Background:
The authors investigated the NF-κB inhibitory role of three Benzisothiazolone (BIT)
derivatives (1, 2 and 3) in Hodgkin’s Lymphoma cells (L428) which constitutively express activated NF-κB. All
three compounds showed dose-dependent NF-κB inhibition (78.3, 70.7 and 34.6%) in the luciferase reporter
gene assay and were found cytotoxic at IC50 values of 3.3μg/ml, 4.35μg/ml and 13.8μg/ml, respectively by the
XTT assay. BIT 1and BIT 2 (but not BIT 3) suppressed both NF-κB subunits p50 and p65 in cytoplasmic and
nuclear extracts in a concentration-dependent manner. Furthermore, BIT 1 showed a moderate synergistic effect
with the standard chemotherapy drugs etoposide and doxorubicin, whereas BIT 2 and 3 showed a moderate
additive effect to antagonistic effect. Cisplatin exhibited an antagonist effect on 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 inhibited the migration of adherent human lung adenocarcinoma cells (A549) in vitro. We conclude that
especially BIT 1 and BIT 2 have in vitro anti-inflammatory and anti-cancer activities, which can be further
investigated for future potential therapeutic use.
Methods:
Inspired by the electrophilic sulfur in Nuphar alkaloids, monomeric and dimeric benzisothiazolones
were synthesized from dithiodibenzoic acid and their NF-κB inhibitory role was explored. NF-κB inhibition and
cytotoxicity of the synthesized derivatives were studied using luciferase reporter gene assay and XTTassay.
Immunocytochemistry studies were performed using L428 cells. Cell migration assay was conducted using the
A549 cell line. L428 cells were used to conduct combination studies and the results were plotted using
CompuSyn software.
Results:
Benzisothiazolone derivatives exhibited cytotoxicity in Hodgkin’s Lymphoma cells through NF-κB
inhibition. Potent compounds showed suppression of both NF-κB subunits p50 and p65 in a concentrationdependent
manner, both in cytoplasmic and nuclear extracts. Combination studies suggest that benzisothiazolone
derivatives possess a synergistic effect with etoposide and doxorubicin. Furthermore, the compounds
also inhibited the migration of A549 cells.
Conclusion:
Benzisothiazolones bearing one or two electrophilic sulfur atoms as part of the heterocyclic
framework exhibited cytotoxicity in Hodgkin’s Lymphoma cells through NF-κB inhibition. In addition, these
derivatives also exhibited a synergistic effect with etoposide and doxorubicin along with the ability to inhibit the
migration of A549 cells. Our study suggests that BIT-based new chemical entities could lead to potential anticancer
agents.
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