Kaffir lime (Citrus hystrix) is a plant member of family Rutaceae, and its leaves are commonly used in folk medicine. The present study explores antileukemic effects of the extracts and purified active compounds from the leaves. The antileukemic activity was investigated via inhibition of Wilms’ tumor 1 (WT1), which is a protein that involves in leukemic cell proliferation. In addition, the compounds were investigated for their effects on WT1 gene expression using real time RT-PCR and Western blotting. Cell cycle arrest and total cell number were investigated using flow cytometry and trypan blue exclusion method, respectively. The results demonstrated that the hexane fractionated extract had the greatest inhibitory effect on WT1 gene expression of many leukemic cell lines and significantly decreased WT1 protein levels of K562 cells (representative of the leukemic cells), in a dose- and time-dependent manner. Subfraction No. 9 (F9) after partial purification of hexane fractioned extract showed the highest suppression on WT1 protein and suppressed cell cycle at G2/M. The organic compounds were isolated from F9 and identified as phytol and lupeol. The bioassays confirmed antiproliferative activities of natural products phytol and lupeol. The results demonstrated anticancer activity of the isolated phytol and lupeol to decrease leukemic cell proliferation.
Zingiber ottensii, is widely used in Asian traditional remedies for the treatment of many diseases. The present study explores anticancer activity of Z. ottensii essential oil (ZOEO) and its nanoformulations. ZOEO obtained from hydrodistillation of Z. ottensii fresh rhizomes was analysis using gas chromatography mass spectroscopy. Zerumbone (25.21%) was the major compound of ZOEO followed by sabinene (23.35%) and terpene-4-ol (15.97%). Four types of ZOEO loaded nanoformulations; nanoemulsion, microemulsion, nanoemulgels, and microemulgel, were developed. The average droplet size of the nanoemulsion and microemulsion was significantly smaller than that of the nanoemulgel and microemulgel. Comparison with other essential oils of plants of the same family on anticancer activity against A549, MCF-7, HeLa, and K562, ZOEO showed the highest cytotoxicity with IC50 of 43.37±6.69, 9.77±1.61, 23.25±7.73, and 60.49±9.41 μg/mL, respectively. Investigation using flow cytometry showed that ZOEO significantly increased the sub-G1 populations (cell death) in cell cycle analysis and induced cell apoptosis by apoptotic analysis. The developed nanoformulations significantly enhanced cytotoxicity of ZOEO, particularly against MCF-7 with the IC50 of 3.08±2.58, 0.74±0.45, 2.31±0.91, and 6.45±5.84 μg/mL, respectively. Among the four nanoformulations developed in the present study, nanoemulsion and microemulsion were superior to nanoemulgel and microemulgel in delivering ZOEO into cancer cells.
Golden cordyceps (Cordyceps militaris) is a mushroom of the genus Cordyceps. It has been used as a food supplement for both healthy and ill people. In this study, the antileukaemic cell proliferation activities of golden cordyceps extracts were examined and compared with standard cordycepin (CDCP) in EoL-1, U937, and KG-1a cells. Wilms’ tumour 1 (WT1) protein was used as a biomarker of leukaemic cell proliferation. The cytotoxicity of the extracts on leukaemic cells was determined using the MTT assay. Their inhibitory effects on WT1 protein expression and cell cycle progression of EoL-1 cells were investigated using Western blotting and flow cytometry, respectively. Induction of KG-1a cell differentiation (using CD11b as a marker) was determined using flow cytometry. The golden cordyceps extracts exhibited cytotoxic effects on leukaemic cells with the highest IC50 value of 16.5 ± 3.9 µg/mL, while there was no effect on normal blood cells. The expression levels of WT1 protein in EoL-1 cells were decreased after treatment with the extracts. Moreover, cell cycle progression and cell proliferation were inhibited. The levels of CD11b increased slightly following the treatment. All these findings confirm the antileukaemic proliferation activity of golden cordyceps.
This study aims to enhance efficacy and reduce toxicity of the combination treatment of a drug and curcumin (Cur) on leukemic stem cell and leukemic cell lines, including KG-1a and KG-1 (FLT3+ LSCs), EoL-1 (FLT3+ LCs), and U937 (FLT3− LCs). The cytotoxicity of co-treatments of doxorubicin (Dox) or idarubicin (Ida) at concentrations of the IC10–IC80 values and each concentration of Cur at the IC20, IC30, IC40, and IC50 values (conditions 1, 2, 3, and 4) was determined by MTT assays. Dox–Cur increased cytotoxicity in leukemic cells. Dox–Cur co-treatment showed additive and synergistic effects in several conditions. The effect of this co-treatment on FLT3 expression in KG-1a, KG-1, and EoL-1 cells was examined by Western blotting. Dox–Cur decreased FLT3 protein levels and total cell numbers in all the cell lines in a dose-dependent manner. In summary, this study exhibits a novel report of Dox–Cur co-treatment in both enhancing cytotoxicity of Dox and inhibiting cell proliferation via FLT3 protein expression in leukemia stem cells and leukemic cells. This is the option of leukemia treatment with reducing side effects of chemotherapeutic drugs to leukemia patients.
Doxorubicin (Dox) is the standard chemotherapeutic agent for acute myeloblastic leukemia (AML) treatment. However, 40% of Dox-treated AML cases relapsed due to the presence of leukemic stem cells (LSCs). Thus, poloxamer 407 and CKR- and EVQ-FLT3 peptides were used to formulate Dox-micelles (DMs) and DM conjugated with peptides (CKR and EVQ) for improving AML-LSC treatment. Results indicated that DMs with a weight ratio of Dox to P407 of 1:200 had a particle size of 23.3 ± 1.3 nm with a high percentage of Dox entrapment. They were able to prolong drug release and maintain physicochemical stability. Following effective DM preparation, P407 was modified and conjugated with FLT3 peptides, CKR and EVQ to formulate DM-CKR, DM-EVQ, and DM-CKR+DM-EVQ. Freshly synthesized DMs displaying FLT3 peptides showed particle sizes smaller than 50 nm and a high drug entrapment level, comparable with DMs. DM-CKR+DM-EVQ was considerably more toxic to KG-1a (AML LSC-like cell model) than Dox-HCl. These FLT3-targeted DMs could increase drug uptake and induce apoptosis induction. Due to an increase in micelle-LSC binding and uptake, DMs displaying both peptides tended to improve the potency of Dox compared to a single peptide-coupled micelle.
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