Gastrointestinal disturbances, such as nausea and vomiting, are considered amongst the main adverse effects associated with oral anticancer drugs due to their fast release in the gastrointestinal tract (GIT). Sustained release formulations with proper release profiles can overcome some side effects of conventional formulations. The current study was designed to prepare sustained release tablets of Capecitabine, which is approved by the Food and Drug Administration (FDA) for the treatment of advanced breast cancer, using hydroxypropyl methylcellulose (HPMC), carbomer934P, sodium alginate, and sodium bicarbonate. Tablets were prepared using the wet granulation method and characterized such that floating lag time, total floating time, hardness, friability, drug content, weight uniformity, and in vitro drug release were investigated. The sustained release tablets showed good hardness and passed the friability test. The tablets' floating lag time was determined to be 30-200 seconds, and it floated more than 24 hours and released the drug for 24 hours. Then, the stability test was done and compared with the initial samples. In conclusion, by adjusting the right ratios of the excipients including release-retarding gel-forming polymers like HPMC K4M, Na alginate, carbomer934P, and sodium bicarbonate, sustained release Capecitabine floating tablet was formulated.
Imatinib mesylate is an anti‑neoplastic targeted chemotherapeutic agent, which can inhibit tyrosine kinase receptors, including BCR‑ABL, platelet‑derived growth factor receptors (PDGFRs) and c‑Kit. Cellular processes, including differentiation, proliferation and survival are regulated by these receptors. The present study aimed to evaluate the antiproliferative effects of imatinib mesylate, and its effects on apoptotic induction and cell cycle arrest in breast cancer cell lines. In addition, the study aimed to determine whether the effects of this drug were associated with the mRNA and protein expression levels of PDGFR‑β, c‑Kit, and their corresponding ligands PDGF‑BB and stem cell factor (SCF), which may potentially modulate cell survival and proliferation. To assess the antiproliferative effects of imatinib mesylate, an MTS assay was conducted following treatment of cells with 2‑10 µM imatinib mesylate for 96, 120 and 144 h; accordingly the half maximal inhibitory concentration of imatinib mesylate was calculated for each cell line. In addition, the proapoptotic effects and cytostatic activity of imatinib mesylate were investigated. To evaluate the expression of imatinib‑targeted genes, PDGFR‑β, c‑Kit, PDGF‑BB and SCF, under imatinib mesylate treatment, mRNA expression was detected using semi‑quantitative polymerase chain reaction and protein expression was detected by western blot analysis in ZR‑75‑1 and MDA‑MB‑231 breast carcinoma cell lines. Treatment with imatinib mesylate suppressed cell proliferation, which was accompanied by apoptotic induction and cell cycle arrest in the investigated cell lines. In addition, PDGFR‑β, PDGF‑BB, c‑Kit and SCF were expressed in both breast carcinoma cell lines; PDGFR‑β and c‑Kit, as imatinib targets, were downregulated in response to imatinib mesylate treatment. The present results revealed that at least two potential targets of imatinib mesylate were expressed in the two breast carcinoma cell lines studied. In conclusion, the antiproliferative, cytostatic and proapoptotic effects of imatinib mesylate may be the result of a reduction in the expression of c‑Kit and PDGFR tyrosine kinase receptors, thus resulting in suppression of the corresponding ligand PDGF‑BB. Therefore, imatinib mesylate may be considered a promising target therapy for the future treatment of breast cancer.
Ferulago angulata leaf hexane extract (FALHE) was found to be a potent inducer of MCF7 cell apoptosis. The aims of the present study were to investigate the in vivo chemopreventive effect of FALHE in rats, to identify the contributing anticancer compound in FALHE and to determine its potential mechanism of action against MCF7 cells. Thirty rats harboring LA7-induced breast tumors were divided into five groups: tumor control, low-dose FALHE, high-dose FALHE, treatment control (tamoxifen) and normal control. Breast tissues were then subjected to histopathological and immunohistochemical analyses. A bioassay-guided investigation on FALHE was performed to identify the cytotoxic compound and its mechanism of action through flow cytometry, real-time qPCR and western blotting analyses. An in vivo study showed that FALHE suppressed the expression of the tumor markers PCNA and Ki67. The tumor size was reduced from 2031 ± 281 mm3 to 432 ± 201 mm3 after FALHE treatment. FALHE administration induced apoptosis in breast tumor cells, and this was confirmed by high expression levels of Bax, p53 and caspase 3. Cell cycle arrest was suggested by the expression of p21 and p27. The in vitro experimental results resulted in the isolation of polycerasoidin as a bioactive ingredient of FALHE with an IC50 value of 3.16 ± 0.31 μg/ml against MCF7 cells. Polycerasoidin induced mitochondrial-dependent apoptosis in breast cancer cells via caspase activation and changes in the mRNA and protein expression of Bax and Bcl-2. In addition, flow cytometric analysis demonstrated that the treated MCF7 cells were arrested at the G1 phase, and this was associated with the up-regulation of p21 and p27 at both the mRNA and protein levels. The results of the present study reinforce further investigations scrutinizing the promising potential of the F. angulata chemical constituents as breast cancer chemopreventive agents.
Columbin, a diterpenoid furanolactone, was isolated purely for the first time from the plant species Tinspora bakis. The anti-inflammatory effects of columbin were studied in vitro, in silico and in vivo. The effect of columbin on nitric oxide was examined on lipopolysaccharide-interferon-gamma (LPS/IFN) induced RAW264.7 macrophages. In vitro and in silico cyclooxygenase-1 and cyclooxygenase-2 inhibitory activities of columbin using biochemical kit and molecular docking, respectively, were investigated. Mechanism of columbin in suppressing NF-kappaB-translocation was tested using Cellomics®NF-κB activation assay and ArrayScan Reader in LPS-stimulated RAW264.7 cells. Moreover, effects of columbin in vivo that were done on carrageenan-induced mice paw-oedema were tested. Lastly, the in vitro and in vivo toxicities of columbin were examined on human liver cells and mice, respectively. Treatment with columbin or N(ω)-nitro-l-arginine methyl ester (l-NAME) inhibited LPS/IFN-γ-induced NO production without affecting the viability of RAW264.7. Pre-treatment of stimulated cells with columbin did not inhibit the translocation of NF-κB to the nucleus in LPS-stimulated cells. COX-1 and COX-2 inhibitory activities of columbin were 63.7±6.4% and 18.8±1.5% inhibition at 100μM, respectively. Molecular docking study further helped in supporting the observed COX-2 selectivity. Whereby, the interaction of columbin with Tyr385 and Arg120 signifies its higher activity in COX-2, as Tyr385 was reported to be involved in the abstraction of hydrogen from C-13 of arachidonate, and Arg120 is critical for high affinity arachidonate binding. Additionally, columbin inhibited oedema formation in mice paw. Lastly, the compound was observed to be safe in vitro and in vivo. This study presents columbin as a potential anti-inflammatory drug.