A Role for the MEK/MAPK Pathway in PMA-Induced Cell Cycle Arrest: Modulation of Megakaryocytic Differentiation of K562 Cells

Chemotherapy can cause multidrug resistance in cancer cells and is cytotoxic to normal cells. Discovering natural bioactive compounds that are not cytotoxic to normal cells but inhibit proliferation and induce apoptosis in drug- sensitive and drug-resistant cancer cells could overcome these drawbacks of chemotherapy. This study investigated the antiproliferative effects of crude extracts of Benchalokawichian (BLW) remedy and its herbal components against drug-sensitive and drug-resistant cancer cells, cytotoxicity of the extracts toward normal cells, and their ability to induce apoptosis and cell cycle arrest in drug-sensitive and drug-resistant cancer cells. The extracts exhibited antiproliferative activity against doxorubicin-sensitive and doxorubicin-resistant erythromyelogenous leukemic cells (K562 and K562/adr). Tiliacora triandra root, BLW, and Harrisonia perforata root extracts displayed an IC50 of 77.00 ± 1.30, 79.33 ± 1.33, and 87.67 ± 0.67 µg/mL, respectively, against K562 cells. In contrast, Clerodendrum petasites, T. triandra, and H. perforata root extracts displayed the lowest IC50 against K562/adr cells (68.89 ± 0.75, 78.33 ± 0.69, and 86.78 ± 1.92 µg/mL, respectively). The resistance factor of the extracts was lower than that of doxorubicin, indicating that the extracts could overcome the multidrug resistance of cancer cells. Importantly, the extracts were negligibly cytotoxic to peripheral mononuclear cells, indicating minimal adverse effects in normal cells. In addition, these extracts induced apoptosis of K562 and K562/adr cells and caused cell cycle arrest at the G0/G1 phase in K562 cells. Keywords: Antiproliferative, Apoptosis, Benchalokawichian, Cell cycle, Multidrug resistance

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A Novel Methoxybenzyl 5-Nitroacridone Derivative Effectively Triggers G1 Cell Cycle Arrest in Chronic Myelogenous Leukemia K562 Cells by Inhibiting CDK4/6-Mediated Phosphorylation of Rb

International Journal of Molecular Sciences ◽

10.3390/ijms21145077 ◽

2020 ◽

Vol 21 (14) ◽

pp. 5077

Author(s):

Bin Zhang ◽

Ting Zhang ◽

Tian-Yi Zhang ◽

Ning Wang ◽

Shan He ◽

...

Keyword(s):

Cell Cycle ◽

Chronic Myeloid Leukemia ◽

Cell Cycle Arrest ◽

Chronic Myelogenous Leukemia ◽

Myeloid Leukemia ◽

K562 Cells ◽

Myelogenous Leukemia ◽

G1 Phase ◽

Cycle Arrest ◽

G1 Cell Cycle Arrest

Chronic myeloid leukemia (CML) is a malignant tumor caused by the abnormal proliferation of hematopoietic stem cells. Among a new series of acridone derivatives previously synthesized, it was found that the methoxybenzyl 5-nitroacridone derivative 8q has nanomolar cytotoxicity in vitro against human chronic myelogenous leukemia K562 cells. In order to further explore the possible anti-leukemia mechanism of action of 8q on K562 cells, a metabolomics and molecular biology study was introduced. It was thus found that most of the metabolic pathways of the G1 phase of K562 cells were affected after 8q treatment. In addition, a concentration-dependent accumulation of cells in the G1 phase was observed by cell cycle analysis. Western blot analysis showed that 8q significantly down-regulated the phosphorylation level of retinoblastoma-associated protein (Rb) in a concentration-dependent manner, upon 48 h treatment. In addition, 8q induced K562 cells apoptosis, through both mitochondria-mediated and exogenous apoptotic pathways. Taken together, these results indicate that 8q effectively triggers G1 cell cycle arrest and induces cell apoptosis in K562 cells, by inhibiting the CDK4/6-mediated phosphorylation of Rb. Furthermore, the possible binding interactions between 8q and CDK4/6 protein were clarified by homology modeling and molecular docking. In order to verify the inhibitory activity of 8q against other chronic myeloid leukemia cells, KCL-22 cells and K562 adriamycin-resistant cells (K562/ADR) were selected for the MTT assay. It is worth noting that 8q showed significant anti-proliferative activity against these cell lines after 48 h/72 h treatment. Therefore, this study provides new mechanistic information and guidance for the development of new acridones for application in the treatment of CML.

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