Combinational treatment of 5‐fluorouracil and casticin induces apoptosis in mouse leukemia <scp>WEHI</scp>‐3 cells in vitro

Cheng, Zhengyu; Chueh, Fu‐Shin; Peng, Shu‐Fen; Lin, Chun-Cheng; Kuo, Chao‐Lin; Huang, Wenwen; Chen, Po‐Yuan; Way, Tzong‐Der; Chung, Jing‐Gung

doi:10.1002/tox.22927

Cited by 8 publications

(8 citation statements)

References 39 publications

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“…5‐fluorouracil (5‐FU or fluorouracil) is an antimetabolite drug which affects various DNA and RNA synthesis pathways, specifically by inhibiting thymidylate synthetase. It is widely prescribed in the treatment of various cancers, mostly colorectal and breast [50] . Studies on 5‐FU activity in hematologic malignancies have been conflicting but have documented antileukemic effect in CEM and other acute lymphocytic leukemia (ALL) cell lines.…”

Section: Resultsmentioning

confidence: 99%

“…It is widely prescribed in the treatment of various cancers, mostly colorectal and breast. [50] Studies on 5-FU activity in hematologic malignancies have been conflicting but have documented antileukemic effect in CEM and other acute lymphocytic leukemia (ALL) cell lines. With this knowledge, we selected 5-FU (CC 50 = 49.0 μM) as a reference for small molecule chemotherapy and cytotoxicity in DNS.…”

Section: Dns Cytotoxicity Assaymentioning

confidence: 99%

“…To evaluate the effect of compound 5 y on the cell cycle, the DNA content of CEM cells were quantified via NIM-DAPI staining and flow cytometry after exposure to the CC 50 (15.2 μM) or 2xCC 50 (30.4 μM) of 5 y for 72 hrs. The standard SAHA was likewise included for comparison using concentrations 2.5 μM and 5.0 μM, respectively.…”

Section: Cell Cycle Analysismentioning

confidence: 99%

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HDAC4 Inhibitors with Cyclic Linker and Non‐hydroxamate Zinc Binding Group: Design, Synthesis, HDAC Screening and in vitro Cytotoxicity evaluation.

et al. 2021

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Recent evidences highlight the usefulness of small molecule (Histone deacetylase 4) HDAC4 inhibitors in the several preclinical paradigms. Major toxicity and mutagenicity issues associated with hydroxamate HDAC inhibitors, stimulated us to develop potent non-hydroxamate inhibitors. In the present work a novel series of thiazolidinedione (TZD) derivatives with pyridine as cyclic linker and TZD ring as zinc binding group was designed and screened in a panel of isoenzymes of HDACs, wherein the most potent compounds exhibiting HDAC4 IC50values < 5 μM were 5 v, 5 w, 5 y and 5 z (IC 50 = 4.2 � 1 μM, 0.75 � 0.03 μM, 4.9 � 0.5 and 2.3 � 0.5 μM, respectively). The docking studies displayed the unique binding mode of this series of compound at active site of HDAC4, wherein TZD ring was indicated as zinc binding group. Further, 5 w and 5 y were found as the most potent antiproliferative agent in lymphoblastic leukemia (CCRF-CEM) and breast cancer MDA-MB-231 cells. Compound 5 y was found to induce the apoptosis and DNA fragmentation of CEM cells. The western blotting analysis of 5 y also showed the presence of cleaved caspases supporting their apoptotic nature. Further, Class IIa (HDAC4) selectivity of 5 y was also supported by western blotting observations, wherein 5 y caused the accumulation of acetylated H3 but not of acetylated Tubulin. Thus, our findings endorse the further investigation of this series of compounds for their potential as targeted cancer therapeutic agents.

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Section: Resultsmentioning

confidence: 99%

Section: Dns Cytotoxicity Assaymentioning

confidence: 99%

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HDAC4 Inhibitors with Cyclic Linker and Non‐hydroxamate Zinc Binding Group: Design, Synthesis, HDAC Screening and in vitro Cytotoxicity evaluation.

et al. 2021

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“…This inhibition of SOD activity contributed to the increase in the ROS level in the cells and sensitized them to paclitaxel-induced apoptosis. A combination of fluorouracil (5-FU) and natural polymethoxyflavonecastin led to an increase in apoptosis in the mouse leukemia cell line (WEHI-3) [49]. Moreover, this effect was associated with an increase in caspase-3, caspase-8, and caspase-9 activity.…”

Section: Discussionmentioning

confidence: 99%

Effect of Kaempferol and Its Glycoside Derivatives on Antioxidant Status of HL-60 Cells Treated with Etoposide

et al. 2022

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Kaempferol is a well-known antioxidant found in many plants and plant-based foods. In plants, kaempferol is present mainly in the form of glycoside derivatives. In this work, we focused on determining the effect of kaempferol and its glycoside derivatives on the expression level of genes related to the reduction of oxidative stress—NFE2L2, NQO1, SOD1, SOD2, and HO-1; the enzymatic activity of superoxide dismutases; and the level of glutathione. We used HL-60 acute promyelocytic leukemia cells, which were incubated with the anticancer drug etoposide and kaempferol or one of its three glycoside derivatives isolated from the aerial parts of Lens culinaris Medik.—kaempferol 3-O-[(6-O-E-caffeoyl)-β-d-glucopyranosyl-(1→2)]-β-d-galactopyranoside-7-O-β-d-glucuropyranoside (P2), kaempferol 3-O-[(6-O-E-p-coumaroyl)-β-d-glucopyranosyl-(1→2)]-β-d-galactopyranoside-7-O-β-d-glucuropyranoside (P5), and kaempferol 3-O-[(6-O-E-feruloyl)-β-d-glucopyranosyl-(1→2)]-β-d-galactopyranoside-7-O-β-d-glucuropyranoside (P7). We showed that none of the tested compounds affected NFE2L2 gene expression. Co-incubation with etoposide (1 µM) and kaempferol (10 and 50 µg/mL) leads to an increase in the expression of the HO-1 (9.49 and 9.33-fold at 10 µg/mL and 50 µg/mL, respectively), SOD1 (1.68-fold at 10 µg/mL), SOD2 (1.72-fold at 10–50 µg/mL), and NQO1 (1.84-fold at 50 µg/mL) genes in comparison to cells treated only with etoposide. The effect of kaempferol derivatives on gene expression differs depending on the derivative. All tested polyphenols increased the SOD activity in cells co-incubated with etoposide. We observed that the co-incubation of HL-60 cells with etoposide and kaempferol or derivative P7 increases the level of total glutathione in these cells. Taken together, our observations suggest that the antioxidant activity of kaempferol is related to the activation of antioxidant genes and proteins. Moreover, we observed that glycoside derivatives can have a different effect on the antioxidant cellular systems than kaempferol.

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“…In combination with rutin, a quercetin flavonoid glycoside, 5-FU exhibited a synergistic effect in the induction of apoptosis in PC3 prostate cancer cells [ 24 ]. Casticin, a polymethexyflavone isolated from Vitex rotundifolia L. and other Vitex species (family: Verbenaceae), in combination with 5-FU also induced apoptosis in mouse leukemia WEHI-3 cells [ 69 ].…”

Section: Discussionmentioning

confidence: 99%

Calotropis gigantea stem bark extract induced apoptosis related to ROS and ATP production in colon cancer cells

et al. 2021

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Conventional chemotherapeutic agents for colorectal cancer (CRC) cause systemic side effects and eventually become less efficacious owing to the development of drug resistance in cancer cells. Therefore, new therapeutic regimens have focused on the use of natural products. The anticancer activity of several parts of Calotropis gigantea has been reported; however, the effects of its stem bark extract on inhibition of cancer cell proliferation have not yet been examined. In this study, the anticancer activity of C. gigantea stem bark extract, both alone and in combination with 5-fluorouracil (5-FU), was evaluated. A crude ethanolic extract was prepared from dry, powdered C. gigantea barks using 95% ethanol. This was then partitioned to obtain dichloromethane (CGDCM), ethyl acetate, and water fractions. Quantitative analysis of the constituent secondary metabolites and calotropin was performed. These fractions exhibited cytotoxicity in HCT116 and HT-29 cells, with CGDCM showing the highest potency in both the cell lines. A combination of CGDCM and 5-FU significantly enhanced the cytotoxic effect. Moreover, the resistance of normal fibroblast, HFF-1, cells to this combination demonstrated its safety in normal cells. The combination significantly enhanced apoptosis through the mitochondria-dependent pathway. Additionally, the combination reduced adenosine triphosphate production and increased the production of reactive oxygen species, demonstrating the mechanisms involved in the induction of apoptosis. Our results suggest that CGDCM is a promising anti-cancer agent and may enhance apoptosis induction by 5-FU in the treatment of CRC, while minimizing toxicity toward healthy cells.

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Combinational treatment of 5‐fluorouracil and casticin induces apoptosis in mouse leukemia WEHI‐3 cells in vitro

Cited by 8 publications

References 39 publications

HDAC4 Inhibitors with Cyclic Linker and Non‐hydroxamate Zinc Binding Group: Design, Synthesis, HDAC Screening and in vitro Cytotoxicity evaluation.

HDAC4 Inhibitors with Cyclic Linker and Non‐hydroxamate Zinc Binding Group: Design, Synthesis, HDAC Screening and in vitro Cytotoxicity evaluation.

Effect of Kaempferol and Its Glycoside Derivatives on Antioxidant Status of HL-60 Cells Treated with Etoposide

Calotropis gigantea stem bark extract induced apoptosis related to ROS and ATP production in colon cancer cells

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