ABSTRACT
Triple negative breast cancer (TNBC) has long been a challenging disease owing to its high aggressive behaviour, poor prognosis and its limited treatment options. The growing demand of new therapeutics against TNBC enables us to examine the therapeutic efficiency of an emerging class of anticancer compounds, azapodophyllotoxin derivative (HTDQ), a nitrogen analogue of podophyllotoxin, using different biochemical, spectroscopic and computational approaches. The anticancer activities of HTDQ are studied by performing MTT assay in a dose depended manner on Triple negative breast cancer cells using MDA-MB-468 and MDA-MB-231 cell lines with IC50 value 937 nM and 1.13 µM respectively while demonstrating minimal effect on normal epithelial cells. The efficacy of HTDQ was further tested in 3D tumour spheroids formed by the human TNBC cell line MDA-MB468 and also the murine MMTV positive TNBC cell line 4 T1. The shrinkage that observed in the tumor spheroid clearly indicates that HTDQ remarkably decreases the growth of tumor spheroid thereby affirming its cytotoxicity. The 2D cell viability assay shows significant morphological alteration that possibly caused by the cytoskeleton disturbances. Hence the binding interaction of HTDQ with cytoskeleton protein tubulin, its effect on tubulin polymerisation as well as depolymerisation of preformed microtubules along with the conformational alternation in the protein itself have been investigated in detail. Moreover, the apoptotic effects of HTDQ have been examined using a range of apoptotic markers. HTDQ-treated cancer cells showed increased expression of cleaved PARP-1 and pro-caspase-3, suggesting activation of the apoptosis process. HTDQ also upregulated pro-apoptotic Bax expression while inhibiting anti-apoptotic Bcl2 expression, supporting its ability to induce apoptosis in cancer cells. Hence the consolidated biochemical and spectroscopic research described herein may provide enormous information to use azapodophyllotoxin as promising anticancer therapeutics for TNBC cells.
ABSTRACT
In recent years, understanding the mechanism of thermally activated delayed fluorescence (TADF) has become the primary choice for designing high-efficiency, low-cost, metal-free organic light emitting diodes (OLEDs). Herein, we propose a strategically designed chalcone based donor-acceptor system, where intensification of delayed fluorescence with decrease in temperature (300â K to 100â K) is observed; the theoretical investigations of electronic states and orbital characters uncovered a new cold rISC pathway in donor-acceptor system, where rISC occurs through the down-conversation of higher triplet exciton (from T3 ) to lowest singlet state (S1 ), having negative energy splitting, thus no thermal energy is required. The comprehensive research described herein might open-up new avenues in donor-acceptor system over the conventional up-convention of triplet exciton and demonstrates that not necessarily all delayed fluorescence are thermally activated (TADF).
ABSTRACT
The use of nanotechnology in nanoparticle-based cancer therapeutics is gaining impetus due to the unique biophysical properties of nanoparticles at the quantum level. Silver nanoparticles (AgNPs) have been reported as one type of potent therapeutic nanoparticles. The present study is aimed to determine the effect of AgNPs in arresting the growth of a murine fibrosarcoma by a reductive mechanism. Initially, a bioavailability study showed that mouse serum albumin (MSA)-coated AgNPs have enhanced uptake; therefore, toxicity studies of AgNP-MSA at 10 different doses (1-10 mg/kg b.w.) were performed in LACA mice by measuring the complete blood count, lipid profile and histological parameters. The complete blood count, lipid profile and histological parameter results showed that the doses from 2 to 8 mg (IC50: 6.15 mg/kg b.w.) sequentially increased the count of leukocytes, lymphocytes and granulocytes, whereas the 9- and 10-mg doses showed conclusive toxicity. In an antitumor study, the incidence and size of fibrosarcoma were reduced or delayed when murine fibrosarcoma groups were treated by AgNP-MSA. Transmission electron micrographs showed that considerable uptake of AgNP-MSA by the sentinel immune cells associated with tumor tissue and a morphologically buckled structure of the immune cells containing AgNP-MSA. Because the toxicity studies revealed a relationship between AgNPs and immune function, the protumorigenic cytokines TNF-α, IL-6 and IL-1ß were also assayed in AgNP-MSA-treated and non-treated fibrosarcoma groups, and these cytokines were found to be downregulated after treatment with AgNP-MSA.