A novel platinum complex containing a piplartine derivative exhibits enhanced cytotoxicity, causes oxidative stress and triggers apoptotic cell death by ERK/p38 pathway in human acute promyelocytic leukemia HL-60 cells

Abstract

Piplartine (piperlongumine) is a plant-derived compound found in some Piper species that became a novel potential antineoplastic agent. In the present study, we synthesized a novel platinum complex containing a piplartine derivative cis-[PtCl(PIP-OH)(PPh3)2]PF6 (where, PIP-OH = piplartine demethylated derivative; and PPh3 = triphenylphosphine) with enhanced cytotoxicity in different cancer cells, and investigated its apoptotic action in human promyelocytic leukemia HL-60 cells. The structure of PIP-OH ligand was characterized by X-ray crystallographic analysis and the resulting platinum complex was characterized by infrared, molar conductance measurements, elemental analysis and NMR experiments. We found that the complex is more potent than piplartine in a panel of cancer cell lines. Apoptotic cell morphology, increased internucleosomal DNA fragmentation, without cell membrane permeability, loss of the mitochondrial transmembrane potential, increased phosphatidylserine externalization and caspase-3 activation were observed in complex-treated HL-60 cells. Treatment with the complex also caused a marked increase in the production of reactive oxygen species (ROS), and the pretreatment with N-acetyl-L-cysteine, an antioxidant, reduced the complex-induced apoptosis, indicating activation of ROS-mediated apoptosis pathway. Important, pretreatment with a p38 MAPK inhibitor (PD 169316) and MEK inhibitor (U-0126), known to inhibit ERK1/2 activation, also prevented the complex-induced apoptosis. The complex did not induce DNA intercalation in cell-free DNA assays. In conclusion, the complex exhibits more potent cytotoxicity than piplartine in a panel of different cancer cells and triggers ROS/ERK/p38-mediated apoptosis in HL-60 cells.

ROS in cancer therapy: the bright side of the moon

“…As noted above, chemotherapy and radiotherapy cause an increase in intracellular ROS that can lead to apoptosis 92,93 via extrinsic or intrinsic pathways 94,95 . Many drugs used in anticancer therapy induce oxidative stress.…”

Down-regulation of RFWD3 inhibits cancer cells proliferation and migration in gastric carcinoma

“…In addition, we discovered that these alterations are related with AKT, ERK/ P38 and Slug pathways. Researches show that AKT, ERK/ P38 and Slug pathways are all involved in the regulation of various biological processes and promote tumorigenesis (Cho et al 2019;Oliveira et al 2019;Revathidevi et al 2019). Moreover, the AKT, ERK/P38 and Slug pathways are activated by diverse cellular stimuli regulating various physiological functions such as cell growth, cell survival, cell cycle progression, protein translation and metabolism (Cho et al 2019;Oliveira et al 2019;Revathidevi et al 2019).…”

“…Researches show that AKT, ERK/ P38 and Slug pathways are all involved in the regulation of various biological processes and promote tumorigenesis (Cho et al 2019;Oliveira et al 2019;Revathidevi et al 2019). Moreover, the AKT, ERK/P38 and Slug pathways are activated by diverse cellular stimuli regulating various physiological functions such as cell growth, cell survival, cell cycle progression, protein translation and metabolism (Cho et al 2019;Oliveira et al 2019;Revathidevi et al 2019). Our results showed that down-regulation of RFWD3 significantly decreases the P-P38, P-ERK, P-AKT, Slug and N-Cadherin protein expression levels in AGS and HGC-27 cells, while the expression level of E-Cadherin is increased, suggesting that the downregulated expression of RFWD3 in gastric cell lines activated AKT, ERK/P38 and Slug signaling pathway.…”

Cytotoxic activity of dimeric acridone alkaloids derived from Citrus plants towards human leukaemia HL-60 cells

“…reported that p38 and extracellular signal-regulated kinase (ERK) mitogen-activated protein kinases also cause oxidative stress and apoptotic cell death in HL-60 cells treated with natural products. [19,20] However, activation of p38 and ERK was not observed in citbismine-E-treated HL-60 cells by immunoblotting of active phosphorylated form (data not shown). To investigate the involvement of JNK signalling pathway further in cibistamine-E-induced cell death, we examined the effect of a selective inhibitor of JNK, JNK-IN-8, on cibistamine-E-induced caspase activation and subsequent apoptosis.…”