Combination studies suggests that benzisothiazolone possess synergistic effect with etoposide and doxorubicin. Furthermore, the compounds also inhibits the migration of A549 cells.

Conclusion: Benzisothiazolones bearing one or two electrophilic sulfur as part of the heterocyclic framework possess cytotoxicity through NF-ҡB. In addition it also exhibits synergistic effect with etoposide and doxorubicin along with its ability to inhibit the migration of A549 cells. Our study suggests that BIT based new chemical entities could lead to potential anticancer agents.

Keywords: Benzisothiazolones, NF-ҡB, Combination studies, Anticancer, Hodgkin’s Lymphoma, Etoposide

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(E-pub Ahead of Print)
DOI: 10.2174/1871520620666200213103513
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