Ning Zhong1, Hankui Chen2, Quanlin Zhao3, Hongwei Wang2, Xin Yu4, Ashley M Eaves2, Weihua Sheng5, Jingcheng Miao5, Fengmei Cui5, Jinzhi Wang5. 1. Department of Surgery, The First People's Hospital of Kunshan City, Kunshan, China. 2. Department of Medicine, University of Chicago, Chicago, Illinois. 3. The Affiliated Hospital, Shandong Tradition Chinese Medicine University, Shandong, China. 4. Wuxi Blood Center, Wuxi, Jiangshu, China. 5. Department of Cell Biology, School of Medicine, Soochow University, Suzhou, China.
Abstract
BACKGROUND: Griseofulvin, an oral nontoxic antifungal drug, has been reported to possess anticancer effect in human cancer cells, while the mechanisms are not completely understood. OBJECTIVE: The aim of this study was to investigate the cytotoxic effect of griseofulvin on K562 cells and to understand its underlying molecular pathways. METHODS: K562 cells were treated with griseofulvin at different concentrations for 24 hours, and the inhibition effect of griseofulvin on K562 cell proliferation was assessed by tetrazolium salt colorimetric assay. Apoptosis was assessed by examining nuclear morphology and quantifying phosphatidylserine externalization, and alterations in cellular morphology were analyzed by laser scanning confocal microscopy for fluorescent analysis. Flow cytometry was used in the analysis of cell cycle, mitochondrial membrane potential, and caspase pathways. RESULTS: Griseofulvin could inhibit the growth of K562 cells in a dose-dependent manner with a mean (SD) inhibitory concentration of 50% value of 15.38 (1.35) μg/mL compared with untreated controls. Apoptosis was induced in K562 cells (38.35% [2.73%]; P < 0.01) by griseofulvin with the observation of both an increase in phosphatidylserine level and accumulation of chromatin nucleation in griseofulvintreated cells. In addition, cell-cycle analysis using propidium iodide staining suggested a significant G2/M accumulation (increase from mean 17.64% [4.49%] to 48.29 [1.89%]; P < 0.01) as a result of griseofulvin treatment. Flow cytometry analysis found that griseofulvin treatment was associated with the depolarization of the mitochondrial membrane in K562 cells. Furthermore, increased activities of caspase-3 by 22.15-fold (P < 0.01) and caspase-9 by 16.73-fold (P < 0.01) were observed in K562 cells after griseofulvin treatment compared with the untreated control; a decrease of caspase-8 activity was also observed, but the change was not statistically significant. CONCLUSIONS: These findings suggest that griseofulvin inhibited growth of K562 cells and induced cell apoptosis through cell-cycle arrest and mitochondrial membrane potential decrease as well as caspase-3 and -9 activation. Further testing is needed to evaluate the potential of griseofulvin as a candidate in the chemotherapy of hematologic malignancies.
BACKGROUND:Griseofulvin, an oral nontoxic antifungal drug, has been reported to possess anticancer effect in humancancer cells, while the mechanisms are not completely understood. OBJECTIVE: The aim of this study was to investigate the cytotoxic effect of griseofulvin on K562 cells and to understand its underlying molecular pathways. METHODS: K562 cells were treated with griseofulvin at different concentrations for 24 hours, and the inhibition effect of griseofulvin on K562 cell proliferation was assessed by tetrazolium salt colorimetric assay. Apoptosis was assessed by examining nuclear morphology and quantifying phosphatidylserine externalization, and alterations in cellular morphology were analyzed by laser scanning confocal microscopy for fluorescent analysis. Flow cytometry was used in the analysis of cell cycle, mitochondrial membrane potential, and caspase pathways. RESULTS:Griseofulvin could inhibit the growth of K562 cells in a dose-dependent manner with a mean (SD) inhibitory concentration of 50% value of 15.38 (1.35) μg/mL compared with untreated controls. Apoptosis was induced in K562 cells (38.35% [2.73%]; P < 0.01) by griseofulvin with the observation of both an increase in phosphatidylserine level and accumulation of chromatin nucleation in griseofulvintreated cells. In addition, cell-cycle analysis using propidium iodide staining suggested a significant G2/M accumulation (increase from mean 17.64% [4.49%] to 48.29 [1.89%]; P < 0.01) as a result of griseofulvin treatment. Flow cytometry analysis found that griseofulvin treatment was associated with the depolarization of the mitochondrial membrane in K562 cells. Furthermore, increased activities of caspase-3 by 22.15-fold (P < 0.01) and caspase-9 by 16.73-fold (P < 0.01) were observed in K562 cells after griseofulvin treatment compared with the untreated control; a decrease of caspase-8 activity was also observed, but the change was not statistically significant. CONCLUSIONS: These findings suggest that griseofulvin inhibited growth of K562 cells and induced cell apoptosis through cell-cycle arrest and mitochondrial membrane potential decrease as well as caspase-3 and -9 activation. Further testing is needed to evaluate the potential of griseofulvin as a candidate in the chemotherapy of hematologic malignancies.
Authors: Blanka Rebacz; Thomas O Larsen; Mads H Clausen; Mads H Rønnest; Harald Löffler; Anthony D Ho; Alwin Krämer Journal: Cancer Res Date: 2007-07-01 Impact factor: 12.701
Authors: Victor F Farinella; Eunizinis S Kawafune; Marcelo M P Tangerina; Helori V Domingos; Leticia V Costa-Lotufo; Marcelo J P Ferreira Journal: Molecules Date: 2021-12-02 Impact factor: 4.411