Cancer cells use elevated glutathione (GSH) levels as an inner line of defense to evade apoptosis and develop drug resistance.Inthis study,wedescribe anovel 2,4-nitrobenzenesulfonyl (DNS) protected 2-hydroxyisophthalamide system that exploits GSH for its activation into free 2-hydroxyisophthalamide forming supramolecular M + /Cl À channels.Better permeation of the DNS protected compound into MCF-7 cells compared to the free 2-hydroxyisophthalamide and GSHactivatable ion transport resulted in higher cytotoxicity,w hich was associated with increased oxidative stress that further reduced the intracellular GSH levels and altered mitochondrial membrane permeability leading to the induction of the intrinsic apoptosis pathway.T he GSH-activatable transport-mediated cell death was further validated in rat insulinoma cells (INS-1E);w herein the intracellular GSH levels showed ad irect correlation to the resulting cytotoxicity.L astly,t he active compound was found to restrict the growth and proliferation of 3D spheroids of MCF-7 cells with efficiency similar to that of the anticancer drug doxorubicin.Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under https://doi.
Cancer cells use elevated glutathione (GSH) levels as an inner line of defense to evade apoptosis and develop drug resistance. In this study, we describe a novel 2,4‐nitrobenzenesulfonyl (DNS) protected 2‐hydroxyisophthalamide system that exploits GSH for its activation into free 2‐hydroxyisophthalamide forming supramolecular M+/Cl− channels. Better permeation of the DNS protected compound into MCF‐7 cells compared to the free 2‐hydroxyisophthalamide and GSH‐activatable ion transport resulted in higher cytotoxicity, which was associated with increased oxidative stress that further reduced the intracellular GSH levels and altered mitochondrial membrane permeability leading to the induction of the intrinsic apoptosis pathway. The GSH‐activatable transport‐mediated cell death was further validated in rat insulinoma cells (INS‐1E); wherein the intracellular GSH levels showed a direct correlation to the resulting cytotoxicity. Lastly, the active compound was found to restrict the growth and proliferation of 3D spheroids of MCF‐7 cells with efficiency similar to that of the anticancer drug doxorubicin.
Multifunctional organic luminogens
exhibiting simultaneous aggregation
induced emission (AIE), room-temperature phosphorescence (RTP), and
mechanochromism have recently attracted considerable attention owing
to their potential applications in optoelectronics and bioimaging.
However, a comprehensive correlation among these three distinguished
properties is yet to be unveiled, which will help to decipher defined
methodologies to design future generation multifunctional organic
materials. Herein, we have demonstrated a route to obtain a multifunctional
organic luminogen, starting from an ACQphore (TPANDI) by simple structural
engineering. We have shown that a slight reduction in length of the
planar acceptor moieties can effectively inhibit the undesirable π–π
stacking interaction between molecules in the condensed state and
thereby cause an ACQ to AIE type transformation from TPANDI to TPANMI
and TPAPMI. Both TPANMI and TPAPMI exhibit RTP properties (even in
ambient condition) because of the presence of a reasonably low singlet–triplet
energy gap (ΔE
ST). In our study,
these two luminogens were found to be mechano-inactive. Interestingly,
an insertion of cyano-ethylene group and benzene linker in between
the triphenylamine and phthalimide moieties introduced another luminogen
TPACNPMI, which can simultaneously exhibit AIE, RTP, and mechanochromic
properties.
Lipid species are known to have various biological functions owing to their structural differences, and each of them possesses a specific role to play depending upon their location and distribution in the cell. Some of these lipids interact with proteins on the cell membrane and acts as second messengers. The level of lipid mediators is generally maintained in the cell by feedback mechanisms; however, their improper degradation or enhanced production leads to their accumulation in the tumor microenvironment and disturbs the homeostasis of the cell. Platelet activating factor (PAF) is a known phospholipid mediator secreted upon immunological challenges by platelets, neutrophils, basophils, and macrophages. PAF, as a potent inflammatory molecule, is well studied, and its role in various cancers and cardiovascular diseases has also been investigated. Interestingly, increased levels of PAF have been found in the blood plasma of smokers, and breast cancer cells have shown the accumulation of PAF in presence of cigarette smoke extract. This accumulation was found to increase tumor cell motility that in turn could promote metastasis. Beyond this, however, the effect of PAF on tumorigenesis has not yet been well explored. Here, we show that the continuous exposure of 3D breast acinar cultures to PAF resulted in the activation of various oncogenic signaling pathways leading to transformation. We also found that the presence of PAF in the micro-environment increased the expression of PAF receptor (PAF-R), which corroborated with the higher expression of PAF-R detected in some epithelial cancers, as per literature. Thus, this study impresses on the fact that the presence of PAF alters the cellular microenvironment and eventually triggers irreversible effects that can cumulatively lead to transformation.
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