RESUMO
Chemoresistance is one of the major factors for treatment failure in OSCC. Reprogramming chemoresistance cells to undergo drug induced apoptotic cell death is a feasible approach to overcome drug resistance. Cyanobacteria is considered important sources of lead compounds for the development of drugs for treating cancer chemoresistance. This study deals with the role of Tolypothrix Dichloromethane Ethyl acetate fraction (TDEF) inducing apoptosis in cisplatin resistance H357 cell (H357cisR) and the underlying mechanisms sensitizing the chemoresistance. TDEF showing effective activity against H357cisR with IC50-14.13±1.18 µg mL-1, inhibits proliferation and migration. Proteome apoptosis arrays were found to stimulate phosphorylation of p53, activation of proapoptotic proteins including BAX and cytochrome C (CYCS), caspase-3/9 (CASP3/9), suppression of anti-apoptotic proteins like Bcl2, survivin and increased expression of the cell cycle checkpoint protein p21, p27. TDEF induced apoptosis with cell death-transducing signals, that regulate the Matrix metalloproteinases (MMPs) by down-regulation of Bcl2 and up-regulation of Bax, triggering the cytochrome c release from mitochondria to cytosol thus triggered the activation of caspases-9 to activate downstream executioner caspase-3/7 required for apoptotic changes. The mechanistic pathway of apoptotic cell death in H357cisR was done through inhibiting ß-catenin through GSK3ß in turn activated by AKT. The phosphorylated ß-catenin leads to proteasome degradation and unable to translocation to nucleus thereby activating c-Myc, survivin, Cyclin D and upregulate p21 expression which lead to cell cycle arrest in G0/G1 phase.
RESUMO
Terminalia chebula Retz. (Fam. Combretaceae), locally called Manahei, is a well-known medicinal plant that grows wildly in Manipur, a Northeastern state of India. It is used as a mild laxative, an anti-inflammatory agent, and a remedy for piles, colds, and ulcers by ethnic communities of the state. The hydroalcoholic extract obtained from four fruit samples of T. chebula collected from different locations in Manipur were analyzed using gas chromatography-mass spectrometry (GC-MS) and high-performance thin-layer chromatography (HPTLC) for their chemical constituents and evaluated for their anticancer activity against the colon cancer cell HCT 116. GC-MS analysis results indicated significant variation in the composition and percentage of major compounds present in the extracts. 1,2,3-Benzenetriol was the most abundant chemical constituent present in all four extracts of T. chebula, ranging from 20.95 to 43.56%. 2-Cyclopenten-1-one, 5-hydroxymethylfurfural, and catechol were commonly present in all extracts. Two marker compounds, gallic acid and ellagic acid, were also quantified usingHPTLC in all four extracts of T. chebula. The highest content of gallic acid (22.44 ± 0.056 µg/mg of dried extract) was observed in TCH, and that of ellagic acidwas found in TYH (11.265 ± 0.089 µg/mg of dried extract). The IC50 value of TYH for the DPPH and ABTS assays (12.16 ± 0.42 and 7.80 ± 0.23 µg/mL) was found to be even lower than that of Trolox (18 ± 0.44 and 10.15 ± 0.24 µg/mL), indicating its strong antioxidant properties among the four extracts of T. chebula. The MTT assay determined the effect of T. chebula extracts on the viability of HCT 116 cells. TYH showed the highest activity with anIC50 value of 52.42 ± 0.87 µg/mL, while the lowest activity was observed in TCH (172.05 ± 2.0 µg/mL). The LDH assay confirmed the cytotoxic effect of TYH in HCT 116 cells. TYH was also found to induce caspase-dependent apoptosis in HCT 116 cells after 48 h of treatment. Our study provides insight into the diversity of T. chebula in Manipur and its potential activity against colon cancer.