Induction of cell cycle arrest and apoptosis in JAR trophoblast by antimalarial drugs

Abstract

Chloroquine, quinine, artemisinin, and pyrimethamine are generally considered safe drugs for treatment of malaria during pregnancy; however, high doses of these drugs are detrimental with adverse outcome of pregnancy. Since antimalarial drugs interaction with placental cells has not been addressed, in this study, we employed a non-radioactive proliferation assay and lactate dehyrogenase (LDH) release assays to investigate the effect of these drugs on JAR trophoblastic cell survival. All drug treatment resulted in inhibition of cell proliferation in a dose-dependent fashion (p < 0.05) with IC50 at 6.96, 6.49, 6.69, and 6.89 μg/mL for chloroquine, quinine, artemisinin and pyrimethamine, respectively. In addition, the inhibition of cell proliferation was accompanied by increased cytotoxicity. Analysis of the progression of the cell cycle showed that these drugs triggered G0/G1 and S phase arrest. Furthermore, these antimalarial drugs induced apoptotic cell death as visualized by DNA fragmentation analysis techniques. Findings in this study revealed that cytotoxicity of these drugs on human placental trophoblast is mediated by both cell cycle arrest and induction of cell death and this could have important implications for the use of antimalarial drugs for treating malaria during pregnancy.

Dihydroartemisinin (DHA) Treatment Causes an Arrest of Cell Division and Apoptosis in Rat Embryonic Erythroblasts in Whole Embryo Culture

“…The findings in the present study are also consistent with other work showing cell proliferation and apoptotic effects with artemisinins with other cell types. Nilkaeo et al found that artemisinins can inhibit cell proliferation and induce apoptosis in trophoblast cells (Nilkaeo et al., ). Artemisinins can inhibit proliferation, cell migration, and vascular endothelial growth factor (VEGF) binding to its receptors and suppression of VEGF receptor expression both in vivo, using chicken chorioallantoic membrane and in vitro, using HUVECs, and human microvascular dermal endothelial cells (Huan‐huan et al., ).…”

“…Artemisinins induced G1 phase accumulation in a P388 murine leukemia cell line, which was followed by apoptosis (Li et al., ). In JAR trophoblast cells, artemisinin caused decreased cell proliferation in a dose‐dependent manner, and delayed the cell cycle by inducing S‐phase arrest at 6 hr, G0/G1 arrest by 12 hr, and caused apoptotic cell death by 24 hr (Nilkaeo et al., ). In the present study, a similar sequence of events occurred, but with even more rapid onset; there was an increase in proliferation defects and an apparent arrest of proliferation at the cytokinesis stage by 2 hr, reduced BrdU staining by 4 hr, and apoptosis by 8 hr.…”

“…More specifically, the apoptotic pathway may be initiated, as can occur in nucleated red blood cells (Weil et al., ) through a toxic insult to the developing EEbs. Apoptosis occurs in human umbilical vein endothelial cells (HUVECs) exposed to artemisinins (Chen et al., ), and also in JAR trophoblast cells (a choriocarcinoma cell line) treated with antimalarial drugs (Nilkaeo et al., ). Therefore, apoptosis could also play a role in the depletion of EEbs after treatment with artemisinins.…”

Chloroquine exerts antitumor effects on NB4 acute promyelocytic leukemia cells and functions synergistically with arsenic trioxide

“…CQ has been reported to induce cell cycle alterations in cancer cells, but the specific results have varied for different types of cancer; CQ has been demonstrated to cause G 2 /M cell cycle arrest in breast cancer cells (29), G 0 /G 1 cell cycle arrest in liver cancer cells (28), S phase arrest in choriocarcinoma cells (30) and no obvious change in colon cancer cells (22). The inconsistency in cell cycle alterations may be due to the intrinsic differences between the tumor cell lines.…”

α-Fetoprotein and Interleukin-18 Gene–Modified Dendritic Cells Effectively Stimulate Specific Type-1 CD4- and CD8-Mediated T-Cell Response from Hepatocellular Carcinoma Patients in Vitro

“…The cells were then restimulated with Ad-AFP-EGFP infected DCs. On day 5 after restimulation, the cytotoxicity analysis was performed by lactate dehydrogenase release assay [14]. Briefly, effector T cells were harvested and incubated with target cells (HepG2, SMMC7721, and K562, respectively) at ratio of 40:1 in 96-microwell plates at 37°C, 5% CO 2 for 4 hours.…”